@misc{HarmsScalbertZamoraRosetal.2020, 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 = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {2}, issn = {1866-8372}, doi = {10.25932/publishup-51577}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-515774}, pages = {13}, year = {2020}, 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} } @misc{SchedlbauerBlaueRailaetal.2020, author = {Schedlbauer, Carola and Blaue, Dominique and Raila, Jens and Vervuert, Ingrid}, title = {Alterations of serum vitamin E and vitamin A concentrations of ponies and horses during experimentally induced obesity}, 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 = {5}, issn = {1866-8372}, doi = {10.25932/publishup-51951}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-519515}, pages = {10}, year = {2020}, abstract = {Vitamin A, vitamin E and retinol-binding protein 4 (RBP4) are a focus of current obesity research in humans. The impact of body weight (BW) gain on fat-soluble vitamins and its associated parameters in equines has not been previously reported. Ten Shetland ponies and 9 Warmblood horses, all adult geldings, non-obese and healthy, were fed an excessive energy diet for 20 months to induce BW gain. Serum alpha-tocopherol (vitamin E), retinol (vitamin A), retinol-binding protein 4 (RBP4) and retinol/RBP4 ratio were analysed before BW gain induction and at six timepoints during the BW gaining period. The mean (+/- SD) \% BW gain achieved during two years of excess energy intake was 29.9 +/- 19.4\% for ponies and 17 +/- 6.74\% for horses. Serum alpha-tocopherol increased significantly in ponies and horses during excess energy intake and circulating alpha-tocopherol levels correlated positively with alpha-tocopherol intake (r = .6; p < .001). Serum retinol concentrations showed variations during the study but without relation to intake. Serum RBP4 decreased at the end of the study. The retinol/RBP4 ratio increased with BW gain without differences between ponies and horses. In comparison with human research, the increase in the retinol/RBP4 ratio was unexpected and needs further elucidation.}, language = {en} } @misc{McNultyGoupilAlbaradoetal.2020, author = {McNulty, Margaret A. and Goupil, Brad A. and Albarado, Diana C. and Casta{\~n}o-Martinez, Teresa and Ambrosi, Thomas H. and Puh, Spela and Schulz, Tim Julius and Sch{\"u}rmann, Annette and Morrison, Christopher D. and Laeger, Thomas}, title = {FGF21, not GCN2, influences bone morphology due to dietary protein restrictions}, series = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, issn = {1866-8372}, doi = {10.25932/publishup-51629}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-516297}, pages = {12}, year = {2020}, abstract = {Background: Dietary protein restriction is emerging as an alternative approach to treat obesity and glucose intolerance because it markedly increases plasma fibroblast growth factor 21 (FGF21) concentrations. Similarly, dietary restriction of methionine is known to mimic metabolic effects of energy and protein restriction with FGF21 as a required mechanism. However, dietary protein has been shown to be required for normal bone growth, though there is conflicting evidence as to the influence of dietary protein restriction on bone remodeling. The purpose of the current study was to evaluate the effect of dietary protein and methionine restriction on bone in lean and obese mice, and clarify whether FGF21 and general control nonderepressible 2 (GCN2) kinase, that are part of a novel endocrine pathway implicated in the detection of protein restriction, influence the effect of dietary protein restriction on bone. Methods: Adult wild-type (WT) or Fgf21 KO mice were fed a normal protein (18 kcal\%; CON) or low protein (4 kcal\%; LP) diet for 2 or 27 weeks. In addition, adult WT or Gcn2 KO mice were fed a CON or LP diet for 27 weeks. Young New Zealand obese (NZO) mice were placed on high-fat diets that provided protein at control (16 kcal\%; CON), low levels (4 kcal\%) in a high-carbohydrate (LP/HC) or high-fat (LP/HF) regimen, or on high-fat diets (protein, 16 kcal\%) that provided methionine at control (0.86\%; CON-MR) or low levels (0.17\%; MR) for up to 9 weeks. Long bones from the hind limbs of these mice were collected and evaluated with micro-computed tomography (mu CT) for changes in trabecular and cortical architecture and mass. Results: In WT mice the 27-week LP diet significantly reduced cortical bone, and this effect was enhanced by deletion of Fgf21 but not Gcn2. This decrease in bone did not appear after 2 weeks on the LP diet. In addition, Fgf21 KO mice had significantly less bone than their WT counterparts. In obese NZO mice dietary protein and methionine restriction altered bone architecture. The changes were mediated by FGF21 due to methionine restriction in the presence of cystine, which did not increase plasma FGF21 levels and did not affect bone architecture. Conclusions: This study provides direct evidence of a reduction in bone following long-term dietary protein restriction in a mouse model, effects that appear to be mediated by FGF21.}, language = {en} } @misc{RaupbachOttKoenigetal.2020, author = {Raupbach, Jana and Ott, Christiane and K{\"o}nig, Jeannette and Grune, Tilman}, title = {Proteasomal degradation of glycated proteins depends on substrate unfolding}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, issn = {1866-8372}, doi = {10.25932/publishup-52757}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-527570}, pages = {516 -- 524}, year = {2020}, abstract = {The Maillard reaction generates protein modifications which can accumulate during hyperglycemia or aging and may have inflammatory consequences. The proteasome is one of the major intracellular systems involved in the proteolytic degradation of modified proteins but its role in the degradation of glycated proteins is scarcely studied. In this study, chemical and structural changes of glycated myoglobin were analyzed and its degradation by 20S proteasome was studied. Myoglobin was incubated with physiological (5-10 mM), moderate (50-100 mM) and severe levels (300 mM) of glucose or methylglyoxal (MGO, 50 mM). Glycation increased myoglobin's fluorescence and surface hydrophobicity. Severe glycation generated crosslinked proteins as shown by gel electrophoresis. The concentration of advanced glycation endproducts (AGEs) N-epsilon-carboxymethyl lysine (CML), N-epsilon-carboxyethyl lysine (CEL), methylglyoxal-derived hydroimidazolone-1 (MG-H1), pentosidine and pyrraline was analyzed after enzymatic hydrolysis followed by UPLC-MS/MS. Higher concentrations of glucose increased all analyzed AGEs and incubation with MGO led to a pronounced increase of CEL and MG-H1. The binding of the heme group to apo-myoglobin was decreased with increasing glycation indicating the loss of tertiary protein structure. Proteasomal degradation of modified myoglobin compared to native myoglobin depends on the degree of glycation: physiological conditions decreased proteasomal degradation whereas moderate glycation increased degradation. Severe glycation again decreased proteolytic cleavage which might be due to crosslinking of protein monomers. The activity of the proteasomal subunit beta 5 is influenced by the presence of glycated myoglobin. In conclusion, the role of the proteasome in the degradation of glycated proteins is highly dependent on the level of glycation and consequent protein unfolding.}, language = {en} } @misc{ChristakoudiTsilidisMulleretal.2020, author = {Christakoudi, Sofa and Tsilidis, Konstantinos K. and Muller, David C. and Freisling, Heinz and Weiderpass, Elisabete and Overvad, Kim and S{\"o}derberg, Stefan and H{\"a}ggstr{\"o}m, Christel and Pischon, Tobias and Dahm, Christina C. and Zhang, Jie and Tj{\o}nneland, Anne and Schulze, Matthias Bernd}, title = {A Body Shape Index (ABSI) achieves better mortality risk stratification than alternative indices of abdominal obesity: results from a large European cohort}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {1}, issn = {1866-8372}, doi = {10.25932/publishup-52582}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-525827}, pages = {17}, year = {2020}, abstract = {Abdominal and general adiposity are independently associated with mortality, but there is no consensus on how best to assess abdominal adiposity. We compared the ability of alternative waist indices to complement body mass index (BMI) when assessing all-cause mortality. We used data from 352,985 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) and Cox proportional hazards models adjusted for other risk factors. During a mean follow-up of 16.1 years, 38,178 participants died. Combining in one model BMI and a strongly correlated waist index altered the association patterns with mortality, to a predominantly negative association for BMI and a stronger positive association for the waist index, while combining BMI with the uncorrelated A Body Shape Index (ABSI) preserved the association patterns. Sex-specific cohort-wide quartiles of waist indices correlated with BMI could not separate high-risk from low-risk individuals within underweight (BMI<18.5 kg/m(2)) or obese (BMI30 kg/m(2)) categories, while the highest quartile of ABSI separated 18-39\% of the individuals within each BMI category, which had 22-55\% higher risk of death. In conclusion, only a waist index independent of BMI by design, such as ABSI, complements BMI and enables efficient risk stratification, which could facilitate personalisation of screening, treatment and monitoring.}, language = {en} } @misc{ChristakoudiPagoniFerrarietal.2020, author = {Christakoudi, Sofia and Pagoni, Panagiota and Ferrari, Pietro and Cross, Amanda J. and Tzoulaki, Ioanna and Muller, David C. and Weiderpass, Elisabete and Freisling, Heinz and Murphy, Neil and Dossus, Laure and Turzanski Fortner, Renee and Agudo, Antonio and Overvad, Kim and Perez-Cornago, Aurora and Key, Timothy J. and Brennan, Paul and Johansson, Mattias and Tjonneland, Anne and Halkjaer, Jytte and Boutron-Ruault, Marie-Christine and Artaud, Fanny and Severi, Gianluca and Kaaks, Rudolf and Schulze, Matthias Bernd and Bergmann, Manuela M. and Masala, Giovanna and Grioni, Sara and Simeon, Vittorio and Tumino, Rosario and Sacerdote, Carlotta and Skeie, Guri and Rylander, Charlotta and Borch, Kristin Benjaminsen and Quiros, J. Ramon and Rodriguez-Barranco, Miguel and Chirlaque, Maria-Dolores and Ardanaz, Eva and Amiano, Pilar and Drake, Isabel and Stocks, Tanja and Haggstrom, Christel and Harlid, Sophia and Ellingjord-Dale, Merete and Riboli, Elio and Tsilidis, Konstantinos K.}, title = {Weight change in middle adulthood and risk of cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort}, 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 = {7}, issn = {1866-8372}, doi = {10.25932/publishup-57360}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-573609}, pages = {17}, year = {2020}, abstract = {Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241 323 participants (31\% men), 20\% lost and 32\% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow-up after the second weight assessment, 20 960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio [HR] = 1.14; 95\% confidence interval: 1.05-1.23). Compared to stable weight (+/- 0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR = 1.41; 1.01-1.96), postmenopausal breast (HR = 1.08; 1.00-1.16) and thyroid (HR = 1.40; 1.04-1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organisation categories) was positively associated with most obesity-related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the postmenopausal breast (HR = 1.19; 1.06-1.33), ovary (HR = 1.40; 1.04-1.91), corpus uteri (HR = 1.42; 1.06-1.91), kidney (HR = 1.80; 1.20-2.68) and pancreas in men (HR = 1.81; 1.11-2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR = 0.40; 0.23-0.69) and colon (HR = 0.69; 0.52-0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood.}, language = {en} } @misc{SaberiHosnijehCasabonneNietersetal.2020, author = {Saberi Hosnijeh, Fatemeh and Casabonne, Delphine and Nieters, Alexandra and Solans, Marta and Naudin, Sabine and Ferrari, Pietro and Mckay, James D. and Benavente, Yolanda and Weiderpass, Elisabete and Freisling, Heinz and Severi, Gianluca and Boutron Ruault, Marie-Christine and Besson, Caroline and Agnoli, Claudia and Masala, Giovanna and Sacerdote, Carlotta and Tumino, Rosario and Huerta, Jose Maria and Amiano, Pilar and Rodriguez-Barranco, Miguel and Bonet, Catalina and Barricarte, Aurelio and Christakoudi, Sofia and Knuppel, Anika and Bueno-de-Mesquita, Bas and Schulze, Matthias Bernd and Kaaks, Rudolf and Canzian, Federico and Spath, Florentin and Jerkeman, Mats and Rylander, Charlotta and Tjonneland, Anne and Olsen, Anja and Borch, Kristin Benjaminsen and Vermeulen, Roel}, title = {Association between anthropometry and lifestyle factors and risk of B-cell lymphoma}, 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 = {9}, issn = {1866-8372}, doi = {10.25932/publishup-57356}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-573562}, pages = {16}, year = {2020}, abstract = {To better understand the role of individual and lifestyle factors in human disease, an exposome-wide association study was performed to investigate within a single-study anthropometry measures and lifestyle factors previously associated with B-cell lymphoma (BCL). Within the European Prospective Investigation into Cancer and nutrition study, 2402 incident BCL cases were diagnosed from 475 426 participants that were followed-up on average 14 years. Standard and penalized Cox regression models as well as principal component analysis (PCA) were used to evaluate 84 exposures in relation to BCL risk. Standard and penalized Cox regression models showed a positive association between anthropometric measures and BCL and multiple myeloma/plasma cell neoplasm (MM). The penalized Cox models additionally showed the association between several exposures from categories of physical activity, smoking status, medical history, socioeconomic position, diet and BCL and/or the subtypes. PCAs confirmed the individual associations but also showed additional observations. The PC5 including anthropometry, was positively associated with BCL, diffuse large B-cell lymphoma (DLBCL) and MM. There was a significant positive association between consumption of sugar and confectionary (PC11) and follicular lymphoma risk, and an inverse association between fish and shellfish and Vitamin D (PC15) and DLBCL risk. The PC1 including features of the Mediterranean diet and diet with lower inflammatory score showed an inverse association with BCL risk, while the PC7, including dairy, was positively associated with BCL and DLBCL risk. Physical activity (PC10) was positively associated with DLBCL risk among women. This study provided informative insights on the etiology of BCL.}, language = {en} } @misc{WeberKochlikDemuthetal.2020, author = {Weber, Daniela and Kochlik, Bastian Max and Demuth, Ilja and Steinhagen-Thiessen, Elisabeth and Grune, Tilman and Norman, Kristina}, title = {Plasma carotenoids, tocopherols and retinol}, series = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, issn = {1866-8372}, doi = {10.25932/publishup-51599}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-515996}, pages = {10}, year = {2020}, abstract = {Regular consumption of fruits and vegetables, which is related to high plasma levels of lipid-soluble micro-nutrients such as carotenoids and tocopherols, is linked to lower incidences of various age-related diseases. Differences in lipid-soluble micronutrient blood concentrations seem to be associated with age. Our retrospective analysis included men and women aged 22-37 and 60-85 years from the Berlin Aging Study II. Participants with simultaneously available plasma samples and dietary data were included (n = 1973). Differences between young and old groups were found for plasma lycopene, alpha-carotene, alpha-tocopherol, beta-cryptoxanthin (only in women), and gamma-tocopherol (only in men). beta-Carotene, retinol and lutein/zeaxanthin did not differ between young and old participants regardless of the sex. We found significant associations for lycopene, alpha-carotene (both inverse), alpha-tocopherol, gamma-tocopherol, and beta-carotene (all positive) with age. Adjusting for BMI, smoking status, season, cholesterol and dietary intake confirmed these associations, except for beta-carotene. These micronutrients are important antioxidants and associated with lower incidence of age-related diseases, therefore it is important to understand the underlying mechanisms in order to implement dietary strategies for the prevention of age-related diseases. To explain the lower lycopene and alpha-carotene concentration in older subjects, bioavailability studies in older participants are necessary.}, language = {en} } @misc{KesslerHornemannRudovichetal.2020, author = {Kessler, Katharina and Hornemann, Silke and Rudovich, Natalia and Weber, Daniela and Grune, Tilman and Kramer, Achim and Pfeiffer, Andreas F. H. and Pivovarova-Ramich, Olga}, title = {Saliva samples as a tool to study the effect of meal timing on metabolic and inflammatory biomarkers}, 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 = {2}, issn = {1866-8372}, doi = {10.25932/publishup-51207}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-512079}, pages = {14}, year = {2020}, abstract = {Meal timing affects metabolic regulation in humans. Most studies use blood samples fortheir investigations. Saliva, although easily available and non-invasive, seems to be rarely used forchrononutritional studies. In this pilot study, we tested if saliva samples could be used to studythe effect of timing of carbohydrate and fat intake on metabolic rhythms. In this cross-over trial, 29 nonobese men were randomized to two isocaloric 4-week diets: (1) carbohydrate-rich meals until13:30 and high-fat meals between 16:30 and 22:00 or (2) the inverse order of meals. Stimulated salivasamples were collected every 4 h for 24 h at the end of each intervention, and levels of hormones andinflammatory biomarkers were assessed in saliva and blood. Cortisol, melatonin, resistin, adiponectin, interleukin-6 and MCP-1 demonstrated distinct diurnal variations, mirroring daytime reports inblood and showing significant correlations with blood levels. The rhythm patterns were similar forboth diets, indicating that timing of carbohydrate and fat intake has a minimal effect on metabolicand inflammatory biomarkers in saliva. Our study revealed that saliva is a promising tool for thenon-invasive assessment of metabolic rhythms in chrononutritional studies, but standardisation of sample collection is needed in out-of-lab studies.}, language = {en} } @misc{WinkelbeinerWandtEbertetal.2020, author = {Winkelbeiner, Nicola Lisa and Wandt, Viktoria Klara Veronika and Ebert, Franziska and Lossow, Kristina and Bankoglu, Ezgi E. and Martin, Maximilian and Mangerich, Aswin and Stopper, Helga and Bornhorst, Julia and Kipp, Anna Patricia and Schwerdtle, Tanja}, title = {A Multi-Endpoint Approach to Base Excision Repair Incision Activity Augmented by PARylation and DNA Damage Levels in Mice}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {1021}, issn = {1866-8372}, doi = {10.25932/publishup-48483}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-484831}, pages = {21}, year = {2020}, abstract = {Investigation of processes that contribute to the maintenance of genomic stability is one crucial factor in the attempt to understand mechanisms that facilitate ageing. The DNA damage response (DDR) and DNA repair mechanisms are crucial to safeguard the integrity of DNA and to prevent accumulation of persistent DNA damage. Among them, base excision repair (BER) plays a decisive role. BER is the major repair pathway for small oxidative base modifications and apurinic/apyrimidinic (AP) sites. We established a highly sensitive non-radioactive assay to measure BER incision activity in murine liver samples. Incision activity can be assessed towards the three DNA lesions 8-oxo-2'-deoxyguanosine (8-oxodG), 5-hydroxy-2'-deoxyuracil (5-OHdU), and an AP site analogue. We applied the established assay to murine livers of adult and old mice of both sexes. Furthermore, poly(ADP-ribosyl)ation (PARylation) was assessed, which is an important determinant in DDR and BER. Additionally, DNA damage levels were measured to examine the overall damage levels. No impact of ageing on the investigated endpoints in liver tissue were found. However, animal sex seems to be a significant impact factor, as evident by sex-dependent alterations in all endpoints investigated. Moreover, our results revealed interrelationships between the investigated endpoints indicative for the synergetic mode of action of the cellular DNA integrity maintaining machinery.}, 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} } @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} } @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} } @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} } @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} } @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} } @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} } @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} } @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} }