TY - THES A1 - Weiß, Stefanie T1 - Contribution of bacterially synthesized folate vitamers to folate status and impact on crohn's Disease Y1 - 2018 ER - TY - JOUR A1 - Laeger, Thomas A1 - Castano-Martinez, Teresa A1 - Werno, Martin W. A1 - Japtok, Lukasz A1 - Baumeier, Christian A1 - Jonas, Wenke A1 - Kleuser, Burkhard A1 - Schürmann, Annette T1 - Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes JF - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) N2 - Aims/hypothesis Low-protein diets are well known to improve glucose tolerance and increase energy expenditure. Increases in circulating fibroblast growth factor 21 (FGF21) have been implicated as a potential underlying mechanism. Methods We aimed to test whether low-protein diets in the context of a high-carbohydrate or high-fat regimen would also protect against type 2 diabetes in New Zealand Obese (NZO) mice used as a model of polygenetic obesity and type 2 diabetes. Mice were placed on high-fat diets that provided protein at control (16 kJ%; CON) or low (4 kJ%; low-protein/high-carbohydrate [LP/HC] or low-protein/high-fat [LP/HF]) levels. Results Protein restriction prevented the onset of hyperglycaemia and beta cell loss despite increased food intake and fat mass. The effect was seen only under conditions of a lower carbohydrate/fat ratio (LP/HF). When the carbohydrate/fat ratio was high (LP/HC), mice developed type 2 diabetes despite the robustly elevated hepatic FGF21 secretion and increased energy expenditure. Conclusion/interpretation Prevention of type 2 diabetes through protein restriction, without lowering food intake and body fat mass, is compromised by high dietary carbohydrates. Increased FGF21 levels and elevated energy expenditure do not protect against hyperglycaemia and type 2 diabetes per se. KW - Energy expenditure KW - FGF21 KW - Hyperglycaemia KW - Insulin resistance KW - NZO KW - Obesity KW - Protein restriction Y1 - 2018 U6 - https://doi.org/10.1007/s00125-018-4595-1 SN - 0012-186X SN - 1432-0428 VL - 61 IS - 6 SP - 1459 EP - 1469 PB - Springer CY - New York ER - TY - JOUR A1 - Odongo, Grace Akinyi A1 - Schlotz, Nina A1 - Baldermann, Susanne A1 - Neugart, Susanne A1 - Ngwene, Benard A1 - Schreiner, Monika A1 - Lamy, Evelyn T1 - Effects of Amaranthus cruentus L. on aflatoxin B1- and oxidative stress-induced DNA damage in human liver (HepG2) cells JF - Food bioscience N2 - Amaranth is presently an underutilized crop despite its high content of micronutrients/bioactive phytochemicals and its capacity to thrive in harsh environmental condition. The present study aimed at determining the health benefits of Amaranthus cruentus L. in terms of protection against DNA damage induced by the mycotoxin aflatoxin B1 (AFB1) and oxidative stress using comet assay. The antioxidant potential was further investigated using electron paramagnetic resonance spectroscopy (EPR) and an ARE/Nrf2 reporter gene assay in vitro in a human liver model using the HepG2 cell line. Ethanolic extracts from fresh leaves grown under controlled conditions were used and additionally analyzed for their phytochemical content using liquid chromatography-mass spectrometry (LC-MS). The extracts inhibited both AFB1- and oxidative stress-induced DNA damage in a concentration dependent way with a maximum effect of 57% and 81%, respectively. Oxidative stress triggered using ferrous sulfate was blocked by up to 38% (EPR); the potential to induce antioxidant enzymes using ARE/Nrf2-mediated gene expression was also confirmed. Based on these in vitro findings, further studies on the health-protecting effects of A. cruentus are encouraged to fully explore its health promoting potential and provide the scientific basis for encouraging its cultivation and consumption. KW - African indigenous vegetables KW - Aflatoxin B1 KW - Amaranthaceae KW - Amaranth KW - Aspergillus KW - Cancer prevention Y1 - 2018 U6 - https://doi.org/10.1016/j.fbio.2018.09.006 SN - 2212-4292 SN - 2212-4306 VL - 26 SP - 42 EP - 48 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Müller, Sandra Marie A1 - Ebert, Franziska A1 - Raber, Georg A1 - Meyer, Sören A1 - Bornhorst, Julia A1 - Hüwel, Stephan A1 - Galla, Hans-Joachim A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja T1 - Effects of arsenolipids on in vitro blood-brain barrier model JF - Archives of toxicology : official journal of EUROTOX N2 - Arsenic-containing hydrocarbons (AsHCs), a subgroup of arsenolipids (AsLs) occurring in fish and edible algae, possess a substantial neurotoxic potential in fully differentiated human brain cells. Previous in vivo studies indicating that AsHCs cross the blood–brain barrier of the fruit fly Drosophila melanogaster raised the question whether AsLs could also cross the vertebrate blood–brain barrier (BBB). In the present study, we investigated the impact of several representatives of AsLs (AsHC 332, AsHC 360, AsHC 444, and two arsenic-containing fatty acids, AsFA 362 and AsFA 388) as well as of their metabolites (thio/oxo-dimethylpropionic acid, dimethylarsinic acid) on porcine brain capillary endothelial cells (PBCECs, in vitro model for the blood–brain barrier). AsHCs exerted the strongest cytotoxic effects of all investigated arsenicals as they were up to fivefold more potent than the toxic reference species arsenite (iAsIII). In our in vitro BBB-model, we observed a slight transfer of AsHC 332 across the BBB after 6 h at concentrations that do not affect the barrier integrity. Furthermore, incubation with AsHCs for 72 h led to a disruption of the barrier at sub-cytotoxic concentrations. The subsequent immunocytochemical staining of three tight junction proteins revealed a significant impact on the cell membrane. Because AsHCs enhance the permeability of the in vitro blood–brain barrier, a similar behavior in an in vivo system cannot be excluded. Consequently, AsHCs might facilitate the transfer of accompanying foodborne toxicants into the brain. KW - Arsenolipids KW - Arsenic-containing hydrocarbons KW - Arsenic-containing fatty acids KW - In vitro blood-brain barrier model Y1 - 2017 SN - 0340-5761 SN - 1432-0738 VL - 92 IS - 2 SP - 823 EP - 832 PB - Springer CY - Heidelberg ER - TY - JOUR A1 - Galbete, Cecilia A1 - Schwingshackl, Lukas A1 - Schwedhelm, Carolina A1 - Boeing, Heiner A1 - Schulze, Matthias Bernd T1 - Evaluating Mediterranean diet and risk of chronic disease in cohort studies BT - an umbrella review of meta-analyses JF - European journal of epidemiology N2 - Several meta-analyses have been published summarizing the associations of the Mediterranean diet (MedDiet) with chronic diseases. We evaluated the quality and credibility of evidence from these meta-analyses as well as characterized the different indices used to define MedDiet and re-calculated the associations with the different indices identified. We conducted an umbrella review of meta-analyses on cohort studies evaluating the association of the MedDiet with type 2 diabetes, cardiovascular disease, cancer and cognitive-related diseases. We used the AMSTAR (A MeaSurement Tool to Assess systematic Reviews) checklist to evaluate the methodological quality of the meta-analyses, and the NutriGrade scoring system to evaluate the credibility of evidence. We also identified different indices used to define MedDiet; tests for subgroup differences were performed to compare the associations with the different indices when at least 2 studies were available for different definitions. Fourteen publications were identified and within them 27 meta-analyses which were based on 70 primary studies. Almost all meta-analyses reported inverse associations between MedDiet and risk of chronic disease, but the credibility of evidence was rated low to moderate. Moreover, substantial heterogeneity was observed on the use of the indices assessing adherence to the MedDiet, but two indices were the most used ones [Trichopoulou MedDiet (tMedDiet) and alternative MedDiet (aMedDiet)]. Overall, we observed little difference in risk associations comparing different MedDiet indices in the subgroup meta-analyses. Future prospective cohort studies are advised to use more homogenous definitions of the MedDiet to improve the comparability across meta-analyses. KW - Mediterranean diet KW - Chronic diseases KW - Umbrella review KW - Meta-analyses KW - Cohort studies KW - Heterogeneity Y1 - 2018 U6 - https://doi.org/10.1007/s10654-018-0427-3 SN - 0393-2990 SN - 1573-7284 VL - 33 IS - 10 SP - 909 EP - 931 PB - Springer CY - Dordrecht ER - TY - THES A1 - Kammel, Anne T1 - Identifizierung früher epigenetischer Veränderungen, die zur Ausbildung einer Fettleber beitragen Y1 - 2018 ER - TY - JOUR A1 - Maares, Maria A1 - Keil, Claudia A1 - Koza, Jenny A1 - Straubing, Sophia A1 - Schwerdtle, Tanja A1 - Haase, Hajo T1 - In Vitro Studies on Zinc Binding and Buffering by Intestinal Mucins JF - International Journal of Molecular Sciences N2 - The investigation of luminal factors influencing zinc availability and accessibility in the intestine is of great interest when analyzing parameters regulating intestinal zinc resorption. Of note, intestinal mucins were suggested to play a beneficial role in the luminal availability of zinc. Their exact zinc binding properties, however, remain unknown and the impact of these glycoproteins on human intestinal zinc resorption has not been investigated in detail. Thus, the aim of this study is to elucidate the impact of intestinal mucins on luminal uptake of zinc into enterocytes and its transfer into the blood. In the present study, in vitro zinc binding properties of mucins were analyzed using commercially available porcine mucins and secreted mucins of the goblet cell line HT-29-MTX. The molecular zinc binding capacity and average zinc binding affinity of these glycoproteins demonstrates that mucins contain multiple zinc-binding sites with biologically relevant affinity within one mucin molecule. Zinc uptake into the enterocyte cell line Caco-2 was impaired by zinc-depleted mucins. Yet this does not represent their form in the intestinal lumen in vivo under zinc adequate conditions. In fact, zinc-uptake studies into enterocytes in the presence of mucins with differing degree of zinc saturation revealed zinc buffering by these glycoproteins, indicating that mucin-bound zinc is still available for the cells. Finally, the impact of mucins on zinc resorption using three-dimensional cultures was studied comparing the zinc transfer of a Caco-2/HT-29-MTX co-culture and conventional Caco-2 monoculture. Here, the mucin secreting co-cultures yielded higher fractional zinc resorption and elevated zinc transport rates, suggesting that intestinal mucins facilitate the zinc uptake into enterocytes and act as a zinc delivery system for the intestinal epithelium. KW - intestinal zinc resorption KW - zinc binding KW - mucus layer KW - intestinal mucins KW - in vitro intestinal model KW - goblet cells KW - Caco-2/HT-29-MTX-model Y1 - 2018 U6 - https://doi.org/10.3390/ijms19092662 SN - 1422-0067 VL - 19 IS - 9 ER - TY - JOUR A1 - Krstic, Jelena A1 - Reinisch, Isabel A1 - Schupp, Michael A1 - Schulz, Tim Julius A1 - Prokesch, Andreas T1 - p53 functions in adipose tissue metabolism and homeostasis JF - International journal of molecular sciences N2 - As a tumor suppressor and the most frequently mutated gene in cancer, p53 is among the best-described molecules in medical research. As cancer is in most cases an age-related disease, it seems paradoxical that p53 is so strongly conserved from early multicellular organisms to humans. A function not directly related to tumor suppression, such as the regulation of metabolism in nontransformed cells, could explain this selective pressure. While this role of p53 in cellular metabolism is gradually emerging, it is imperative to dissect the tissue-and cell-specific actions of p53 and its downstream signaling pathways. In this review, we focus on studies reporting p53's impact on adipocyte development, function, and maintenance, as well as the causes and consequences of altered p53 levels in white and brown adipose tissue (AT) with respect to systemic energy homeostasis. While whole body p53 knockout mice gain less weight and fat mass under a high-fat diet owing to increased energy expenditure, modifying p53 expression specifically in adipocytes yields more refined insights: (1) p53 is a negative regulator of in vitro adipogenesis; (2) p53 levels in white AT are increased in diet-induced and genetic obesity mouse models and in obese humans; (3) functionally, elevated p53 in white AT increases senescence and chronic inflammation, aggravating systemic insulin resistance; (4) p53 is not required for normal development of brown AT; and (5) when p53 is activated in brown AT in mice fed a high-fat diet, it increases brown AT temperature and brown AT marker gene expression, thereby contributing to reduced fat mass accumulation. In addition, p53 is increasingly being recognized as crucial player in nutrient sensing pathways. Hence, despite existence of contradictory findings and a varying density of evidence, several functions of p53 in adipocytes and ATs have been emerging, positioning p53 as an essential regulatory hub in ATs. Future studies need to make use of more sophisticated in vivo model systems and should identify an AT-specific set of p53 target genes and downstream pathways upon different (nutrient) challenges to identify novel therapeutic targets to curb metabolic diseases KW - p53 KW - adipose tissue KW - metabolic syndrome KW - obesity KW - adipogenesis KW - insulin resistance Y1 - 2018 U6 - https://doi.org/10.3390/ijms19092622 SN - 1422-0067 VL - 19 IS - 9 PB - MDPI CY - Basel ER - TY - GEN A1 - Uhlig, Katja A1 - Gehre, Christian P. A1 - Kammerer, Sarah A1 - Küpper, Jan-Heiner A1 - Coleman, Charles Dominic A1 - Püschel, Gerhard Paul A1 - Duschl, Claus T1 - Real-time monitoring of oxygen consumption of hepatocytes in a microbioreactor T2 - Toxicology letters Y1 - 2018 U6 - https://doi.org/10.1016/j.toxlet.2018.06.652 SN - 0378-4274 SN - 1879-3169 VL - 295 SP - S115 EP - S115 PB - Elsevier CY - Clare ER - TY - GEN A1 - Kleuser, Burkhard T1 - The enigma of sphingolipids in health and disease T2 - International journal of molecular sciences Y1 - 2018 U6 - https://doi.org/10.3390/ijms19103126 SN - 1422-0067 VL - 19 IS - 10 PB - MDPI CY - Basel ER - TY - JOUR A1 - Knebel, Constanze A1 - Neeb, Jannika A1 - Zahn, Elisabeth A1 - Schmidt, Flavia A1 - Carazo, Alejandro A1 - Holas, Ondej A1 - Pavek, Petr A1 - Püschel, Gerhard Paul A1 - Zanger, Ulrich M. A1 - Süssmuth, Roderich A1 - Lampen, Alfonso A1 - Marx-Stoelting, Philip A1 - Braeuning, Albert T1 - Unexpected Effects of Propiconazole, Tebuconazole, and Their Mixture on the Receptors CAR and PXR in Human Liver Cells JF - Toxicological sciences N2 - Analyzing mixture toxicity requires an in-depth understanding of the mechanisms of action of its individual components. Substances with the same target organ, same toxic effect and same mode of action (MoA) are believed to cause additive effects, whereas substances with different MoAs are assumed to act independently. Here, we tested 2 triazole fungicides, propiconazole, and tebuconazole (Te), for individual and combined effects on liver toxicity-related endpoints. Both triazoles are proposed to belong to the same cumulative assessment group and are therefore thought to display similar and additive behavior. Our data show that Te is an antagonist of the constitutive androstane receptor (CAR) in rats and humans, while propiconazole is an agonist of this receptor. Both substances activate the pregnane X-receptor (PXR) and further induce mRNA expression of CYP3A4. CYP3A4 enzyme activity, however, is inhibited by propiconazole. For common targets of PXR and CAR, the activation of PXR by Te overrides CAR inhibition. In summary, propiconazole and Te affect different hepatotoxicity-relevant cellular targets and, depending on the individual endpoint analyzed, act via similar or dissimilar mechanisms. The use of molecular data based on research in human cell systems extends the picture to refine cumulative assessment group grouping and substantially contributes to the understanding of mixture effects of chemicals in biological systems. KW - triazole fungicides KW - constitutive androstane receptor KW - pregnane X-receptor KW - enzyme induction KW - liver toxicity KW - mixtures Y1 - 2018 U6 - https://doi.org/10.1093/toxsci/kfy026 SN - 1096-6080 SN - 1096-0929 VL - 163 IS - 1 SP - 170 EP - 181 PB - Oxford Univ. Press CY - Oxford ER -