TY  - JOUR
A1  - Schell, Mareike
A1  - Wardelmann, Kristina
A1  - Kleinridders, Andre
T1  - Untangling the effect of insulin action on brain mitochondria and metabolism
JF  - Journal of neuroendocrinology
N2  - The regulation of energy homeostasis is controlled by the brain and, besides requiring high amounts of energy, it relies on functional insulin/insulin-like growth factor (IGF)-1 signalling in the central nervous system. This energy is mainly provided by mitochondria in form of ATP. Thus, there is an intricate interplay between mitochondrial function and insulin/IGF-1 action to enable functional brain signalling and, accordingly, propagate a healthy metabolism. To adapt to different nutritional conditions, the brain is able to sense the current energy status via mitochondrial and insulin signalling-dependent pathways and exerts an appropriate metabolic response. However, regional, cell type and receptor-specific consequences of this interaction occur and are linked to diverse outcomes such as altered nutrient sensing, body weight regulation or even cognitive function. Impairments of this cross-talk can lead to obesity and glucose intolerance and are linked to neurodegenerative diseases, yet they also induce a self-sustainable, dysfunctional 'metabolic triangle' characterised by insulin resistance, mitochondrial dysfunction and inflammation in the brain. The identification of causal factors deteriorating insulin action, mitochondrial function and concomitantly a signature of metabolic stress in the brain is of utter importance to offer novel mechanistic insights into development of the continuously rising prevalence of non-communicable diseases such as type 2 diabetes and neurodegeneration. This review aims to determine the effect of insulin action on brain mitochondrial function and energy metabolism. It precisely outlines the interaction and differences between insulin action, insulin-like growth factor (IGF)-1 signalling and mitochondrial function; distinguishes between causality and association; and reveals its consequences for metabolism and cognition. We hypothesise that an improvement of at least one signalling pathway can overcome the vicious cycle of a self-perpetuating metabolic dysfunction in the brain present in metabolic and neurodegenerative diseases.
KW  - brain
KW  - energy homeostasis
KW  - inflammation
KW  - insulin signalling
KW  - metabolism
KW  - mitochondrial function
Y1  - 2021
U6  - https://doi.org/10.1111/jne.12932
SN  - 0953-8194
SN  - 1365-2826
VL  - 33
IS  - 4
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - CHAP
A1  - Wandt, Viktoria Klara Veronika
A1  - Winkelbeiner, Nicola
A1  - Loßow, Kristina
A1  - Kopp, Johannes
A1  - Simon, Luise
A1  - Ebert, Franziska
A1  - Kipp, Anna Patricia
A1  - Schwerdtle, Tanja
T1  - Trace elements, ageing, and sex. Impact on genome stability
BT  - Abstracts of the 87th Annual Meeting of the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT) with contribution of the Arbeitsgemeinschaft für Angewandte Humanpharmakologie e. V. (AGAH)
T2  - Naunyn-Schmiedeberg's archives of pharmacology
Y1  - 2021
U6  - https://doi.org/10.1007/s00210-021-02066-6
SN  - 0028-1298
SN  - 1432-1912
VL  - 394
IS  - Suppl. 1
SP  - S13
EP  - S13
PB  - Springer
CY  - Berlin ; Heidelberg
ER  - 
TY  - JOUR
A1  - Herpich, Catrin
A1  - Haß, Ulrike
A1  - Kochlik, Bastian Max
A1  - Franz, Kristina
A1  - Laeger, Thomas
A1  - Klaus, Susanne
A1  - Bosy-Westphal, Anja
A1  - Norman, Kristina
T1  - Postprandial dynamics and response of fibroblast growth factor 21 in older adults
JF  - Clinical Nutrition
N2  - Background & aims: Fibroblast growth factor 21 (FGF21) plays a pivotal role in glucose and lipid metabolism and has been proposed as a longevity hormone. However, elevated plasma FGF21 concentrations are paradoxically associated with mortality in higher age and little is known about the postprandial regulation of FGF21 in older adults. In this parallel group study, we investigated postprandial FGF21 dynamics and response in older (65-85 years) compared to younger (18-35 years) adults following test meals with varying macronutrient composition.

Methods: Participants (n = 60 older; n = 60 younger) were randomized to one of four test meals: dextrose, high carbohydrate (HC), high fat (HF) or high protein (HP). Blood was drawn before and 15, 30, 60, 120, 240 min after meal ingestion. Postprandial dynamics were evaluated using repeated measures ANCOVA. FGF21 response was assessed by incremental area under the curve.

Results: Fasting FGF21 concentrations were significantly higher in older adults. FGF21 dynamics were affected by test meal (p < 0.001) and age (p = 0.013), when adjusted for BMI and fasting FGF21. Postprandial FGF21 concentrations steadily declined over 240 min in both age groups after HF and HP, but not after dextrose or HC ingestion. At 240 min, FGF21 concentrations were significantly higher in older than in younger adults following dextrose (133 pg/mL, 95%CI: 103, 172 versus 91.2 pg/mL, 95%CI: 70.4, 118; p = 0.044), HC (109 pg/mL, 95%CI: 85.1, 141 versus 70.3 pg/mL, 95%CI: 55.2, 89.6; p = 0.014) and HP ingestion (45.4 pg/mL, 95%CI: 34.4, 59.9 versus 27.9 pg/mL 95%CI: 20.9, 37.1; p = 0.018). FGF21 dynamics and response to HF were similar for both age groups.

Conclusions: The age-specific differences in postprandial FGF21 dynamics and response in healthy adults, potentially explain higher FGF21 concentrations in older age. Furthermore, there appears to be a significant impact of acute and recent protein intake on FGF21 secretion.
Y1  - 2021
U6  - https://doi.org/10.1016/j.clnu.2021.04.037
SN  - 0261-5614
SN  - 1532-1983
VL  - 40
IS  - 6
SP  - 3765
EP  - 3771
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - GEN
A1  - Figueroa Campos, Gustavo A.
A1  - Perez, Jeffrey Paulo H.
A1  - Block, Inga
A1  - Tchewonpi Sagu, Sorel
A1  - Saravia Celis, Pedro
A1  - Taubert, Andreas
A1  - Rawel, Harshadrai Manilal
T1  - Preparation of activated carbons from spent coffee and coffee parchment and assessment of their adsorbent efficiency
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - The valorization of coffee wastes through modification to activated carbon has been considered as a low-cost adsorbent with prospective to compete with commercial carbons. So far, very few studies have referred to the valorization of coffee parchment into activated carbon. Moreover, low-cost and efficient activation methods need to be more investigated. The aim of this work was to prepare activated carbon from spent coffee grounds and parchment, and to assess their adsorption performance. The co-calcination processing with calcium carbonate was used to prepare the activated carbons, and their adsorption capacity for organic acids, phenolic compounds and proteins was evaluated. Both spent coffee grounds and parchment showed yields after the calcination and washing treatments of around 9.0%. The adsorption of lactic acid was found to be optimal at pH 2. The maximum adsorption capacity of lactic acid with standard commercial granular activated carbon was 73.78 mg/g, while the values of 32.33 and 14.73 mg/g were registered for the parchment and spent coffee grounds activated carbons, respectively. The Langmuir isotherm showed that lactic acid was adsorbed as a monolayer and distributed homogeneously on the surface. Around 50% of total phenols and protein content from coffee wastewater were adsorbed after treatment with the prepared activated carbons, while 44, 43, and up to 84% of hydrophobic compounds were removed using parchment, spent coffee grounds and commercial activated carbon, respectively; the adsorption efficiencies of hydrophilic compounds ranged between 13 and 48%. Finally, these results illustrate the potential valorization of coffee by-products parchment and spent coffee grounds into activated carbon and their use as low-cost adsorbent for the removal of organic compounds from aqueous solutions.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1158 
KW  - coffee by-products
KW  - spent coffee grounds
KW  - parchment
KW  - valorization
KW  - calcination
KW  - activated carbon
KW  - organic compounds adsorption
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-521914
SN  - 1866-8372
IS  - 8
ER  - 
TY  - THES
A1  - Nieschalke, Kai
T1  - Proteinaddukte und Urinmetaboliten des Nagetierkanzerogens Methyleugenol als Biomarker der Exposition
Y1  - 2021
ER  - 
TY  - JOUR
A1  - Wigger, Dominik
A1  - Schumacher, Fabian
A1  - Schneider-Schaulies, Sibylle
A1  - Kleuser, Burkhard
T1  - Sphingosine 1-phosphate metabolism and insulin signaling
JF  - Cellular signalling
N2  - Insulin is the main anabolic hormone secreted by 13-cells of the pancreas stimulating the assimilation and storage of glucose in muscle and fat cells. It modulates the postprandial balance of carbohydrates, lipids and proteins via enhancing lipogenesis, glycogen and protein synthesis and suppressing glucose generation and its release from the liver. Resistance to insulin is a severe metabolic disorder related to a diminished response of peripheral tissues to the insulin action and signaling. This leads to a disturbed glucose homeostasis that precedes the onset of type 2 diabetes (T2D), a disease reaching epidemic proportions. A large number of studies reported an association between elevated circulating fatty acids and the development of insulin resistance. The increased fatty acid lipid flux results in the accumulation of lipid droplets in a variety of tissues. However, lipid intermediates such as diacylglycerols and ceramides are also formed in response to elevated fatty acid levels. These bioactive lipids have been associated with the pathogenesis of insulin resistance. More recently, sphingosine 1-phosphate (S1P), another bioactive sphingolipid derivative, has also been shown to increase in T2D and obesity. Although many studies propose a protective role of S1P metabolism on insulin signaling in peripheral tissues, other studies suggest a causal role of S1P on insulin resistance. In this review, we critically summarize the current state of knowledge of S1P metabolism and its modulating role on insulin resistance. A particular emphasis is placed on S1P and insulin signaling in hepatocytes, skeletal muscle cells, adipocytes and pancreatic 13-cells. In particular, modulation of receptors and enzymes that regulate S1P metabolism can be considered as a new therapeutic option for the treatment of insulin resistance and T2D.
KW  - Insulin resistance
KW  - Type 2 diabetes
KW  - Sphingolipids
KW  - Hepatocytes
KW  - Adipocytes
KW  - Skeletal muscle cells
Y1  - 2021
U6  - https://doi.org/10.1016/j.cellsig.2021.109959
SN  - 0898-6568
SN  - 1873-3913
VL  - 82
PB  - Elsevier Science
CY  - Amsterdam [u.a.]
ER  - 
TY  - JOUR
A1  - Pan, Yuanwei
A1  - Ma, Xuehua
A1  - Liu, Chuang
A1  - Xing, Jie
A1  - Zhou, Suqiong
A1  - Parshad, Badri
A1  - Schwerdtle, Tanja
A1  - Li, Wenzhong
A1  - Wu, Aiguo
A1  - Haag, Rainer
T1  - Retinoic acid-loaded dendritic polyglycerol-conjugated gold nanostars for targeted photothermal therapy in breast cancer stem cells
JF  - ACS nano
N2  - The existence of cancer stem cells (CSCs) poses a major obstacle for the success of current cancer therapies, especially the fact that non-CSCs can spontaneously turn into CSCs, which lead to the failure of the treatment and tumor relapse. Therefore, it is very important to develop effective strategies for the eradication of the CSCs. In this work, we have developed a CSCs-specific targeted, retinoic acid (RA)-loaded gold nanostars-dendritic polyglycerol (GNSs-dPG) nanoplatform for the efficient eradication of CSCs. The nanocomposites possess good biocompatibility and exhibit effective CSCs-specific multivalent targeted capability due to hyaluronic acid (HA) decorated on the multiple attachment sites of the bioinert dendritic polyglycerol (dPG). With the help of CSCs differentiation induced by RA, the self-renewal of breast CSCs and tumor growth were suppressed by the high therapeutic efficacy of photothermal therapy (PTT) in a synergistic inhibitory manner. Moreover, the stemness gene expression and CSC-driven tumorsphere formation were significantly diminished. In addition, the in vivo tumor growth and CSCs were also effectively eliminated, which indicated superior anticancer activity, effective CSCs suppression, and prevention of relapse. Taken together, we developed a CSCs-specific targeted, RA-loaded GNSs-dPG nanoplatform for the targeted eradication of CSCs and for preventing the relapse.
KW  - cancer stem cells
KW  - dendritic polyglycerol
KW  - gold nanostars
KW  - retinoic acid
KW  - photothermal therapy
Y1  - 2021
U6  - https://doi.org/10.1021/acsnano.1c05452
SN  - 1936-0851
SN  - 1936-086X
VL  - 15
IS  - 9
SP  - 15069
EP  - 15084
PB  - American Chemical Society
CY  - Washington
ER  - 
TY  - JOUR
A1  - Klaus, Susanne
A1  - Igual Gil, Carla
A1  - Ost, Mario
T1  - Regulation of diurnal energy balance by mitokines
JF  - Cellular and molecular life sciences : CMLS
N2  - The mammalian system of energy balance regulation is intrinsically rhythmic with diurnal oscillations of behavioral and metabolic traits according to the 24 h day/night cycle, driven by cellular circadian clocks and synchronized by environmental or internal cues such as metabolites and hormones associated with feeding rhythms. Mitochondria are crucial organelles for cellular energy generation and their biology is largely under the control of the circadian system. Whether mitochondrial status might also feed-back on the circadian system, possibly via mitokines that are induced by mitochondrial stress as endocrine-acting molecules, remains poorly understood. Here, we describe our current understanding of the diurnal regulation of systemic energy balance, with focus on fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), two well-known endocrine-acting metabolic mediators. FGF21 shows a diurnal oscillation and directly affects the output of the brain master clock. Moreover, recent data demonstrated that mitochondrial stress-induced GDF15 promotes a day-time restricted anorexia and systemic metabolic remodeling as shown in UCP1-transgenic mice, where both FGF21 and GDF15 are induced as myomitokines. In this mouse model of slightly uncoupled skeletal muscle mitochondria GDF15 proved responsible for an increased metabolic flexibility and a number of beneficial metabolic adaptations. However, the molecular mechanisms underlying energy balance regulation by mitokines are just starting to emerge, and more data on diurnal patterns in mouse and man are required. This will open new perspectives into the diurnal nature of mitokines and action both in health and disease.
KW  - Mitochondria
KW  - FGF21
KW  - GDF15
KW  - Circadian rhythm
KW  - Hormones
KW  - Nutrition
Y1  - 2021
U6  - https://doi.org/10.1007/s00018-020-03748-9
SN  - 1420-682X
SN  - 1420-9071
VL  - 78
IS  - 7
SP  - 3369
EP  - 3384
PB  - Springer International Publishing AG
CY  - Cham (ZG)
ER  - 
TY  - THES
A1  - Rausch, Ann-Kristin
T1  - Development of LC-MS/MS Multi-Methods for the Analysis of Contaminants and Residues
N2  - Mycotoxins are secondary metabolites produced by several filamentous fungal species, thus occurring ubiquitously in the environment and food. While the heterogeneous group shows differences in their bioavailability and toxicity, the low-molecular-weight xenobiotics are capable of impacting human and animal health acutely and chronically. Therefore, maximum levels for the major mycotoxins in food and feed are regulated in the current European legislation. Besides free mycotoxins, naturally occurring modified mycotoxins are gaining more attention in recent years. Modified mycotoxins constitute toxins altered by plants, microorganisms, and living organisms in different metabolic pathways or food processing steps. The toxicological relevant compounds often co-occur with their free forms in infested food and feed. Thus, the toxins may contribute to the overall toxicity of mycotoxins, wherefore their presence and toxicity should be considered in risk assessment. Until now, however, there are no regulated limits for modified mycotoxins within the European Union. In this thesis, rapid, sensitive, and robust methods for the analysis of mycotoxins and their modified forms were developed and validated using state-of-the-art high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) systems. Firstly, two analytical methods for determining 38 mycotoxins in cereals and 41 mycotoxins in beer were established since agricultural products count as the primary source of mycotoxin contamination. For the analysis of cereal samples, a QuEChERS- based extraction approach was pursued, while analytes from beer samples were extracted using an acetonitrile precipitation scheme. Validation in cereals, namely wheat, corn, rice, and barley, as well as in beer, demonstrated satisfactory results. To obtain information regarding the natural occurrence of mycotoxins in food products, the developed methods were applied to the analysis of several commercial samples partly produced worldwide. The Fusarium toxins deoxynivalenol and its conjugated metabolite deoxynivalenol-3-glucoside turned out to be the most abundant toxins. None of the other modified mycotoxins were quantified in the samples. However, one cereal sample showed traces of zearalenone- 14-sulfate below the limit of quantification. Moreover, pesticides, plant growth regulators, and tropane alkaloids were investigated in this thesis. Pesticides present biologically highly effective compounds applied in the environment to protect humans from the hazardous effects of pests. While plant growth regulators show similar functions, mainly improving agricultural production, tropane alkaloids are naturally occurring secondary metabolites mainly in the species of Solanaceae that may pose unintended poisoning of humans. The third part of the present thesis aimed to analyze cereal-relevant compounds simultaneously, wherefore a multi-method for the analysis of (modified) mycotoxins, pesticides, plant growth regulators, and tropane alkaloids was established. After processing the samples, this should be done in a single extraction step with subsequent one-time measurements. Various sample preparation procedures were compared, whereby an approach based on an acidified acetonitrile/water extraction, followed by an online clean-up, was finally chosen. The simultaneous determination of more than 350 analytes required an analytical tool that offered an increased resolving power, represented as an enhanced peak capacity, and the possibility of analyzing a broad polarity range. Thus, a two-dimensional LC-MS/MS system based on two different separation mechanisms that performed orthogonal to one another was used for the analysis. Validation of the developed method revealed good performance characteristics for most analytes, while subsequent application showed that 86% of the samples were contaminated with at least one compound. In summary, this thesis provides novel insights into the analysis of food-relevant (modified) mycotoxins. Different sample preparation and LC-MS/MS approaches were introduced, resulting in the development of three new analytical methods. For the first time, such a high number of modified mycotoxins was included in multi-mycotoxin methods and a multi-method ranging both contaminants and residues. Although first steps towards the analysis of modified mycotoxins have been made, further research is needed to elucidate their (co-) occurrence and toxicological behavior in order to understand their relevance to human health in the future.
KW  - Mycotoxins
KW  - LC-MS/MS
KW  - Multi-Methods
KW  - Cereals
KW  - Beer
Y1  - 2021
ER  - 
TY  - CHAP
A1  - Michaelis, Vivien
A1  - Aengenheister, Leonie
A1  - Schwerdtle, Tanja
A1  - Buerki-Thurnherr, Tina
A1  - Bornhorst, Julia
T1  - Manganese translocation across an in vitro model of human villous trophoblast
T2  - Placenta
Y1  - 2021
SN  - 0143-4004
SN  - 1532-3102
VL  - 112
SP  - E63
EP  - E64
PB  - Elsevier
CY  - Amsterdam [u.a.]
ER  - 
TY  - GEN
A1  - Baesler, Jessica
A1  - Michaelis, Vivien
A1  - Stiboller, Michael
A1  - Haase, Hajo
A1  - Aschner, Michael
A1  - Schwerdtle, Tanja
A1  - Sturzenbaum, Stephen R.
A1  - Bornhorst, Julia
T1  - Nutritive manganese and zinc overdosing in aging c. elegans result in a metallothionein-mediated alteration in metal homeostasis
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Manganese (Mn) and zinc (Zn) are not only essential trace elements, but also potential exogenous risk factors for various diseases. Since the disturbed homeostasis of single metals can result in detrimental health effects, concerns have emerged regarding the consequences of excessive exposures to multiple metals, either via nutritional supplementation or parenteral nutrition. This study focuses on Mn-Zn-interactions in the nematode Caenorhabditis elegans (C. elegans) model, taking into account aspects related to aging and age-dependent neurodegeneration.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1364 
KW  - aging
KW  - C. elegans
KW  - homeostasis
KW  - manganese
KW  - zinc
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-514995
SN  - 1866-8372
IS  - 8
ER  - 
TY  - JOUR
A1  - Kuhn, Eugênia Carla
A1  - Tavares Jacques, Maurício
A1  - Teixeira, Daniela
A1  - Meyer, Sören
A1  - Gralha, Thiago
A1  - Roehrs, Rafael
A1  - Camargo, Sandro
A1  - Schwerdtle, Tanja
A1  - Bornhorst, Julia
A1  - Ávila, Daiana Silva
T1  - Ecotoxicological assessment of Uruguay River and affluents pre- and biomonitoring
JF  - Environmental science and pollution research : ESPR
N2  - Uruguay River is the most important river in western Rio Grande do Sul, separating Brazil from Argentina and Uruguay. However, its pollution is of great concern due to agricultural activities in the region and the extensive use of pesticides. In a long term, this practice leads to environmental pollution, especially to the aquatic system. The objective of this study was to analyze the physicochemical characteristics, metals and pesticides levels in water samples obtained before and after the planting and pesticides' application season from three sites: Uruguay River and two minor affluents, Mezomo Dam and Salso Stream. For biomonitoring, the free-living nematode Caenorhabditis elegans was used, which were exposed for 24 h. We did not find any significant alteration in physicochemical parameters. In the pre- and post-pesticides' samples we observed a residual presence of three pesticides (tebuconazole, imazethapyr, and clomazone) and metals which levels were above the recommended (As, Hg, Fe, and Mn). Exposure to both pre- and post-pesticides' samples impaired C. elegans reproduction and post-pesticides samples reduced worms' survival rate and lifespan. PCA analysis indicated that the presence of metals and pesticides are important variables that impacted C. elegans biological endpoints. Our data demonstrates that Uruguay River and two affluents are contaminated independent whether before or after pesticides' application season. In addition, it reinforces the usefulness of biological indicators, since simple physicochemical analyses are not sufficient to attest water quality and ecological safety.
KW  - Heavy metals
KW  - Pesticides
KW  - Contamination
KW  - Arsenic
KW  - Environmental
KW  - pollution
KW  - Uruguay River
Y1  - 2021
U6  - https://doi.org/10.1007/s11356-020-11986-4
SN  - 0944-1344
SN  - 1614-7499
VL  - 28
IS  - 17
SP  - 21730
EP  - 21741
PB  - Springer
CY  - Berlin ; Heidelberg
ER  - 
TY  - JOUR
A1  - Fitzner, Maria
A1  - Fricke, Anna
A1  - Schreiner, Monika
A1  - Baldermann, Susanne
T1  - Utilization of regional natural brines for the indoor cultivation of Salicornia europaea
JF  - Sustainability / Multidisciplinary Digital Publishing Institute (MDPI)
N2  - Scaling agriculture to the globally rising population demands new approaches for future crop production such as multilayer and multitrophic indoor farming. Moreover, there is a current trend towards sustainable local solutions for aquaculture and saline agriculture. In this context, halophytes are becoming increasingly important for research and the food industry. As Salicornia europaea is a highly salt-tolerant obligate halophyte that can be used as a food crop, indoor cultivation with saline water is of particular interest. Therefore, finding a sustainable alternative to the use of seawater in non-coastal regions is crucial. Our goal was to determine whether natural brines, which are widely distributed and often available in inland areas, provide an alternative water source for the cultivation of saline organisms. This case study investigated the potential use of natural brines for the production of S. europaea. In the control group, which reflects the optimal growth conditions, fresh weight was increased, but there was no significant difference between the treatment groups comparing natural brines with artificial sea water. A similar pattern was observed for carotenoids and chlorophylls. Individual components showed significant differences. However, within treatments, there were mostly no changes. In summary, we showed that the influence of the different chloride concentrations was higher than the salt composition. Moreover, nutrient-enriched natural brine was demonstrated to be a suitable alternative for cultivation of S. europaea in terms of yield and nutritional quality. Thus, the present study provides the first evidence for the future potential of natural brine waters for the further development of aquaculture systems and saline agriculture in inland regions.
KW  - carotenoids
KW  - glasswort
KW  - land-based aquaculture
KW  - seawater
KW  - phytochemicals
KW  - halophytes
KW  - salt composition
KW  - chlorophylls
KW  - artificial
KW  - salt
KW  - saline agriculture
Y1  - 2021
U6  - https://doi.org/10.3390/su132112105
SN  - 2071-1050
VL  - 13
IS  - 21
PB  - MDPI
CY  - Basel
ER  - 
TY  - THES
A1  - Engel, Anika
T1  - Endocrine effects of plasticizers and the development of a breast cell-based toxicity screening system
N2  - Humans are frequently exposed to a variety of endocrine disrupting chemicals (EDCs), which can cause harmful effects, e.g. disturbance of growth, development and reproduction, and cancer (UBA, 2016). EDCs are often components of synthetically manufactured products. Materials made of plastics, building materials, electronic items, textiles or cosmetic products can be particularly contaminated (Ain et al., 2021). One group of EDCs that has gained increased interest in recent years is phthalates. They are used as plasticizers in plastic materials to which people are daily exposed to. Phthalate plasticizers exert their harmful effects among others via activation of the estrogen receptor α (ERα), the estrogen receptor β (ERβ) and via inhibition of the androgen receptor (AR). Some phthalates have already been classified by the EU as Cancerogenic-, Mutagenic-, Reprotoxic- (CMR) substances and their use in industry has been restricted. After oral ingestion, phthalates are metabolized and are finally excreted with the urine. Numerous toxicological studies exist on phthalates, but mainly with the parent substances, not with their primary and secondary metabolites. In the course of the restriction of phthalates by the EU, the phthalate-free plasticizer di-isononylcyclohexane-1,2-dicarboxylate (DINCH®), was introduced to the market. So far, almost no toxicologically relevant properties have been identified for DINCH®. However, the effects of DINCH® have only been studied in animal experiments and, as with phthalates, almost exclusively with the parent substance. However, toxic effects of a particular compound may be induced by its metabolites and not by the parent compound itself. Therefore, potential endocrine effects of 15 phthalates, 19 phthalate metabolites, DINCH®, and five of its metabolites were investigated using reporter gene assays on the ERα, ERβ, and the AR. In addition, studies of the influence of some selected plasticizers on peroxisome proliferator-activated receptor α (PPARα) and peroxisome proliferator-activated receptor γ (PPARγ) activity were performed. Furthermore, a H295R steroidogenesis assay was performed to determine the influence of DINCH® and its metabolites on estradiol or testosterone synthesis. Analysis of the experiments shows that the phthalates either stimulated or inhibited ERα and ERβ activity and inhibited AR activity, whereas the phthalate metabolites did not affect the activity of these human hormone receptors. In contrast, metabolites of di-(2-ethylhexyl) phthalate (DEHP) stimulated transactivation of the human PPARα and PPARγ in analogous reporter gene assays, although DEHP itself did not activate these nuclear receptors. Therefore, primary and secondary phthalate metabolites appear to exert different effects at the molecular level compared to the parent compounds. Similarly, the results showed that the phthalate-free plasticizer DINCH® itself did not affect the activity of ERα, ERβ, AR, PPARα and PPARγ, while the DINCH® metabolites were shown to activate all these receptors. In the case of AR, DINCH® metabolites mainly enhanced AR activity stimulated by dihydrotestosterone (DHT). In the H295R steroidogenesis assay, neither DINCH® nor any of its metabolites affected estradiol or testosterone synthesis. Primary and secondary metabolites of DINCH® thus exert different effects at the molecular level than DINCH® itself. However, all these in vitro effects of DINCH® metabolites were observed only at high concentrations, which were about three orders of magnitude higher than the reported DINCH® metabolite concentrations in human urine. Therefore, the in vitro data does not support the assumption that DINCH® or any of the metabolites studied could have significant endocrine effects in vivo at relevant exposure levels in humans. Following the demonstration of direct and indirect endocrine effects of the studied plasticizers, a new effect-based in vitro 3D screening tool for toxicity assays of non-genotoxic carcinogens was developed using estrogen receptor-negative (ER-) MCF10-A cells and estrogen receptor-positive (ER+) MCF-12A cells. This arose from the background that breast cancer is the most common cancer occurring in women and estrogenic substances, such as phthalates, can probably influence the disease. The human mammary epithelial cell lines MCF-10A and MCF-12A form well-differentiated acini-like structures when cultured in three-dimensional Matrigel culture for a period of 20 days. The model should make it possible to detect substance effects on cell differentiation and growth, on mammary cell acini, and to differentiate between estrogenic and non-estrogenic effects at the same time. In the present study, both cell lines were tested for their suitability as an effect-based in vitro assay system for non-genotoxic carcinogens. An Automated Acinus Detection And Morphological Evaluation (ADAME) software solution has been developed for automatic acquisition of acinus images and determination of morphological parameters such as acinus size, lumen size, and acinus roundness. Several test substances were tested for their ability to affect acinus formation and cellular differentiation. Human epithelial growth factor (EGF) stimulated acinus growth for both cell lines, while all trans retinoic acid (RA) inhibited acinar growth. The potent estrogen 17β-estradiol had no effect on acinus formation of MCF-10A cells but resulted in larger MCF-12A acini. Thus, the parallel use of both cell lines together with the developed high content screening and evaluation tool allows the rapid identification of the estrogenic and cancerogenic properties of a given test compound. The morphogenesis of the acini was only slightly affected by the test substances. On the one hand, this suggests a robust test system, on the other hand, it probably cannot detect low-potent estrogenic compounds such as phthalates or DINCH®. The advantage of the robustness of the system, however, may be that vast numbers of "positive" results with questionable biological relevance could be avoided, such as those observed in sensitive reporter gene assays.
N2  - Der Mensch ist häufig einer Vielzahl von endokrin wirksamen Chemikalien (EDCs) ausgesetzt, die schädliche Auswirkungen haben können, z. B. Störungen von Wachstum, Entwicklung und Fortpflanzung sowie Krebs (UBA, 2016). Eine Gruppe von EDCs, die in den letzten Jahren vermehrt an Interesse gewonnen hat, sind die Phthalate. Diese werden als Weichmacher in Kunststoffen verwendet. Einige Phthalate wurden bereits von der EU als Kanzerogene-, Mutagene-, Reproduktionstoxische- (CMR) Stoffe klassifiziert und ihre Verwendung in der Industrie beschränkt. Nach der oralen Aufnahme werden Phthalate metabolisiert und schließlich mit dem Urin ausgeschieden. Für die Phthalate existieren zwar zahlreiche toxikologische Studien, allerdings vorwiegend mit den Ausgangssubstanzen, nicht mit ihren primären und sekundären Metaboliten. Im Zuge der Beschränkung der Phthalate durch die EU wurde der phthalatfreie Weichmacher Diisononylcyclohexan-1,2-dicarboxylat (DINCH®), auf den Markt gebracht. DINCH® werden bisher kaum toxikologisch relevante Eigenschaften zugeordnet. Bislang wurden die Auswirkungen von DINCH® jedoch lediglich in Tierexperimenten untersucht und fast ausschließlich mit der Stamm-Substanz. Aus diesem Grund wurden potentiell endokrine Effekte von 15 Phthalaten, 19 Phthalat-Metaboliten, DINCH® und fünf seiner Metabolite unter Verwendung von Reportergen-Assays auf den ERα, ERβ und den AR untersucht. Zusätzlich wurden Untersuchungen des Einflusses einiger ausgewählter Substanzen auf die Aktivität des Peroxisom-Proliferator-aktivierten Rezeptor α (PPARα) und des Peroxisom-Proliferator-aktivierten Rezeptor γ (PPARγ) durchgeführt. Weiterhin wurde ein H295R-Steroidogenese-Assay durchgeführt, um den Einfluss von DINCH® und seinen Metaboliten auf die Estradiol- oder Testosteronsynthese zu bestimmen. Die Auswertung der Experimente zeigt, dass die Phthalate entweder die ERα- und ERβ-Aktivität stimulierten oder hemmten und die AR-Aktivität hemmten, während die Phthalatmetaboliten keinen Einfluss auf die Aktivität dieser menschlichen Hormonrezeptoren hatten. Im Gegensatz dazu stimulierten die Metaboliten von Di-(2-ethylhexyl) phthalat (DEHP) die Transaktivierung des humanen PPARα und PPARγ in analogen Reportergen-Assays, obwohl DEHP selbst diese Kernrezeptoren nicht aktivierte. Daher scheinen primäre und sekundäre Phthalatmetaboliten im Vergleich zu den Ausgangsverbindungen unterschiedliche Wirkungen auf molekularer Ebene auszuüben. Ebenso zeigten die Ergebnisse, dass der phthaltfreie Weichmacher DINCH® selbst keinen Einfluss auf die Aktivität von ERα, ERβ, AR, PPARα und PPARγ hatte, während die DINCH®-Metaboliten nachweislich alle diese Rezeptoren aktivierten. Im Falle des AR verstärkten die DINCH®-Metaboliten vor allem die durch Dihydrotestosteron (DHT) stimulierte AR-Aktivität. Im H295R-Steroidogenese-Assay beeinflusste weder DINCH® noch einer seiner Metaboliten die Estradiol- oder Testosteronsynthese. Primäre und sekundäre Metabolite von DINCH® üben demnach auf molekularer Ebene andere Effekte aus als DINCH® selbst. Die hier gewonnenen in vitro-Daten unterstützen die Annahme nicht, dass DINCH® oder einer der untersuchten Metaboliten erhebliche endokrine Wirkungen in vivo bei relevanten Expositionsmengen beim Menschen haben könnten. Nachdem endokrine Wirkungen der untersuchten Weichmacher nachgewiesen werden konnten, wurde ein neues wirkungsbasiertes in vitro 3D-Screening-Tool für Toxizitäts-Tests nicht genotoxischer Karzinogene mit östrogenrezeptor-negativen (ER-) MCF10-A-Zellen und östrogenrezeptor-positiven (ER+) MCF-12A-Zellen entwickelt. Dies geschah aus dem Hintergrund, dass Brustkrebs die häufigste Krebsart bei Frauen ist und östrogene Stoffe wie Phthalate die Krankheit vermutlich beeinflussen können. Die humanen Brustepithelzelllinien MCF-10A und MCF-12A bilden gut differenzierte azinusartige Strukturen, wenn sie in dreidimensionaler Matrigel-Kultur über einen Zeitraum von 20 Tagen kultiviert werden. Das Modell sollte es ermöglichen Substanzeffekte auf die Zelldifferenzierung und das Zellwachstum der Brustzell-Azini zu detektieren und dabei gleichzeitig zwischen östrogenen und nicht östrogenen Effekten differenzieren. Eine Softwarelösung zur automatisierten Acinus Detection And Morphological Evaluation (ADAME) wurde zur automatischen Erfassung von Acinus-Bildern und zur Bestimmung morphologischer Parameter wie Azinus-Größe, Lumengröße und Azinus-Rundheit entwickelt. Eine Reihe von Testsubstanzen wurde auf ihre Fähigkeit getestet, die Azinusbildung und die zelluläre Differenzierung zu beeinflussen. Der humane epitheliale Wachstumsfaktor (EGF) stimulierte das Azinuswachstum für beide Zelllinien, während all-trans-Retinsäure (RA) das Azinuswachstum hemmte. Das starke Östrogen 17β-Östradiol hatte keinen Einfluss auf die Azinusbildung von MCF-10A-Azini, führte aber zu größeren MCF-12A-Azini. Die parallele Verwendung beider Zelllinien zusammen mit dem hierbei entwickelten High-Content-Screening- und Evaluierungstool ermöglicht somit die schnelle Identifizierung der östrogenen oder kanzerogenen Eigenschaften einer gegebenen Testverbindung. Die Morphogenese der Azini wurde durch die Testsubstanzen nur geringfügig beeinflusst. Dies spricht einerseits für ein robustes Testsystem, andererseits kann es wahrscheinlich keine niedrigpotenten östrogenen Verbindungen wie Phthalate oder DINCH® erkennen. Der Vorteil der Robustheit des Systems kann jedoch darin liegen, dass eine große Zahl "positiver" Ergebnisse mit fragwürdiger biologischer Relevanz vermieden werden könnte, wie sie bei empfindlichen Reportergen-Assays zu beobachten sind.
KW  - phthalates
KW  - 3D breast cell model
KW  - endocrine disruption
Y1  - 2021
U6  - https://doi.org/10.25932/publishup-53117
ER  - 
TY  - JOUR
A1  - Solovyev, Nikolay
A1  - Drobyshev, Evgenii
A1  - Blume, Bastian
A1  - Michalke, Bernhard
T1  - Selenium at the neural barriers
BT  - a review
JF  - Frontiers in neuroscience / Frontiers Research Foundation
N2  - Selenium (Se) is known to contribute to several vital physiological functions in mammals: antioxidant defense, fertility, thyroid hormone metabolism, and immune response. Growing evidence indicates the crucial role of Se and Se-containing selenoproteins in the brain and brain function. As for the other essential trace elements, dietary Se needs to reach effective concentrations in the central nervous system (CNS) to exert its functions. To do so, Se-species have to cross the blood-brain barrier (BBB) and/or blood-cerebrospinal fluid barrier (BCB) of the choroid plexus. The main interface between the general circulation of the body and the CNS is the BBB. Endothelial cells of brain capillaries forming the so-called tight junctions are the primary anatomic units of the BBB, mainly responsible for barrier function. The current review focuses on Se transport to the brain, primarily including selenoprotein P/low-density lipoprotein receptor-related protein 8 (LRP8, also known as apolipoprotein E receptor-2) dependent pathway, and supplementary transport routes of Se into the brain via low molecular weight Se-species. Additionally, the potential role of Se and selenoproteins in the BBB, BCB, and neurovascular unit (NVU) is discussed. Finally, the perspectives regarding investigating the role of Se and selenoproteins in the gut-brain axis are outlined.
KW  - selenium
KW  - selenoprotein P
KW  - low molecular weight selenium species
KW  - blood– cerebrospinal fluid barrier
KW  - blood– brain barrier
KW  - selenium transport
KW  - brain-gut axis
KW  - LRP8
Y1  - 2021
U6  - https://doi.org/10.3389/fnins.2021.630016
SN  - 1662-453X
VL  - 15
PB  - Frontiers Media
CY  - Lausanne
ER  - 
TY  - JOUR
A1  - Döll, Stefanie
A1  - Djalali Farahani-Kofoet, Roxana
A1  - Zrenner, Rita
A1  - Henze, Andrea
A1  - Witzel, Katja
T1  - Tissue-specific signatures of metabolites and proteins in asparagus roots and exudates
JF  - Horticulture research
N2  - Comprehensive untargeted and targeted analysis of root exudate composition has advanced our understanding of rhizosphere processes. However, little is known about exudate spatial distribution and regulation. We studied the specific metabolite signatures of asparagus root exudates, root outer (epidermis and exodermis), and root inner tissues (cortex and vasculature). The greatest differences were found between exudates and root tissues. In total, 263 non-redundant metabolites were identified as significantly differentially abundant between the three root fractions, with the majority being enriched in the root exudate and/or outer tissue and annotated as 'lipids and lipid-like molecules' or 'phenylpropanoids and polyketides'. Spatial distribution was verified for three selected compounds using MALDI-TOF mass spectrometry imaging. Tissue-specific proteome analysis related root tissue-specific metabolite distributions and rhizodeposition with underlying biosynthetic pathways and transport mechanisms. The proteomes of root outer and inner tissues were spatially very distinct, in agreement with the fundamental differences between their functions and structures. According to KEGG pathway analysis, the outer tissue proteome was characterized by a high abundance of proteins related to 'lipid metabolism', 'biosynthesis of other secondary metabolites' and 'transport and catabolism', reflecting its main functions of providing a hydrophobic barrier, secreting secondary metabolites, and mediating water and nutrient uptake. Proteins more abundant in the inner tissue related to 'transcription', 'translation' and 'folding, sorting and degradation', in accord with the high activity of cortical and vasculature cell layers in growth- and development-related processes. In summary, asparagus root fractions accumulate specific metabolites. This expands our knowledge of tissue-specific plant cell function.
Y1  - 2021
U6  - https://doi.org/10.1038/s41438-021-00510-5
SN  - 2052-7276
VL  - 8
IS  - 1
PB  - Nanjing Agricultural Univ.
CY  - Nanjing
ER  - 
TY  - JOUR
A1  - Baesler, Jessica
A1  - Michaelis, Vivien
A1  - Stiboller, Michael
A1  - Haase, Hajo
A1  - Aschner, Michael
A1  - Schwerdtle, Tanja
A1  - Sturzenbaum, Stephen R.
A1  - Bornhorst, Julia
T1  - Nutritive manganese and zinc overdosing in aging c. elegans result in a metallothionein-mediated alteration in metal homeostasis
JF  - Molecular Nutrition and Food Research
N2  - Manganese (Mn) and zinc (Zn) are not only essential trace elements, but also potential exogenous risk factors for various diseases. Since the disturbed homeostasis of single metals can result in detrimental health effects, concerns have emerged regarding the consequences of excessive exposures to multiple metals, either via nutritional supplementation or parenteral nutrition. This study focuses on Mn-Zn-interactions in the nematode Caenorhabditis elegans (C. elegans) model, taking into account aspects related to aging and age-dependent neurodegeneration.
KW  - aging
KW  - C. elegans
KW  - homeostasis
KW  - manganese
KW  - zinc
Y1  - 2021
U6  - https://doi.org/10.1002/mnfr.202001176
SN  - 1613-4133
SN  - 1613-4125
VL  - 65
IS  - 8
SP  - 1
EP  - 11
PB  - Wiley-VCH GmbH
CY  - Weinheim
ER  - 
TY  - THES
A1  - Aga-Barfknecht, Heja
T1  - Investigation of the phenotype and genetic variant(s) of the diabetes locus Nidd/DBA
N2  - Diabetes is a major public health problem with increasing global prevalence. Type 2 diabetes (T2D), which accounts for 90% of all diagnosed cases, is a complex polygenic disease also modulated by epigenetics and lifestyle factors. For the identification of T2D-associated genes, linkage analyses combined with mouse breeding strategies and bioinformatic tools were useful in the past. In a previous study in which a backcross population of the lean and diabetes-prone dilute brown non-agouti (DBA) mouse and the obese and diabetes-susceptible New Zealand obese (NZO) mouse was characterized, a major diabetes quantitative trait locus (QTL) was identified on chromosome 4. The locus was designated non-insulin dependent diabetes from DBA (Nidd/DBA). The aim of this thesis was (i) to perform a detailed phenotypic characterization of the Nidd/DBA mice, (ii) to further narrow the critical region and (iii) to identify the responsible genetic variant(s) of the Nidd/DBA locus. The phenotypic characterization of recombinant congenic mice carrying a 13.6 Mbp Nidd/DBA fragment with 284 genes presented a gradually worsening metabolic phenotype. Nidd/DBA allele carriers exhibited severe hyperglycemia (~19.9 mM) and impaired glucose clearance at 12 weeks of age. Ex vivo perifusion experiments with islets of 13-week-old congenic mice revealed a tendency towards reduced insulin secretion in homozygous DBA mice. In addition, 16-week-old mice showed a severe loss of β-cells and reduced pancreatic insulin content. Pathway analysis of transcriptome data from islets of congenic mice pointed towards a downregulation of cell survival genes. Morphological analysis of pancreatic sections displayed a reduced number of bi-hormonal cells co-expressing glucagon and insulin in homozygous DBA mice, which could indicate a reduced plasticity of endocrine cells in response to hyperglycemic stress. Further generation and phenotyping of recombinant congenic mice enabled the isolation of a 3.3 Mbp fragment that was still able to induce hyperglycemia and contained 61 genes. Bioinformatic analyses including haplotype mapping, sequence and transcriptome analysis were integrated in order to further reduce the number of candidate genes and to identify the presumable causative gene variant. Four putative candidate genes (Ttc39a, Kti12, Osbpl9, Calr4) were defined, which were either differentially expressed or carried a sequence variant. In addition, in silico ChIP-Seq analyses of the 3.3 Mbp region indicated a high number of SNPs located in active regions of binding sites of β-cell transcription factors. This points towards potentially altered cis-regulatory elements that could be responsible for the phenotype conferred by the Nidd/DBA locus. In summary, the Nidd/DBA locus mediates impaired glucose homeostasis and reduced insulin secretion capacity which finally leads to β-cell death. The downregulation of cell survival genes and reduced plasticity of endocrine cells could further contribute to the β-cell loss. The critical region was narrowed down to a 3.3 Mbp fragment containing 61 genes, of which four might be involved in the development of the diabetogenic Nidd/DBA phenotype.
N2  - Die Diabetesprävalenz nimmt seit Jahren weltweit zu, wobei etwa 90% der diagnostizierten Diabeteserkrankungen einem Typ-2-Diabetes (T2D) zuzuordnen sind. T2D ist eine komplexe polygene Stoffwechselerkrankung, die auch durch epigenetische Faktoren und den Lebensstil beeinflusst wird. Die Identifizierung und Untersuchung von Diabetes-assoziierten Genen wird unter anderem durch Kopplungsanalysen und darauf aufbauende zuchtstrategische und bioinformatische Analysen ermöglicht. In einer vorangegangenen Studie wurde der schlanke, Diabetes-anfällige dilute brown non-agouti (DBA)-Mausstamm mit der adipösen und ebenfalls Diabetes-suszeptiblen New Zealand obese (NZO)-Maus verpaart und die erste Rückkreuzungsgeneration einer Kopplungsanalyse unterzogen. Hierbei wurde ein hoch signifikanter quantitative trait locus (QTL) für Diabetes auf Chromosom 4 nachgewiesen. Dieser Locus ist mit erhöhten Blutzuckerwerten, reduzierten Plasmainsulinkonzentrationen und einem niedrigen pankreatischen Insulingehalt assoziiert und wurde als Nidd/DBA (engl. für nicht insulinabhängiger Diabetes von DBA-Allelen) bezeichnet. Das Ziel der vorliegenden Arbeit war es, (i) das kritische Fragment des Nidd/DBA-Locus‘ zu verkleinern, (ii) die phänotypische Ausprägung des Nidd/DBA-Locus‘ zu untersuchen sowie (iii) die ursächliche(n) genetische(n) Variante(n) zu identifizieren. Die phänotypische Charakterisierung von kongenen Mäusen mit einem kritischen Fragment von 13.6 Mbp, welches 284 Gene enthält, zeigte bereits im Alter von 12 Wochen eine starke Hyperglykämie (~19.9 mM) und eine unzureichende Glucose-Clearance bei Nidd/DBA-Allelträgern. Ex-vivo Perifusionsversuche mit isolierten Inseln von 13 Wochen alten kongenen Mäusen zeigten eine tendenziell reduzierte Insulinsekretion in homozygoten DBA-Allelträgern. Im Alter von 16 Wochen wiesen die Tiere einen erheblichen Verlust der β-Zellen, sowie eine Abnahme der pankreatischen Insulinkonzentration auf. Transkriptomdaten der Langerhans-Inseln mit anschließender Signalweganalyse deuteten darauf hin, dass Nidd/DBA-Allelträger eine verminderte Expression von Genen aufzeigen, die für das Überleben von Zellen essentiell sind. In homozygoten DBA-Allelträgern wurde eine reduzierte Anzahl von Glucagon/Insulin-bi-hormonellen Zellen nachgewiesen, was auf eine verminderte Plastizität der endokrinen Zellen hinweisen könnte. Die Zucht weiterer kongener Mäuse und ihre Phänotypisierung ermöglichten die Isolierung eines 3.3 Mbp großen Fragments, das 61 Gene enthielt und eine Hyperglykämie auslöste. Bioinformatische Analysen, wie die Kartierung von Haplotypen und Datenbank-, Sequenz- sowie Transkriptomanalysen, wurden integriert, um die Anzahl der Kandidatengene weiter zu reduzieren und die Hyperglykämie auslösende(n) Genvariante(n) zu identifizieren. Es konnten vier potentielle Kandidatengene (Ttc39a, Osbpl9, Kti12, Calr4) definiert werden, die entweder eine differenzielle Expression oder eine Sequenzvariante aufwiesen. Mit Hilfe von in-silico-Analysen von ChIP-Seq-Daten wurden SNPs in aktiven Bindungsstellen von β-Zell-Transkriptionsfaktoren identifiziert. Diese könnten cis-regulatorische Elemente darstellen, die Gene außerhalb dieses 3.3 Mbp großen Fragments beeinflussen und möglichweise für den Phänotyp verantwortlich sind. Zusammenfassend konnte gezeigt werden, dass der Nidd/DBA-Locus für eine beeinträchtigte Glucosehomöostase und eine Verschlechterung der Insulinsekretion verantwortlich ist, welche langfristig zum Verlust von β-Zellen führen. Die bisherigen Ergebnisse deuten darauf hin, dass sowohl die verringerte Expression der für das Zellüberleben essentiellen Gene als auch eine verringerte Plastizität der endokrinen Zellen zum Untergang von Langerhans-Inseln beitragen. Das kritische Fragment wurde auf eine Größe von 3.3 Mbp mit 61 Genen reduziert, von denen vier Gene als verantwortliche Kandidaten für den beschriebenen Nidd/DBA-Phänotyp bedeutsam sein können
KW  - Diabetes
KW  - Genetics
KW  - Glucose intolerance
KW  - Insulin secretion
KW  - Susceptibility-genes
KW  - Diabetes
KW  - Genetik
KW  - Glukoseintoleranz
KW  - Insulinsekretion
KW  - Suszeptibilitätsgene
Y1  - 2021
ER  - 
TY  - THES
A1  - Alfine, Eugenia
T1  - Investigation of Sirtuin 3 overexpression as a genetic model of fasting in hypothalamic neurons
Y1  - 2021
ER  - 
TY  - THES
A1  - Mancini, Carola
T1  - Analysis of the effects of age-related changes of metabolic flux on brown adipocyte formation and function
N2  - Brown adipose tissue (BAT) is responsible for non-shivering thermogenesis, thereby allowing mammals to maintain a constant body temperature in a cold environment. Thermogenic capacity of this tissue is due to a high mitochondrial density and expression of uncoupling protein 1 (UCP1), a unique brown adipocyte marker which dissipates the mitochondrial proton gradient to produce heat instead of ATP. BAT is actively involved in whole-body metabolic homeostasis and during aging there is a loss of classical brown adipose tissue with concomitantly reduced browning capacity of white adipose tissue. Therefore, an age-dependent decrease of BAT-related energy expenditure capacity may exacerbate the development of metabolic diseases, including obesity and type 2 diabetes mellitus. Given that direct effects of age-related changes of BAT-metabolic flux have yet to be unraveled, the aim of the current thesis is to investigate potential metabolic mechanisms involved in BAT-dysfunction during aging and to identify suitable metabolic candidates as functional biomarkers of BAT-aging. To this aim, integration of transcriptomic, metabolomic and proteomic data analyses of BAT from young and aged mice was performed, and a group of candidates with age-related changes was revealed. Metabolomic analysis showed age-dependent alterations of metabolic intermediates involved in energy, nucleotide and vitamin metabolism, with major alterations regarding the purine nucleotide pool. These data suggest a potential role of nucleotide intermediates in age-related BAT defects. In addition, the screening of transcriptomic and proteomic data sets from BAT of young and aged mice allowed identification of a 60-kDa lysophospholipase, also known as L-asparaginase (Aspg), whose expression declines during BAT-aging. Involvement of Aspg in brown adipocyte thermogenic function was subsequently analyzed at the molecular level using in vitro approaches and animal models. The findings revealed sensitivity of Aspg expression to β3-adrenergic activation via different metabolic cues, including cold exposure and treatment with β3-adrenergic agonist CL. To further examine ASPG function in BAT, an over-expression model of Aspg in a brown adipocyte cell line was established and showed that these cells were metabolically more active compared to controls, revealing increased expression of the main brown-adipocyte specific marker UCP1, as well as higher lipolysis rates. An in vitro loss-of-function model of Aspg was also functionally analyzed, revealing reduced brown adipogenic characteristics and an impaired lipolysis, thus confirming physiological relevance of Aspg in brown adipocyte function. Characterization of a transgenic mouse model with whole-body inactivation of the Aspg gene (Aspg-KO) allowed investigation of the role of ASPG under in vivo conditions, indicating a mild obesogenic phenotype, hypertrophic white adipocytes, impairment of the early thermogenic response upon cold-stimulation and dysfunctional insulin sensitivity. Taken together, these data show that ASPG may represent a new functional biomarker of BAT-aging that regulates thermogenesis and therefore a potential target for the treatment of age-related metabolic disease.
KW  - adipose tissue
KW  - aging
KW  - nutrients
KW  - metabolism
KW  - Fettgewebe
KW  - Alterung
KW  - Stoffwechsel
KW  - Nährstoffe
Y1  - 2021
U6  - https://doi.org/10.25932/publishup-51266
ER  - 
TY  - JOUR
A1  - Jannasch, Franziska
A1  - Nickel, Daniela
A1  - Schulze, Matthias Bernd
T1  - The reliability and relative validity of predefined dietary patterns were higher than that of exploratory dietary patterns in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam population
JF  - British journal of nutrition : BJN : an international journal of nutritional science / published on behalf of The Nutrition Society
N2  - The aim of this study was to assess the ability of the FFQ to describe reliable and valid dietary pattern (DP) scores. In a total of 134 participants of the European Prospective Investigation into Cancer and Nutrition-Potsdam study aged 35-67 years, the FFQ was applied twice (baseline and after 1 year) to assess its reliability. Between November 1995 and March 1997, twelve 24-h dietary recalls (24HDR) as reference instrument were applied to assess the validity of the FFQ. Exploratory DP were derived by principal component analyses. Investigated predefined DP were the Alternative Healthy Eating Index (AHEI) and two Mediterranean diet indices. From dietary data of each FFQ, two exploratory DP were retained, but differed in highly loading food groups, resulting in moderate correlations (r 0 center dot 45-0 center dot 58). The predefined indices showed higher correlations between the FFQ (r(AHEI) 0 center dot 62, r(Mediterranean Diet Pyramid Index (MedPyr)) 0 center dot 62 and r(traditional Mediterranean Diet Score (tMDS)) 0 center dot 51). From 24HDR dietary data, one exploratory DP retained differed in composition to the first FFQ-based DP, but showed similarities to the second DP, reflected by a good correlation (r 0 center dot 70). The predefined DP correlated moderately (r 0 center dot 40-0 center dot 60). To conclude, long-term analyses on exploratory DP should be interpreted with caution, due to only moderate reliability. The validity differed extensively for the two exploratory DP. The investigated predefined DP showed a better reliability and a moderate validity, comparable to other studies. Within the two Mediterranean diet indices, the MedPyr performed better than the tMDs in this middle-aged, semi-urban German study population.
KW  - dietary patterns
KW  - reliability
KW  - validity
Y1  - 2020
U6  - https://doi.org/10.1017/S0007114520003517
SN  - 1475-2662
SN  - 0007-1145
VL  - 125
IS  - 11
SP  - 1270
EP  - 1280
PB  - Cambridge University Press
CY  - Cambridge
ER  - 
TY  - GEN
A1  - Perez-Cornago, Aurora
A1  - Crowe, Francesca L.
A1  - Appleby, Paul N.
A1  - Bradbury, Kathryn E.
A1  - Wood, Angela M.
A1  - Jakobsen, Marianne Uhre
A1  - Johnson, Laura
A1  - Sacerdote, Carlotta
A1  - Steur, Marinka
A1  - Weiderpass, Elisabete
A1  - Wurtz, Anne Mette L.
A1  - Kuhn, Tilman
A1  - Katzke, Verena
A1  - Trichopoulou, Antonia
A1  - Karakatsani, Anna
A1  - La Vecchia, Carlo
A1  - Masala, Giovanna
A1  - Tumino, Rosario
A1  - Panico, Salvatore
A1  - Sluijs, Ivonne
A1  - Skeie, Guri
A1  - Imaz, Liher
A1  - Petrova, Dafina
A1  - Quiros, J. Ramon
A1  - Yohar, Sandra Milena Colorado
A1  - Jakszyn, Paula
A1  - Melander, Olle
A1  - Sonestedt, Emily
A1  - Andersson, Jonas
A1  - Wennberg, Maria
A1  - Aune, Dagfinn
A1  - Riboli, Elio
A1  - Schulze, Matthias Bernd
A1  - di Angelantonio, Emanuele
A1  - Wareham, Nicholas J.
A1  - Danesh, John
A1  - Forouhi, Nita G.
A1  - Butterworth, Adam S.
A1  - Key, Timothy J.
T1  - Plant foods, dietary fibre and risk of ischaemic heart disease in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Background:
Epidemiological evidence indicates that diets rich in plant foods are associated with a lower risk of ischaemic heart disease (IHD), but there is sparse information on fruit and vegetable subtypes and sources of dietary fibre. This study examined the associations of major plant foods, their subtypes and dietary fibre with risk of IHD in the European Prospective Investigation into Cancer and Nutrition (EPIC). 

Methods:
We conducted a prospective analysis of 490 311 men and women without a history of myocardial infarction or stroke at recruitment (12.6 years of follow-up, n cases = 8504), in 10 European countries. Dietary intake was assessed using validated questionnaires, calibrated with 24-h recalls. Multivariable Cox regressions were used to estimate hazard ratios (HR) of IHD. 

Results: 
There was a lower risk of IHD with a higher intake of fruit and vegetables combined [HR per 200 g/day higher intake 0.94, 95% confidence interval (CI): 0.90-0.99, P-trend = 0.009], and with total fruits (per 100 g/day 0.97, 0.95-1.00, P-trend = 0.021). There was no evidence for a reduced risk for fruit subtypes, except for bananas. Risk was lower with higher intakes of nuts and seeds (per 10 g/day 0.90, 0.82-0.98, Ptrend = 0.020), total fibre (per 10 g/day 0.91, 0.85-0.98, P-trend = 0.015), fruit and vegetable fibre (per 4 g/day 0.95, 0.91-0.99, P-trend = 0.022) and fruit fibre (per 2 g/day 0.97, 0.95-1.00, P-trend = 0.045). No associations were observed between vegetables, vegetables subtypes, legumes, cereals and IHD risk. 

Conclusions:
In this large prospective study, we found some small inverse associations between plant foods and IHD risk, with fruit and vegetables combined being the most strongly inversely associated with risk. Whether these small associations are causal remains unclear.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1367 
KW  - fruit
KW  - vegetables
KW  - legumes
KW  - nuts
KW  - seeds
KW  - coronary heart disease
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-560340
SN  - 1866-8372
IS  - 1
ER  - 
TY  - JOUR
A1  - Perez-Cornago, Aurora
A1  - Crowe, Francesca L.
A1  - Appleby, Paul N.
A1  - Bradbury, Kathryn E.
A1  - Wood, Angela M.
A1  - Jakobsen, Marianne Uhre
A1  - Johnson, Laura
A1  - Sacerdote, Carlotta
A1  - Steur, Marinka
A1  - Weiderpass, Elisabete
A1  - Wurtz, Anne Mette L.
A1  - Kuhn, Tilman
A1  - Katzke, Verena
A1  - Trichopoulou, Antonia
A1  - Karakatsani, Anna
A1  - La Vecchia, Carlo
A1  - Masala, Giovanna
A1  - Tumino, Rosario
A1  - Panico, Salvatore
A1  - Sluijs, Ivonne
A1  - Skeie, Guri
A1  - Imaz, Liher
A1  - Petrova, Dafina
A1  - Quiros, J. Ramon
A1  - Yohar, Sandra Milena Colorado
A1  - Jakszyn, Paula
A1  - Melander, Olle
A1  - Sonestedt, Emily
A1  - Andersson, Jonas
A1  - Wennberg, Maria
A1  - Aune, Dagfinn
A1  - Riboli, Elio
A1  - Schulze, Matthias Bernd
A1  - di Angelantonio, Emanuele
A1  - Wareham, Nicholas J.
A1  - Danesh, John
A1  - Forouhi, Nita G.
A1  - Butterworth, Adam S.
A1  - Key, Timothy J.
T1  - Plant foods, dietary fibre and risk of ischaemic heart disease in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
JF  - International journal of epidemiology
N2  - Background:
Epidemiological evidence indicates that diets rich in plant foods are associated with a lower risk of ischaemic heart disease (IHD), but there is sparse information on fruit and vegetable subtypes and sources of dietary fibre. This study examined the associations of major plant foods, their subtypes and dietary fibre with risk of IHD in the European Prospective Investigation into Cancer and Nutrition (EPIC). 

Methods:
We conducted a prospective analysis of 490 311 men and women without a history of myocardial infarction or stroke at recruitment (12.6 years of follow-up, n cases = 8504), in 10 European countries. Dietary intake was assessed using validated questionnaires, calibrated with 24-h recalls. Multivariable Cox regressions were used to estimate hazard ratios (HR) of IHD. 

Results: 
There was a lower risk of IHD with a higher intake of fruit and vegetables combined [HR per 200 g/day higher intake 0.94, 95% confidence interval (CI): 0.90-0.99, P-trend = 0.009], and with total fruits (per 100 g/day 0.97, 0.95-1.00, P-trend = 0.021). There was no evidence for a reduced risk for fruit subtypes, except for bananas. Risk was lower with higher intakes of nuts and seeds (per 10 g/day 0.90, 0.82-0.98, Ptrend = 0.020), total fibre (per 10 g/day 0.91, 0.85-0.98, P-trend = 0.015), fruit and vegetable fibre (per 4 g/day 0.95, 0.91-0.99, P-trend = 0.022) and fruit fibre (per 2 g/day 0.97, 0.95-1.00, P-trend = 0.045). No associations were observed between vegetables, vegetables subtypes, legumes, cereals and IHD risk. 

Conclusions:
In this large prospective study, we found some small inverse associations between plant foods and IHD risk, with fruit and vegetables combined being the most strongly inversely associated with risk. Whether these small associations are causal remains unclear.
KW  - fruit
KW  - vegetables
KW  - legumes
KW  - nuts
KW  - seeds
KW  - coronary heart disease
Y1  - 2021
U6  - https://doi.org/10.1093/ije/dyaa155
SN  - 0300-5771
SN  - 1464-3685
VL  - 50
IS  - 1
SP  - 212
EP  - 222
PB  - Oxford Univ. Press
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Beckmann, Nadine
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Gulbins, Erich
A1  - Nomellini, Vanessa
A1  - Caldwell, Charles C.
T1  - Burn injury impairs neutrophil chemotaxis through increased ceramide
JF  - Shock : injury, inflammation, and sepsis, laboratory and clinical approaches
N2  - Infection is a common and often deadly complication after burn injury. A major underlying factor is burn-induced immune dysfunction, particularly with respect to neutrophils as the primary responders to infection. Temporally after murine scald injury, we demonstrate impaired bone marrow neutrophil chemotaxis toward CXCL1 ex vivo. Additionally, we observed a reduced recruitment of neutrophils to the peritoneal after elicitation 7 days after injury. We demonstrate that neutrophil ceramide levels increase after burn injury, and this is associated with decreased expression of CXCR2 and blunted chemotaxis. A major signaling event upon CXCR2 activation is Akt phosphorylation and this was reduced when ceramide was elevated. In contrast, PTEN levels were elevated and PTEN-inhibition elevated phospho-Akt levels and mitigated the burn-induced neutrophil chemotaxis defect. Altogether, this study identifies a newly described pathway of ceramide-mediated suppression of neutrophil chemotaxis after burn injury and introduces potential targets to mitigate this defect and reduce infection-related morbidity and mortality after burn.
KW  - Acid sphingomyelinase
KW  - Akt
KW  - burn injury
KW  - ceramide
KW  - CXCR2
KW  - immune
KW  - dysfunction
KW  - neutrophil chemotaxis
KW  - PTEN
Y1  - 2021
U6  - https://doi.org/10.1097/SHK.0000000000001693
SN  - 1073-2322
SN  - 1540-0514
VL  - 56
IS  - 1
SP  - 125
EP  - 132
PB  - Lippincott Williams & Wilkins
CY  - Hagerstown, Md.
ER  - 
TY  - THES
A1  - Ziemann, Vanessa
T1  - Toxische Effekte von Arsenolipiden in humanen Kulturzellen und Caenorhabditis elegans
Y1  - 2020
ER  - 
TY  - JOUR
A1  - Figueroa Campos, Gustavo A.
A1  - Sagu Tchewonpi, Sorel
A1  - Saravia Celis, Pedro
A1  - Rawel, Harshadrai Manilal
T1  - Comparison of batch and continuous wet-processing of coffee
BT  - changes in the main compounds in beans, by-products and wastewater
JF  - Foods
N2  - Many technical challenges still need to be overcome to improve the quality of the green coffee beans. In this work, the wet Arabica coffee processing in batch and continuous modus were investigated. Coffee beans samples as well as by-products and wastewaters collected at different production steps were analyzed in terms of their content in total phenols, antioxidant capacity, caffeine content, organic acids, reducing sugars, free amino group and protein content. The results showed that 40% of caffeine was removed with pulp. Green coffee beans showed highest concentration of organic acids and sucrose (4.96 ± 0.25 and 5.07 ± 0.39 g/100 g DW for the batch and continuous processing). Batch green coffee beans contained higher amount of phenols. 5-caffeoylquinic Acid (5-CQA) was the main constituent (67.1 and 66.0% for the batch and continuous processing, respectively). Protein content was 15 and 13% in the green coffee bean in batch and continuous processing, respectively. A decrease of 50 to 64% for free amino groups during processing was observed resulting in final amounts of 0.8 to 1.4% in the processed beans. Finally, the batch processing still revealed by-products and wastewater with high nutrient content encouraging a better concept for valorization.
KW  - Arabica coffee beans
KW  - coffee by-products
KW  - batch process
KW  - continuous process
KW  - nutritional characteristics
Y1  - 2020
U6  - https://doi.org/10.3390/foods9081135
SN  - 2304-8158
VL  - 9
IS  - 8
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Jonas, Wenke
A1  - Schürmann, Annette
T1  - Genetic and epigenetic factors determining NAFLD risk
JF  - Molecular metabolism
N2  - Background: Hepatic steatosis is a common chronic liver disease that can progress into more severe stages of NAFLD or promote the development of life-threatening secondary diseases for some of those affected. These include the liver itself (nonalcoholic steatohepatitis or NASH; fibrosis and cirrhosis, and hepatocellular carcinoma) or other organs such as the vessels and the heart (cardiovascular disease) or the islets of Langerhans (type 2 diabetes). In addition to elevated caloric intake and a sedentary lifestyle, genetic and epigenetic predisposition contribute to the development of NAFLD and the secondary diseases. Scope of review: We present data from genome-wide association studies (GWAS) and functional studies in rodents which describe polymorphisms identified in genes relevant for the disease as well as changes caused by altered DNA methylation and gene regulation via specific miRNAs. The review also provides information on the current status of the use of genetic and epigenetic factors as risk markers. Major conclusion: With our overview we provide an insight into the genetic and epigenetic landscape of NAFLD and argue about the applicability of currently defined risk scores for risk stratification and conclude that further efforts are needed to make the scores more usable and meaningful.
KW  - NAFLD
KW  - genetic variants
KW  - epigenetics
KW  - risk score
Y1  - 2020
U6  - https://doi.org/10.1016/j.molmet.2020.101111
SN  - 2212-8778
VL  - 50
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - THES
A1  - Finke, Hannah
T1  - Toxicological Characterization of Arsenolipids in vitro and Analysis of Global DNA (Hydroxy)methylation in the Context of Aging, Trace Element Status, and Genomic Stability
Y1  - 2020
ER  - 
TY  - JOUR
A1  - Zhou, Suqiong
A1  - Pan, Yuanwei
A1  - Zhang, Jianguang
A1  - Li, Yan
A1  - Neumann, Falko
A1  - Schwerdtle, Tanja
A1  - Li, Wenzhong
A1  - Haag, Rainer
T1  - Dendritic polyglycerol-conjugated gold nanostars with different densities of functional groups to regulate osteogenesis in human mesenchymal stem cells
JF  - Nanoscale
N2  - Nanomaterials play an important role in mimicking the biochemical and biophysical cues of the extracellular matrix in human mesenchymal stem cells (MSCs). Increasing studies have demonstrated the crucial impact of functional groups on MSCs, while limited research is available on how the functional group's density on nanoparticles regulates MSC behavior. Herein, the effects of dendritic polyglycerol (dPG)-conjugated gold nanostars (GNSs) with different densities of functional groups on the osteogenesis of MSCs are systematically investigated. dPG@GNS nanocomposites have good biocompatibility and the uptake by MSCs is in a functional group density-dependent manner. The osteogenic differentiation of MSCs is promoted by all dPG@GNS nanocomposites, in terms of alkaline phosphatase activity, calcium deposition, and expression of osteogenic protein and genes. Interestingly, the dPGOH@GNSs exhibit a slight upregulation in the expression of osteogenic markers, while the different charged densities of sulfate and amino groups show more efficacy in the promotion of osteogenesis. Meanwhile, the sulfated nanostars dPGS20@GNSs show the highest enhancement. Furthermore, various dPG@GNS nanocomposites exerted their effects by regulating the activation of Yes-associated protein (YAP) to affect osteogenic differentiation. These results indicate that dPG@GNS nanocomposites have functional group density-dependent influence on the osteogenesis of MSCs, which may provide a new insight into regulating stem cell fate.
Y1  - 2020
U6  - https://doi.org/10.1039/d0nr06570f
SN  - 2040-3364
SN  - 2040-3372
VL  - 12
IS  - 47
SP  - 24006
EP  - 24019
PB  - Royal Society of Chemistry
CY  - Cambridge
ER  - 
TY  - JOUR
A1  - Bußler, Sara
A1  - Rawel, Harshadrai Manilal
A1  - Schlüter, Oliver K.
T1  - Impact of plasma processed air (PPA) on phenolic model systems
BT  - suggested mechanisms and relevance for food applications
JF  - Innovative food science & emerging technologies : the official journal of the European Federation of Food Science and Technology
N2  - Cold plasma is considered to be a novel, non-thermal, chemical-free and eco-friendly disinfection and surface modification technology. Plasma treatment of air to generate the so called plasma processed air (PPA) induces the formation of reactive oxygen (ROS) and nitrogen species (RNS). As a result, PPA has a different chemical composition compared to untreated air and suits therefore as an alternative method for microbial disinfection. However, depending on the product properties of the food matrix and its composition, a number of plasmainduced reactions also need to be taken into consideration. 
This necessitates also the elucidation and understanding of the basic interactions of plasma species with bioactive compounds. The intention here is to avoid the degradation of these valuable substances and to prevent other undesirable effects in future food related applications.
In the present study, the effects of PPA treatment on selected antioxidants such as pyrocatechol and derivatives of hydroxycinnimic acid were investigated in model systems to specify possible reactions induced. Antioxidant capacity, pH value, UV-Vis spectroscopy, RP-HPLC and LC-MS analysis were applied to identify reaction products providing information on possible changes induced in food matrices by PPA treatment. 
Exposure to PPA caused a perceptible color change towards yellow-brown accompanied by a strong reduction of the pH and the formation of insoluble sediments in the model solutions. The accumulation of nitrate, nitrite, but not of hydrogen peroxide was shown. LC-MS analysis demonstrated the formation of plasma-modified derivatives in all tested systems. The main reactions in liquid model solutions exposed to PPA were attributed to oxidation, nitration and polymerization of the phenolic compounds.
KW  - cold atmospheric pressure plasma
KW  - reactive oxygen and nitrogen species
KW  - food safety
KW  - antioxidative phenolic ingredients
KW  - phenol oxidation
KW  - phenol nitration
KW  - plasma process indicators
Y1  - 2020
U6  - https://doi.org/10.1016/j.ifset.2020.102432
SN  - 1466-8564
SN  - 1878-5522
VL  - 64
PB  - Elsevier
CY  - Oxford
ER  - 
TY  - GEN
A1  - Müller, Sandra
A1  - Dawczynski, Christine
A1  - Wiest, Johanna
A1  - Lorkowski, Stefan
A1  - Kipp, Anna Patricia
A1  - Schwerdtle, Tanja
T1  - Functional Biomarkers for the Selenium Status in a Human Nutritional Intervention Study
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Soils in Germany are commonly low in selenium; consequently, a sufficient dietary supply is not always ensured. The extent of such provision adequacy is estimated by the optimal effect range of biomarkers, which often reflects the physiological requirement. Preceding epidemiological studies indicate that low selenium serum concentrations could be related to cardiovascular diseases. Inter alia, risk factors for cardiovascular diseases are physical inactivity, overweight, as well as disadvantageous eating habits. In order to assess whether these risk factors can be modulated, a cardio-protective diet comprising fixed menu plans combined with physical exercise was applied in the German MoKaRi (modulation of cardiovascular risk factors) intervention study. We analyzed serum samples of the MoKaRi cohort (51 participants) for total selenium, GPx activity, and selenoprotein P at different timepoints of the study (0, 10, 20, 40 weeks) to explore the suitability of these selenium-associated markers as indicators of selenium status. Overall, the time-dependent fluctuations in serum selenium concentration suggest a successful change in nutritional and lifestyle behavior. Compared to baseline, a pronounced increase in GPx activity and selenoprotein P was observed, while serum selenium decreased in participants with initially adequate serum selenium content. SELENOP concentration showed a moderate positive monotonic correlation (r = 0.467, p < 0.0001) to total Se concentration, while only a weak linear relationship was observed for GPx activity versus total Se concentration (r = 0.186, p = 0.021). Evidently, other factors apart from the available Se pool must have an impact on the GPx activity, leading to the conclusion that, without having identified these factors, GPx activity should not be used as a status marker for Se
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 878 
KW  - Se
KW  - selenoprotein P
KW  - GPx activity
KW  - cardiovascular disease
KW  - status markers
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-460115
SN  - 1866-8372
IS  - 878
ER  - 
TY  - GEN
A1  - Witt, Barbara
A1  - Schaumlöffel, Dirk
A1  - Schaumlöffel, Dirk
A1  - Schwerdtle, Tanja
T1  - Subcellular Localization of Copper
BT  - Cellular Bioimaging with Focus on Neurological Disorders
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - As an essential trace element, copper plays a pivotal role in physiological body functions. In fact, dysregulated copper homeostasis has been clearly linked to neurological disorders including Wilson and Alzheimer’s disease. Such neurodegenerative diseases are associated with progressive loss of neurons and thus impaired brain functions. However, the underlying mechanisms are not fully understood. Characterization of the element species and their subcellular localization is of great importance to uncover cellular mechanisms. Recent research activities focus on the question of how copper contributes to the pathological findings. Cellular bioimaging of copper is an essential key to accomplish this objective. Besides information on the spatial distribution and chemical properties of copper, other essential trace elements can be localized in parallel. Highly sensitive and high spatial resolution techniques such as LA-ICP-MS, TEM-EDS, S-XRF and NanoSIMS are required for elemental mapping on subcellular level. This review summarizes state-of-the-art techniques in the field of bioimaging. Their strengths and limitations will be discussed with particular focus on potential applications for the elucidation of copper-related diseases. Based on such investigations, further information on cellular processes and mechanisms can be derived under physiological and pathological conditions. Bioimaging studies might enable the clarification of the role of copper in the context of neurodegenerative diseases and provide an important basis to develop therapeutic strategies for reduction or even prevention of copper-related disorders and their pathological consequences.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 862 
KW  - copper
KW  - cellular bioimaging
KW  - neurodegenerative diseases
KW  - copper-related disorders
KW  - SIMS techniques
KW  - TEM
KW  - S-XRF
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-459544
SN  - 1866-8372
IS  - 862
ER  - 
TY  - JOUR
A1  - Bishop, Christopher Allen
A1  - Schulze, Matthias Bernd
A1  - Klaus, Susanne
A1  - Weitkunat, Karolin
T1  - The branched-chain amino acids valine and leucine have differential effects on hepatic lipid metabolism
JF  - The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology
N2  - Dairy intake, as a source of branched-chain amino acids (BCAA), has been linked to a lower incidence of type-2-diabetes and increased circulating odd-chain fatty acids (OCFA). To understand this connection, we aimed to investigate differences in BCAA metabolism of leucine and valine, a possible source of OCFA, and their role in hepatic metabolism. Male mice were fed a high-fat diet supplemented with leucine and valine for 1 week and phenotypically characterized with a focus on lipid metabolism. Mouse primary hepatocytes were treated with the BCAA or a Ppar alpha activator WY-14643 to systematically examine direct hepatic effects and their mechanisms. Here, we show that only valine supplementation was able to increase hepatic and circulating OCFA levels via two pathways; a PPAR alpha-dependent induction of alpha-oxidation and an increased supply of propionyl-CoA for de novo lipogenesis. Meanwhile, we were able to confirm leucine-mediated effects on the inhibition of food intake and transport of fatty acids, as well as induction of S6 ribosomal protein phosphorylation. Taken together, these data illustrate differential roles of the BCAA in lipid metabolism and provide preliminary evidence that exclusively valine contributes to the endogenous formation of OCFA which is important for a better understanding of these metabolites in metabolic health.
KW  - fatty acid metabolism
KW  - leucine
KW  - liver
KW  - OCFA
KW  - valine
Y1  - 2020
U6  - https://doi.org/10.1096/fj.202000195R
SN  - 0892-6638
SN  - 1530-6860
VL  - 34
IS  - 7
SP  - 9727
EP  - 9739
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - GEN
A1  - Schenke, Maren
A1  - Schjeide, Brit-Maren
A1  - Püschel, Gerhard Paul
A1  - Seeger, Bettina
T1  - Analysis of motor neurons differentiated from human induced pluripotent stem cells for the use in cell-based Botulinum neurotoxin activity assays
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Botulinum neurotoxins (BoNTs) are potent neurotoxins produced by bacteria, which inhibit neurotransmitter release, specifically in their physiological target known as motor neurons (MNs). For the potency assessment of BoNTs produced for treatment in traditional and aesthetic medicine, the mouse lethality assay is still used by the majority of manufacturers, which is ethically questionable in terms of the 3Rs principle. In this study, MNs were differentiated from human induced pluripotent stem cells based on three published protocols. The resulting cell populations were analyzed for their MN yield and their suitability for the potency assessment of BoNTs. MNs produce specific gangliosides and synaptic proteins, which are bound by BoNTs in order to be taken up by receptor-mediated endocytosis, which is followed by cleavage of specific soluble N-ethylmaleimide-sensitive-factor attachment receptor (SNARE) proteins required for neurotransmitter release. The presence of receptors and substrates for all BoNT serotypes was demonstrated in MNs generated in vitro. In particular, the MN differentiation protocol based on Du et al. yielded high numbers of MNs in a short amount of time with high expression of BoNT receptors and targets. The resulting cells are more sensitive to BoNT/A1 than the commonly used neuroblastoma cell line SiMa. MNs are, therefore, an ideal tool for being combined with already established detection methods.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1083 
KW  - Botulinum neurotoxin
KW  - motor neurons
KW  - cell-based in vitro assay
KW  - potency assessment
KW  - induced pluripotent stem cells
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-472071
SN  - 1866-8372
IS  - 1083
ER  - 
TY  - JOUR
A1  - Boekstegers, Felix
A1  - Marcelain, Katherine
A1  - Barahona Ponce, Carol
A1  - Baez Benavides, Pablo F.
A1  - Müller, Bettina
A1  - de Toro, Gonzalo
A1  - Retamales, Javier
A1  - Barajas, Olga
A1  - Ahumada, Monica
A1  - Aleksandrova, Krasimira
A1  - Bermejo, Justo Lorenzo
T1  - ABCB1/4 gallbladder cancer risk variants identified in India also show strong effects in Chileans
JF  - Cancer Epidemiology
N2  - Background: The first large-scale genome-wide association study of gallbladder cancer (GBC) recently identified and validated three susceptibility variants in the ABCB1 and ABCB4 genes for individuals of Indian descent. We investigated whether these variants were also associated with GBC risk in Chileans, who show the highest incidence of GBC worldwide, and in Europeans with a low GBC incidence.
Methods: This population-based study analysed genotype data from retrospective Chilean case-control (255 cases, 2042 controls) and prospective European cohort (108 cases, 181 controls) samples consistently with the original publication.
Results: Our results confirmed the reported associations for Chileans with similar risk effects. Particularly strong associations (per-allele odds ratios close to 2) were observed for Chileans with high Native American (=Mapuche) ancestry. No associations were noticed for Europeans, but the statistical power was low.
Conclusion: Taking full advantage of genetic and ethnic differences in GBC risk may improve the efficiency of current prevention programs.
KW  - cancer epidemiology
KW  - gallbladder cancer
KW  - native American ancestry
KW  - population-specific risk marker
Y1  - 2020
VL  - 65
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Li, Chen
A1  - Stoma, Svetlana
A1  - Lotta, Luca A.
A1  - Warner, Sophie
A1  - Albrecht, Eva
A1  - Allione, Alessandra
A1  - Arp, Pascal P.
A1  - Broer, Linda
A1  - Buxton, Jessica L.
A1  - Boeing, Heiner
A1  - Langenberg, Claudia
A1  - Codd, Veryan
T1  - Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length
JF  - American Journal of Human Genetics
N2  - Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1 , PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
KW  - Mendelian randomization
KW  - risk
KW  - variants
KW  - disease
KW  - cancer
KW  - loci
KW  - database
KW  - genes
KW  - heart
KW  - gwas
Y1  - 2019
VL  - 106
IS  - 3
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Christakoudi, Sofa
A1  - Tsilidis, Konstantinos K.
A1  - Muller, David C.
A1  - Freisling, Heinz
A1  - Weiderpass, Elisabete
A1  - Overvad, Kim
A1  - Söderberg, Stefan
A1  - Häggström, Christel
A1  - Pischon, Tobias
A1  - Dahm, Christina C.
A1  - Zhang, Jie
A1  - Tjønneland, Anne
A1  - Schulze, Matthias Bernd
T1  - A Body Shape Index (ABSI) achieves better mortality risk stratification than alternative indices of abdominal obesity: results from a large European cohort
JF  - Scientific Reports
N2  - 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.
KW  - all-cause mortality
KW  - anthropometric measures
KW  - mass index
KW  - overweight
KW  - cancer
KW  - prediction
KW  - adiposity
KW  - size
Y1  - 2020
VL  - 10
IS  - 1
PB  - Springer Nature
CY  - Berlin
ER  - 
TY  - THES
A1  - Henkel-Oberländer, Janin
T1  - Einfluss von Prostaglandin E2 auf die Entstehung von Insulinresistenz und die Regulation der Entzündungsantwort bei der Diät-induzierten nicht-alkoholischen Fettlebererkrankung
N2  - Weltweit sind fast 40 % der Bevölkerung übergewichtig und die Prävalenz von Adipositas, Insulinresistenz und den resultierenden Folgeerkrankungen wie dem Metabolischen Syndrom und Typ-2-Diabetes steigt rapide an. Als häufigste Ursachen werden diätetisches Fehlverhalten und mangelnde Bewegung angesehen. Die nicht-alkoholische Fettlebererkrankung (NAFLD), deren Hauptcharakteristikum die exzessive Akkumulation von Lipiden in der Leber ist, korreliert mit dem Body Mass Index (BMI). NAFLD wird als hepatische Manifestation des Metabolischen Syndroms angesehen und ist inzwischen die häufigste Ursache für Leberfunktionsstörungen. Die Erkrankung umfasst sowohl die benigne hepatische Steatose (Fettleber) als auch die progressive Form der nicht-alkoholischen Steatohepatitis (NASH), bei der die Steatose von Entzündung und Fibrose begleitet ist. Die Ausbildung einer NASH erhöht das Risiko, ein hepatozelluläres Karzinom (HCC) zu entwickeln und kann zu irreversibler Leberzirrhose und terminalem Organversagen führen. Nahrungsbestandteile wie Cholesterol und Fett-reiche Diäten werden als mögliche Faktoren diskutiert, die den Übergang einer einfachen Fettleber zur schweren Verlaufsform der Steatohepatitis / NASH begünstigen. Eine Ausdehnung des Fettgewebes wird von Insulinresistenz und einer niedrig-gradigen chronischen Entzündung des Fettgewebes begleitet. Neben Endotoxinen aus dem Darm gelangen Entzündungsmediatoren aus dem Fettgewebe zur Leber. Als Folge werden residente Makrophagen der Leber, die Kupfferzellen, aktiviert, die eine Entzündungsantwort initiieren und weitere pro-inflammatorische Mediatoren freisetzen, zu denen Chemokine, Cytokine und Prostanoide wie Prostaglandin E2 (PGE2) gehören. In dieser Arbeit soll aufgeklärt werden, welchen Beitrag PGE2 an der Ausbildung von Insulinresistenz, hepatischer Steatose und Entzündung im Rahmen von Diät-induzierter NASH im komplexen Zusammenspiel mit der Regulation der Cytokin-Produktion und anderen Co-Faktoren wie Hyperinsulinämie und Hyperlipidämie hat. In murinen und humanen Makrophagen-Populationen wurde untersucht, welche Faktoren die Bildung von PGE2 fördern und wie PGE2 die Entzündungsantwort aktivierter Makrophagen reguliert. In primären Hepatozyten der Ratte sowie in isolierten humanen Hepatozyten und Zelllinien wurde der Einfluss von PGE2 allein und in Kombination mit Cytokinen, deren Bildung durch PGE2 beeinflusst werden kann, auf die Insulin-abhängige Regulation des Glucose- und Lipid-stoffwechsels untersucht. Um den Einfluss von PGE2 im komplexen Zusammenspiel der Zelltypen in der Leber und im Gesamtorganismus zu erfassen, wurden Mäuse, in denen die PGE2-Synthese durch die Deletion der mikrosomalen PGE-Synthase 1 (mPGES1) vermindert war, mit einer NASH-induzierenden Diät gefüttert. In Lebern von Patienten mit NASH oder in Mäusen mit Diät-induzierter NASH war die Expression der PGE2-synthetisierenden Enzyme Cyclooxygenase 2 (COX2) und mPGES1 sowie die Bildung von PGE2 im Vergleich zu gesunden Kontrollen gesteigert und korrelierte mit dem Schweregrad der Lebererkrankung. In primären Makrophagen aus den Spezies Mensch, Maus und Ratte sowie in humanen Makrophagen-Zelllinien war die Bildung pro-inflammatorischer Mediatoren wie Chemokinen, Cytokinen und Prostaglandinen wie PGE2 verstärkt, wenn die Zellen mit Endotoxinen wie Lipopolysaccharid (LPS), Fettsäuren wie Palmitinsäure, Cholesterol und Cholesterol-Kristallen oder Insulin, das als Folge der kompensatorischen Hyperinsulinämie bei Insulinresistenz verstärkt freigesetzt wird, inkubiert wurden. Insulin steigerte dabei synergistisch mit LPS oder Palmitinsäure die Synthese von PGE2 sowie der anderen Entzündungsmediatoren wie Interleukin (IL) 8 und IL-1β. PGE2 reguliert die Entzündungsantwort: Neben der Induktion der eigenen Synthese-Enzyme verstärkte PGE2 die Expression der Immunzell-rekrutierenden Chemokine IL-8 und (C-C-Motiv)-Ligand 2 (CCL2) sowie die der pro-inflammatorischen Cytokine IL-1β und IL-6 in Makrophagen und kann so zur Verstärkung der Entzündungsreaktion beitragen. Außerdem förderte PGE2 die Bildung von Oncostatin M (OSM) und OSM induzierte in einer positiven Rückkopplungsschleife die Expression der PGE2-synthetisierenden Enzyme. Andererseits hemmte PGE2 die basale und LPS-vermittelte Bildung des potenten pro-inflammatorischen Cytokins Tumornekrosefaktor α (TNFα) und kann so die Entzündungsreaktion abschwächen. In primären Hepatozyten der Ratte und humanen Hepatozyten beeinträchtigte PGE2 direkt die Insulin-abhängige Aktivierung der Insulinrezeptor-Signalkette zur Steigerung der Glucose-Verwertung, in dem es durch Signalketten, die den verschiedenen PGE2-Rezeptoren nachgeschaltet sind, Kinasen wie ERK1/2 und IKKβ aktivierte und eine inhibierende Serin-Phosphorylierung der Insulinrezeptorsubstrate bewirkte. PGE2 verstärkte außerdem die IL-6- oder OSM-vermittelte Insulinresistenz und Steatose in primären Hepatozyten der Ratte. Die Wirkung von PGE2 im Gesamtorganismus sollte in Mäusen mit Diät-induzierter NASH untersucht werden. Die Fütterung einer Hochfett-Diät mit Schmalz als Fettquelle, das vor allem gesättigte Fettsäuren enthält, verursachte Fettleibigkeit, Insulinresistenz und eine hepatische Steatose in Wildtyp-Mäusen. In Tieren, die eine Hochfett-Diät mit Sojaöl als Fettquelle, das vor allem (ω-6)-mehrfach-ungesättigte Fettsäuren (PUFAs) enthält, oder eine Niedrigfett-Diät mit Cholesterol erhielten, war lediglich eine hepatische Steatose nachweisbar, jedoch keine verstärkte Gewichtszunahme im Vergleich zu Geschwistertieren, die eine Standard-Diät bekamen. Im Gegensatz dazu verursachte die Fütterung einer Hochfett-Diät mit PUFA-reichem Sojaöl als Fettquelle in Kombination mit Cholesterol sowohl Fettleibigkeit und Insulinresistenz als auch hepatische Steatose mit Hepatozyten-Hypertrophie, lobulärer Entzündung und beginnender Fibrose in Wildtyp-Mäusen. Diese Tiere spiegelten alle klinischen und histologischen Parameter der humanen NASH im Metabolischen Syndrom wider. Nur die Kombination von hohen Mengen ungesättigter Fettsäuren aus Sojaöl und Cholesterol in der Nahrung führte zu einer exzessiven Akkumulation des Cholesterols und der Bildung von Cholesterol-Kristallen in den Hepatozyten, die zur Schädigung der Mitochondrien, schwerem oxidativem Stress und schließlich zum Absterben der Zellen führten. Als Konsequenz phagozytieren Kupfferzellen die Zelltrümmer der Cholesterol-überladenen Hepatozyten, werden dadurch aktiviert, setzen Chemokine, Cytokine und PGE2 frei, die die Entzündungsreaktion verstärken und die Infiltration von weiteren Immunzellen initiieren können und verursachen so eine Progression zur Steatohepatitis (NASH). Die Deletion der mikrosomalen PGE-Synthase 1 (mPGES1), dem induzierbaren Enzym der PGE2-Synthese aus Cyclooxygenase-abhängigen Vorstufen, reduzierte die Diät-abhängige Bildung von PGE2 in der Leber. Die Fütterung der NASH-induzierenden Diät verursachte in Wildtyp- und mPGES1-defizienten Mäusen eine ähnliche Fettleibigkeit und Zunahme der Fettmasse sowie die Ausbildung von hepatischer Steatose mit Entzündung und Fibrose (NASH) im histologischen Bild. In mPGES1-defizienten Mäusen waren jedoch Parameter für die Infiltration von Entzündungszellen und die Diät-abhängige Schädigung der Leber im Vergleich zu Wildtyp-Tieren erhöht, was sich auch in einer stärkeren Diät-induzierten systemischen Insulinresistenz widerspiegelte. Die Bildung des pro-inflammatorischen und pro-apoptotischen Cytokins TNFα war in mPGES1-defizienten Mäusen durch die Aufhebung der negativen Rückkopplungshemmung verstärkt, was einen gesteigerten Diät-induzierten Zelluntergang gestresster Lipid-überladener Hepatozyten und eine nach-geschaltete Entzündungsantwort zur Folge hatte. Zusammenfassend wurde unter den gewählten Versuchsbedingungen in vivo eine anti-inflammatorische Rolle von PGE2 verifiziert, da das Prostanoid vor allem indirekt durch die Hemmung der TNFα-vermittelten Entzündungsreaktion die Schädigung der Leber, die Verstärkung der Entzündung und die Ausbildung von Insulinresistenz im Rahmen der Diät-abhängigen Fettlebererkrankung abschwächte.
N2  - Obesity is a worldwide problem affecting almost 40 % of the population. The prevalence of obesity, insulin resistance and the consequent diseases such as type-2-diabetes and metabolic syndrome is increasing rapidly. The main underlying reasons are high caloric diets and reduced physical exercise. The incidence of non-alcoholic fatty liver disease (NAFLD), characterized by hepatic lipid accumulation, is correlated with the body mass index. NAFLD is generally considered to be the hepatic manifestation of metabolic syndrome and is the most frequent cause of functional disorders of the liver. NAFLD comprises both the mild form of benign hepatic steatosis (fatty liver) as well as the progressive form of non-alcoholic steatohepatitis (NASH), in which hepatic steatosis is accompanied by inflammation and fibrosis. The development of NASH may result in hepatocellular carcinoma, liver cirrhosis and terminal organ failure. High fat diets and dietary cholesterol might impact the transistion from fatty liver to NASH. The diet induced expansion of the white adipose tissue is associated with the development of insulin resistance as well as low-grade chronic inflammation. Inflammatory mediators from the adipose tissue in combination with dietary components from the gut reach the liver and activate Kupffer cells, the resident liver macrophages. As a consequence, macrophages initiate an inflammatory response that involves secretion of immune cell recruiting chemokines, pro-inflammatory cytokines and prostanoids like prostaglandin E2 (PGE2). The aim of the study was to elucidate the impact of PGE2 in the development of insulin resistance, hepatic steatosis and inflammation in diet-induced NASH. These processes implicate a complex interplay of various cell types in the liver, the PGE2-mediated regulation of cytokine synthesis, as well as factors like hyperinsulinemia and hyperlipidemia. In vitro studies with murine and human macrophage populations characterise the generation of PGE2 and the PGE2-mediated regulation of the inflammatory response. Primary rat and human hepatocytes, in addition to immortal cell lines, were incubated with PGE2 alone and in combination with PGE2-dependent generated cytokines. The intent of this experimental series was to clarify the impact of these mediators on the activation of the insulin signaling chain and resulting metabolic processes in glucose and lipid metabolism. The role of PGE2 in vivo was examined in mice with reduced PGE2 synthesis due to the genetic deletion of microsomal PGE synthase 1 (mPGES1), which were additionally fed a NASH-inducing diet. The hepatic expression of the PGE2-generating enzymes cyclooxygenase 2 (COX2) and mPGES1 was increased in mice with diet-induced NASH as well as in liver biopsies of patients with NASH compared to patients with simple hepatic steatosis or non-steatotic controls, indicating an enlarged capacity for PGE2 synthesis in NASH. Furthermore, the expression of COX2 and mPGES1 in the human study cohort correlated with the severity of the hepatic disease.. Treatment of macrophages with endotoxins like lipopolysaccharide (LPS), fatty acids like palmitic acid, cholesterol and cholesterol crystals, or insulin, which is released as a consequence of insulin resistance in the context of a compensatory hyperinsulinemia, resulted in an enhanced production of pro-inflammatory mediators such as chemokines, cytokines and PGE2. A combinatory treatment of human macrophages with insulin and LPS or palmitic acid induced a synergistic increase in PGE2 synthesis and production of interleukins (IL) like IL-8 and IL-1β. PGE2 itself modulates the inflammatory response: The prostanoid induced the enzymes involved in its own synthesis, in addition to immune cell recruiting chemokines such as IL-8 and (C-C-motiv) ligand 2 (CCL2), and pro-inflammatory cytokines such as IL-1β and IL-6 in macrophages. This may result in an amplification of the inflammatory response. Furthermore, PGE2 induced the production of oncostatin M (OSM), which in turn enhanced the expression of the enzymes generating PGE2 in a positive feedback loop. On the other hand, PGE2 inhibited the basal and LPS-mediated synthesis of the potent pro-inflammatory cytokine tumor necrosis factor α (TNFα). This may result in a reduced inflammatory response. In primary rat and human hepatocytes PGE2 directly interfered with the insulin mediated activation of the insulin receptor signaling chain and impaired glucose utilisation. Mechanistically, through interaction with different PGE2 receptors, PGE2 activated serine kinases including ERK1/2 and IKKβ, which cause inhibitory phosphorylations at serine residues of the insulin receptor substrates and force their degradation. PGE2 enhanced the insulin resistance and increased hepatic steatosis induced by IL-6 or OSM in primary rat hepatocytes. A murine model of diet-induced NASH was established to elucidate the impact of PGE2 in the complex in vivo regulation. Lard-based high fat diets containing mainly saturated fatty acids initiated a strong body weight gain, obesity, insulin resistance and hepatic steatosis without further damage of the liver in mice. Furthermore, mice fed a high fat diet based on soybean oil with high amounts of (ω-6)-poly-unsaturated fatty acids (PUFAs) or a low fat diet with high cholesterol did not result in increased body weight gain compaired to mice fed a chow (low fat) diet, but did cause mild hepatic steatosis. In contrast, mice fed a high fat diet based on PUFA-rich soybean oil in combination with high dietary cholesterol caused body weight gain, obesity, insulin resistance and hepatic steatosis accompanied by hepatocyte hypertrophy, lobular inflammation and fibrosis in wildtype mice. This dietary model displayed all clinical and histological parameters of human NASH in the metabolic syndrome. Only the combination of soybean oil derived fatty acids and dietary cholesterol provoked an excessive accumulation of cholesterol in hepatocytes and the generation of cholesterol crystals that caused mitochondrial damage, severe oxidative stress, and subsequently hepatocyte death. Hepatic macrophages phagocytose hepatocyte debris, lipids and cholesterol crystals and thereby were activated to produce pro-inflammatory mediators like chemokines, cytokines and prostanoids like PGE2 that initiate an inflammatory response. This included immune cell infiltration, inflammation and fibrogenic processes that determine the progression to steatohepatitis (NASH). The deletion of microsomal PGE synthase 1 (mPGES1), the inducible enzyme generating PGE2 from COX2 derived PGH2, reduced the diet-dependent increase in hepatic PGE2 production in mice fed a NASH-inducing diet. While body weight gain, obesity and histological parameters of NASH including steatosis, inflammation and fibrosis were comparable in wild type and mPGES1-deficient mice fed a NASH inducing diet, parameters of immune cell infiltration and hepatic damage were augmented only in mPGES1-deficient mice. This results in a more pronounced diet-induced glucose intolerance and insulin resistance index in mPGES1-deficient mice compared to wild type littermates. In parallel, hepatic production of the potent pro-inflammatory and pro-apoptotic cytokine TNFα was enhanced in mice with the deletion of mPGES1 due to the abolished PGE2-mediated negative feedback loop. This was accompanied by increased diet induced cell death of lipid loaded stressed hepatocytes and could result in an intensified inflammatory response. In summary, in vivo studies verify an anti-inflammatory role of PGE2. The prostanoid PGE2 acts mainly indirectly and could attenuate the TNFα-mediated liver damage, immune response and the resulting insulin resistance in the context of diet induced fatty liver diseases.
KW  - Prostaglandine
KW  - Entzündung
KW  - Insulin
KW  - Leber
KW  - Fettleibigkeit
KW  - prostaglandins
KW  - inflammation
KW  - insulin
KW  - liver
KW  - obesity
Y1  - 2021
ER  - 
TY  - THES
A1  - Winkelbeiner, Nicola Lisa
T1  - Impact of element species on DNA repair processes
Y1  - 2020
ER  - 
TY  - THES
A1  - Aleksandrova, Krasimira
T1  - Understanding the link between obesity and colorectal cancer
BT  - the role of biomarkers of iflammation, immunity and metabolic dysfunction
Y1  - 2020
ER  - 
TY  - THES
A1  - Schiborn, Catarina
T1  - Extension of the German Diabetes Risk Score with regard to risk communication and cardiovascular outcomes
Y1  - 2020
ER  - 
TY  - THES
A1  - Lenihan-Geels, Georgia Ngawai
T1  - The regulation of metabolic flexibility by p53 in skeletal muscle and brown adipose tissue
Y1  - 2020
ER  - 
TY  - THES
A1  - Martinez, Maria Teresa Castaño
T1  - Effects of Dietary Methionine and Protein Restriction on the Prevention and Treatment of Type 2 Diabetes
Y1  - 2020
ER  - 
TY  - JOUR
A1  - Wei, Xiaoyan
A1  - Franke, Julia
A1  - Ost, Mario
A1  - Wardelmann, Kristina
A1  - Börno, Stefan
A1  - Timmermann, Bernd
A1  - Meierhofer, David
A1  - Kleinridders, Andre
A1  - Klaus, Susanne
A1  - Stricker, Sigmar
T1  - Cell autonomous requirement of neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis
JF  - Journal of cachexia, sarcopenia and muscle
N2  - Background Neurofibromatosis type 1 (NF1) is a multi-organ disease caused by mutations in neurofibromin 1 (NF1). Amongst other features, NF1 patients frequently show reduced muscle mass and strength, impairing patients' mobility and increasing the risk of fall. The role of Nf1 in muscle and the cause for the NF1-associated myopathy are mostly unknown. Methods To dissect the function ofNf1in muscle, we created muscle-specific knockout mouse models for NF1, inactivatingNf1in the prenatal myogenic lineage either under the Lbx1 promoter or under the Myf5 promoter. Mice were analysed during prenatal and postnatal myogenesis and muscle growth. Results Nf1(Lbx1)and Nf1(Myf5)animals showed only mild defects in prenatal myogenesis. Nf1(Lbx1)animals were perinatally lethal, while Nf1(Myf5)animals survived only up to approximately 25 weeks. A comprehensive phenotypic characterization of Nf1(Myf5)animals showed decreased postnatal growth, reduced muscle size, and fast fibre atrophy. Proteome and transcriptome analyses of muscle tissue indicated decreased protein synthesis and increased proteasomal degradation, and decreased glycolytic and increased oxidative activity in muscle tissue. High-resolution respirometry confirmed enhanced oxidative metabolism in Nf1(Myf5)muscles, which was concomitant to a fibre type shift from type 2B to type 2A and type 1. Moreover, Nf1(Myf5)muscles showed hallmarks of decreased activation of mTORC1 and increased expression of atrogenes. Remarkably, loss of Nf1 promoted a robust activation of AMPK with a gene expression profile indicative of increased fatty acid catabolism. Additionally, we observed a strong induction of genes encoding catabolic cytokines in muscle Nf1(Myf5)animals, in line with a drastic reduction of white, but not brown adipose tissue. Conclusions Our results demonstrate a cell autonomous role for Nf1 in myogenic cells during postnatal muscle growth required for metabolic and proteostatic homeostasis. Furthermore, Nf1 deficiency in muscle drives cross-tissue communication and mobilization of lipid reserves.
KW  - neurofibromatosis
KW  - NF1
KW  - myopathy
KW  - muscle atrophy
KW  - muscle metabolism
KW  - muscle fibre type
KW  - AMPK
Y1  - 2020
U6  - https://doi.org/10.1002/jcsm.12632
SN  - 2190-5991
SN  - 2190-6009
VL  - 11
IS  - 6
SP  - 1758
EP  - 1778
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Wilhelmi, Ilka
A1  - Grunwald, Stephan
A1  - Gimber, Niclas
A1  - Popp, Oliver
A1  - Dittmar, Gunnar
A1  - Arumughan, Anup
A1  - Wanker, Erich E.
A1  - Laeger, Thomas
A1  - Schmoranzer, Jan
A1  - Daumke, Oliver
A1  - Schürmann, Annette
T1  - The ARFRP1-dependent Golgi scaffolding protein GOPC is required for insulin secretion from pancreatic 13-cells
JF  - Molecular metabolism
N2  - Objective: Hormone secretion from metabolically active tissues, such as pancreatic islets, is governed by specific and highly regulated signaling pathways. Defects in insulin secretion are among the major causes of diabetes. The molecular mechanisms underlying regulated insulin secretion are, however, not yet completely understood. In this work, we studied the role of the GTPase ARFRP1 on insulin secretion from pancreatic 13-cells. <br /> Methods: A 13-cell-specific Arfrp1 knockout mouse was phenotypically characterized. Pulldown experiments and mass spectrometry analysis were employed to screen for new ARFRP1-interacting proteins. Co-immunoprecipitation assays as well as super-resolution microscopy were applied for validation. <br /> Results: The GTPase ARFRP1 interacts with the Golgi-associated PDZ and coiled-coil motif-containing protein (GOPC). Both proteins are co localized at the trans-Golgi network and regulate the first and second phase of insulin secretion by controlling the plasma membrane localization of the SNARE protein SNAP25. Downregulation of both GOPC and ARFRP1 in Min6 cells interferes with the plasma membrane localization of SNAP25 and enhances its degradation, thereby impairing glucose-stimulated insulin release from 13-cells. In turn, overexpression of SNAP25 as well as GOPC restores insulin secretion in islets from 13-cell-specific Arfrp1 knockout mice. <br /> Conclusion: Our results identify a hitherto unrecognized pathway required for insulin secretion at the level of trans-Golgi sorting. (c) 2020 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
KW  - Insulin secretion
KW  - Endosomal sorting
KW  - SNARE proteins
KW  - trans-Golgi
KW  - network
Y1  - 2020
U6  - https://doi.org/10.1016/j.molmet.2020.101151
SN  - 2212-8778
VL  - 45
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Witt, Barbara
A1  - Schaumlöffel, Dirk
A1  - Schwerdtle, Tanja
T1  - Subcellular Localization of Copper
BT  - Cellular Bioimaging with Focus on Neurological Disorders
JF  - International Journal of Molecular Sciences
N2  - As an essential trace element, copper plays a pivotal role in physiological body functions. In fact, dysregulated copper homeostasis has been clearly linked to neurological disorders including Wilson and Alzheimer’s disease. Such neurodegenerative diseases are associated with progressive loss of neurons and thus impaired brain functions. However, the underlying mechanisms are not fully understood. Characterization of the element species and their subcellular localization is of great importance to uncover cellular mechanisms. Recent research activities focus on the question of how copper contributes to the pathological findings. Cellular bioimaging of copper is an essential key to accomplish this objective. Besides information on the spatial distribution and chemical properties of copper, other essential trace elements can be localized in parallel. Highly sensitive and high spatial resolution techniques such as LA-ICP-MS, TEM-EDS, S-XRF and NanoSIMS are required for elemental mapping on subcellular level. This review summarizes state-of-the-art techniques in the field of bioimaging. Their strengths and limitations will be discussed with particular focus on potential applications for the elucidation of copper-related diseases. Based on such investigations, further information on cellular processes and mechanisms can be derived under physiological and pathological conditions. Bioimaging studies might enable the clarification of the role of copper in the context of neurodegenerative diseases and provide an important basis to develop therapeutic strategies for reduction or even prevention of copper-related disorders and their pathological consequences.
KW  - copper
KW  - cellular bioimaging
KW  - neurodegenerative diseases
KW  - copper-related disorders
KW  - SIMS techniques
KW  - TEM
KW  - S-XRF
Y1  - 2020
U6  - https://doi.org/10.3390/ijms21072341
SN  - 1422-0067
VL  - 21
IS  - 7
PB  - Molecular Diversity Preservation International
CY  - Basel
ER  - 
TY  - JOUR
A1  - Müller, Sandra
A1  - Dawczynski, Christine
A1  - Wiest, Johanna
A1  - Lorkowski, Stefan
A1  - Kipp, Anna Patricia
A1  - Schwerdtle, Tanja
T1  - Functional Biomarkers for the Selenium Status in a Human Nutritional Intervention Study
JF  - Nutrients
N2  - Soils in Germany are commonly low in selenium; consequently, a sufficient dietary supply is not always ensured. The extent of such provision adequacy is estimated by the optimal effect range of biomarkers, which often reflects the physiological requirement. Preceding epidemiological studies indicate that low selenium serum concentrations could be related to cardiovascular diseases. Inter alia, risk factors for cardiovascular diseases are physical inactivity, overweight, as well as disadvantageous eating habits. In order to assess whether these risk factors can be modulated, a cardio-protective diet comprising fixed menu plans combined with physical exercise was applied in the German MoKaRi (modulation of cardiovascular risk factors) intervention study. We analyzed serum samples of the MoKaRi cohort (51 participants) for total selenium, GPx activity, and selenoprotein P at different timepoints of the study (0, 10, 20, 40 weeks) to explore the suitability of these selenium-associated markers as indicators of selenium status. Overall, the time-dependent fluctuations in serum selenium concentration suggest a successful change in nutritional and lifestyle behavior. Compared to baseline, a pronounced increase in GPx activity and selenoprotein P was observed, while serum selenium decreased in participants with initially adequate serum selenium content. SELENOP concentration showed a moderate positive monotonic correlation (r = 0.467, p < 0.0001) to total Se concentration, while only a weak linear relationship was observed for GPx activity versus total Se concentration (r = 0.186, p = 0.021). Evidently, other factors apart from the available Se pool must have an impact on the GPx activity, leading to the conclusion that, without having identified these factors, GPx activity should not be used as a status marker for Se
KW  - Se
KW  - selenoprotein P
KW  - GPx activity
KW  - cardiovascular disease
KW  - status markers
Y1  - 2020
U6  - https://doi.org/10.3390/nu12030676
SN  - 2072-6643
VL  - 12
IS  - 3
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Kotthoff, Lisa
A1  - O'Callaghan, Sarah-Louise
A1  - Lisec, Jan
A1  - Schwerdtle, Tanja
A1  - Koch, Matthias
T1  - Structural annotation of electro- and photochemically generated transformation products of moxidectin using high-resolution mass spectrometry
JF  - Analytical and bioanalytical chemistry : a merger of Fresenius' journal of analytical chemistry, Analusis and Quimica analitica
N2  - Moxidectin (MOX) is a widely used anthelmintic drug for the treatment of internal and external parasites in food-producing and companion animals. Transformation products (TPs) of MOX, formed through metabolic degradation or acid hydrolysis, may pose a potential environmental risk, but only few were identified so far. In this study, we therefore systematically characterized electro- and photochemically generated MOX TPs using high-resolution mass spectrometry (HRMS). Oxidative electrochemical (EC) TPs were generated in an electrochemical reactor and photochemical (PC) TPs by irradiation with UV-C light. Subsequent HRMS measurements were performed to identify accurate masses and deduce occurring modification reactions of derived TPs in a suspected target analysis. In total, 26 EC TPs and 59 PC TPs were found. The main modification reactions were hydroxylation, (de-)hydration, and derivative formation with methanol for EC experiments and isomeric changes, (de-)hydration, and changes at the methoxime moiety for PC experiments. In addition, several combinations of different modification reactions were identified. For 17 TPs, we could predict chemical structures through interpretation of acquired MS/MS data. Most modifications could be linked to two specific regions of MOX. Some previously described metabolic reactions like hydroxylation or O-demethylation were confirmed in our EC and PC experiments as reaction type, but the corresponding TPs were not identical to known metabolites or degradation products. The obtained knowledge regarding novel TPs and reactions will aid to elucidate the degradation pathway of MOX which is currently unknown.
KW  - veterinary drug
KW  - moxidectin
KW  - transformation products
KW  - electrochemistry
KW  - photochemistry
KW  - LC
KW  - HRMS
Y1  - 2020
U6  - https://doi.org/10.1007/s00216-020-02572-1
SN  - 1618-2642
SN  - 1618-2650
VL  - 412
IS  - 13
SP  - 3141
EP  - 3152
PB  - Springer
CY  - Heidelberg
ER  - 
TY  - THES
A1  - Seebeck, Nicole
T1  - Regulation of the organokines FGF21 and chemerin by diet
BT  - metabolic and molecular effects in liver and adipose tissue of obese human subjects
BT  - metabolische und molekulare Effekte in Leber und Fettgewebe adipöser humaner Probanden
N2  - The hepatokine FGF21 and the adipokine chemerin have been implicated as metabolic regulators and mediators of inter-tissue crosstalk. While FGF21 is associated with beneficial metabolic effects and is currently being tested as an emerging therapeutic for obesity and diabetes, chemerin is linked to inflammation-mediated insulin resistance. However, dietary regulation of both organokines and their role in tissue interaction needs further investigation.
The LEMBAS nutritional intervention study investigated the effects of two diets differing in their protein content in obese human subjects with non-alcoholic fatty liver disease (NAFLD). The study participants consumed hypocaloric diets containing either low (LP: 10 EN%, n = 10) or high (HP: 30 EN%, n = 9) dietary protein 3 weeks prior to bariatric surgery. Before and after the intervention the participants were anthropometrically assessed, blood samples were drawn, and hepatic fat content was determined by MRS. During bariatric surgery, paired subcutaneous and visceral adipose tissue biopsies as well as liver biopsies were collected. The aim of this thesis was to investigate circulating levels and tissue-specific regulation of (1) FGF21 and (2) chemerin in the LEMBAS cohort. The results were compared to data obtained in 92 metabolically healthy subjects with normal glucose tolerance and normal liver fat content.
(1) Serum FGF21 concentrations were elevated in the obese subjects, and strongly associated with intrahepatic lipids (IHL). In accordance, FGF21 serum concentrations increased with severity of NAFLD as determined histologically in the liver biopsies. Though both diets were successful in reducing IHL, the effect was more pronounced in the HP group. FGF21 serum concentrations and mRNA expression were bi-directionally regulated by dietary protein, independent from metabolic improvements. In accordance, in the healthy study subjects, serum FGF21 concentrations dropped by more than 60% in response to the HP diet. A short-term HP intervention confirmed the acute downregulation of FGF21 within 24 hours. Lastly, experiments in HepG2 cell cultures and primary murine hepatocytes identified nitrogen metabolites (NH4Cl and glutamine) to dose-dependently suppress FGF21 expression.
(2) Circulating chemerin concentrations were considerably elevated in the obese versus lean study participants and differently associated with markers of obesity and NAFLD in the two cohorts. The adipokine decreased in response to the hypocaloric interventions while an unhealthy high-fat diet induced a rise in chemerin serum levels. In the lean subjects, mRNA expression of RARRES2, encoding chemerin, was strongly and positively correlated with expression of several cytokines, including MCP1, TNFα, and IL6, as well as markers of macrophage infiltration in the subcutaneous fat depot. However, RARRES2 was not associated with any cytokine assessed in the obese subjects and the data indicated an involvement of chemerin not only in the onset but also resolution of inflammation. Analyses of the tissue biopsies and experiments in human primary adipocytes point towards a role of chemerin in adipogenesis while discrepancies between the in vivo and in vitro data were detected. 
Taken together, the results of this thesis demonstrate that circulating FGF21 and chemerin levels are considerably elevated in obesity and responsive to dietary interventions. FGF21 was acutely and bi-directionally regulated by dietary protein in a hepatocyte-autonomous manner. Given that both, a lack in essential amino acids and excessive nitrogen intake, exert metabolic stress, FGF21 may serve as an endocrine signal for dietary protein balance. Lastly, the data revealed that chemerin is derailed in obesity and associated with obesity-related inflammation. However, future studies on chemerin should consider functional and regulatory differences between secreted and tissue-specific isoforms.
N2  - Extremes Übergewicht einhergehend mit einer starken Vermehrung des Körperfetts (Adipositas) stellt ein weltweites Gesundheitsproblem dar und geht oft mit assoziierten Erkrankungen, wie Diabetes, einer Fettleber und Herz-Kreislauf-Erkrankungen einher. Die Ernährung spielt in der Entstehung und Therapie der Adipositas eine zentrale Rolle. Gerät der Stoffwechsel aufgrund anhaltender Energieüberschüsse aus dem Gleichgewicht, werden von Leber und Fettgewebe Entzündungsmarker sowie Signalmoleküle, darunter Chemerin und FGF21, ausgesendet. Während vorhergehende Studien für FGF21 vorteilhafte Effekte auf den Zucker- und Energiestoffwechsel demonstriert haben, steht Chemerin im Zusammenhang mit der Entwicklung chronisch-entzündlicher Erkrankungen. Die vorliegende Arbeit untersucht die nahrungsabhängige Regulation von FGF21 und Chemerin in humanen Blut-, Leber- und Fettgewebsproben aus stark übergewichtigen Probanden, um ein besseres Verständnis für die Physiologie der beiden Moleküle zu gewinnen.  
Die Studienteilnehmer konsumierten drei Wochen vor bariatrischer Operation zwei kalorienreduzierte Diäten, die sich in ihrem Proteinanteil (10% versus 30% der Gesamtenergie) unterschieden. Vor und nach der Diätintervention wurde die körperliche Konstitution und der Leberfettanteil der Probanden bestimmt sowie klinische Marker im Blut ermittelt. Während der bariatrischen Operation wurden zudem Leber- und Fettgewebsbiopsien entnommen. Die Ergebnisse wurden bezüglich der Regulation von FGF21 und Chemerin ausgewertet und anschließend mit Daten von gesunden, schlanken Probanden verglichen.
FGF21 war in den adipösen Probanden deutlich erhöht und wies eine starke Assoziation mit dem Leberfettgehalt auf. Beide Diäten konnten das Leberfett deutlich senken, wobei die Hochproteindiät effektiver war. Die FGF21 Blutspiegel sanken mit steigender Proteinaufnahme, was sich auch in der hepatischen Genexpression widerspiegelte. Zellkulturversuche bestätigten eine negative Regulation von FGF21 durch Zwischenprodukte des Proteinstoffwechsels. Zusammenfassend zeigen die Ergebnisse, dass eine Hochproteindiät FGF21 kurzfristig und dosisabhängig supprimiert bei gleichzeitiger Verbesserung der Stoffwechsellage. 
Chemerin war in den übergewichtigen und gesunden Probanden unterschiedlich mit Markern der Adipositas und der Fettlebererkrankung assoziiert. Zudem konnte eine ernährungsabhängige Regulation von Chemerin aufgezeigt werden, wobei der Proteingehalt der Diät unerheblich war. Interessanterweise deuten die Daten aus den Fettgewebsbiopsien auf eine Rolle von Chemerin sowohl in der Entstehung als auch in der Auflösung entzündlicher Vorgänge hin. Die Ergebnisse dieser Arbeit zeigen, dass Chemerin im Zusammenhang mit der Entwicklung der Adipositas steht aber auch günstige Effekte auf dessen Verlauf haben könnte.
T2  - Regulation der Organokine FGF21 und Chemerin durch Ernährung
KW  - Obesity
KW  - FGF21
KW  - Chemerin
KW  - Adipositas
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-471140
ER  - 
TY  - JOUR
A1  - Gehre, Christian
A1  - Flechner, Marie
A1  - Kammerer, Sarah
A1  - Küpper, Jan-Heiner
A1  - Coleman, Charles Dominic
A1  - Püschel, Gerhard Paul
A1  - Uhlig, Katja
A1  - Duschl, Claus
T1  - Real time monitoring of oxygen uptake of hepatocytes in a microreactor using optical microsensors
JF  - Scientific reports
N2  - Most in vitro test systems for the assessment of toxicity are based on endpoint measurements and cannot contribute much to the establishment of mechanistic models, which are crucially important for further progress in this field. Hence, in recent years, much effort has been put into the development of methods that generate kinetic data. Real time measurements of the metabolic activity of cells based on the use of oxygen sensitive microsensor beads have been shown to provide access to the mode of action of compounds in hepatocytes. However, for fully exploiting this approach a detailed knowledge of the microenvironment of the cells is required. In this work, we investigate the cellular behaviour of three types of hepatocytes, HepG2 cells, HepG2-3A4 cells and primary mouse hepatocytes, towards their exposure to acetaminophen when the availability of oxygen for the cell is systematically varied. We show that the relative emergence of two modes of action, one NAPQI dependent and the other one transient and NAPQI independent, scale with expression level of CYP3A4. The transient cellular response associated to mitochondrial respiration is used to characterise the influence of the initial oxygen concentration in the wells before exposure to acetaminophen on the cell behaviour. A simple model is presented to describe the behaviour of the cells in this scenario. It demonstrates the level of control over the role of oxygen supply in these experiments. This is crucial for establishing this approach into a reliable and powerful method for the assessment of toxicity.
Y1  - 2020
U6  - https://doi.org/10.1038/s41598-020-70785-6
SN  - 2045-2322
VL  - 10
IS  - 1
PB  - Macmillan Publishers Limited, part of Springer Nature
CY  - [London]
ER  - 
TY  - THES
A1  - Wolf, Kristine
T1  - Produktentwicklung eines luteinhaltigen, kolloidalen Nahrungsergänzungsmittels: physikochemische und ernährungsphysiologische Aspekte
N2  - Sekundäre Pflanzenstoffe und ihre gesundheitsfördernden Eigenschaften sind in den letzten zwei Jahrzehnten vielfach ernährungsphysiologisch untersucht und spezifische positive Effekte im humanen Organismus zum Teil sehr genau beschrieben worden. Zu den Carotinoiden zählend ist der sekundäre Pflanzenstoff Lutein insbesondere in der Prävention von ophthalmologischen Erkrankungen in den Mittelpunkt der Forschung gerückt. Das ausschließlich von Pflanzen und einigen Algen synthetisierte Xanthophyll wird über die pflanzliche Nahrung insbesondere grünes Blattgemüse in den humanen Organismus aufgenommen. Dort akkumuliert es bevorzugt im Makulapigment der Retina des menschlichen Auges und ist bedeutend im Prozess der Aufrechterhaltung der Funktionsfähigkeit der Photorezeptorzellen. Im Laufe des Alterns kann die Abnahme der Dichte des Makulapigments und der Abbau von Lutein beobachtet werden. Die dadurch eintretende Destabilisierung der Photorezeptorzellen im Zusammenhang mit einer veränderten Stoffwechsellage im alternden Organismus kann zur Ausprägung der altersbedingten Makuladegeneration (AMD) führen. Die pathologische Symptomatik der Augenerkrankung reicht vom Verlust der Sehschärfe bis hin zum irreversiblen Erblinden. Da therapeutische Mittel ausschließlich ein Fortschreiten verhindern, bestehen hier Forschungsansätze präventive Maßnahmen zu finden. Die Supplementierung von luteinhaltigen Präparaten bietet dabei einen Ansatzpunkt. Auf dem Markt finden sich bereits Nahrungsergänzungsmittel (NEM) mit Lutein in verschiedenen Applikationen. Limitierend ist dabei die Stabilität und Bioverfügbarkeit von Lutein, welches teilweise kostenintensiv und mit unbekannter Reinheit zu erwerben ist. Aus diesem Grund wäre die Verwendung von Luteinestern als die pflanzliche Speicherform des Luteins im Rahmen eines NEMs vorteilhaft. Neben ihrer natürlichen, höheren Stabilität sind Luteinester nachhaltig und kostengünstig einsetzbar.
In dieser Arbeit wurden physikochemische und ernährungsphysiologisch relevante Aspekte in dem Produktentwicklungsprozess eines NEMs mit Luteinestern in einer kolloidalen Formulierung untersucht. Die bisher einzigartige Anwendung von Luteinestern in einem Mundspray sollte die Aufnahme des Wirkstoffes insbesondere für ältere Menschen erleichtern und verbessern. Unter Beachtung der Ergebnisse und der ernährungsphysiologischen Bewertung sollten u.a. Empfehlungen für die Rezepturzusammensetzungen einer Miniemulsion (Emulsion mit Partikelgrößen <1,0 µm) gegeben werden. Eine Einschätzung der Bioverfügbarkeit der Luteinester aus den entwickelten, kolloidalen Formulierungen konnte anhand von Studien zur Resorption- und Absorptionsverfügbarkeit in vitro ermöglicht werden.
In physikalischen Untersuchungen wurden zunächst Basisbestandteile für die Formulierungen präzisiert. In ersten wirkstofffreien Musteremulsionen konnten ausgewählte Öle als Trägerphase sowie Emulgatoren und Löslichkeitsvermittler (Peptisatoren) hinsichtlich ihrer Eignung zur Bereitstellung einer Miniemulsion physikalisch geprüft werden. Die beste Stabilität und optimale Eigenschaften einer Miniemulsion zeigten sich bei der Verwendung von MCT-Öl (engl. medium chain triglyceride) bzw. Rapsöl in der Trägerphase sowie des Emulgators Tween® 80 (Tween 80) allein oder in Kombination mit dem Molkenproteinhydrolysat Biozate® 1 (Biozate 1).
Aus den physikalischen Untersuchungen der Musteremulsionen gingen die Präemulsionen als Prototypen hervor. Diese enthielten den Wirkstoff Lutein in verschiedenen Formen. So wurden Präemulsionen mit Lutein, mit Luteinestern sowie mit Lutein und Luteinestern konzipiert, welche den Emulgator Tween 80 oder die Kombination mit Biozate 1 enthielten. Bei der Herstellung der Präemulsionen führte die Anwendung der Emulgiertechniken Ultraschall mit anschließender Hochdruckhomogenisation zu den gewünschten Miniemulsionen. Beide eingesetzten Emulgatoren boten optimale Stabilisierungseffekte. Anschließend erfolgte die physikochemische Charakterisierung der Wirkstoffe. Insbesondere Luteinester aus Oleoresin erwiesen sich hier als stabil gegenüber verschiedenen Lagerungsbedingungen. Ebenso konnte bei einer kurzzeitigen Behandlung der Wirkstoffe unter spezifischen mechanischen, thermischen, sauren und basischen Bedingungen eine Stabilität von Lutein und Luteinestern gezeigt werden. Die Zugabe von Biozate 1 bot dabei nur für Lutein einen zusätzlichen Schutz. Bei längerer physikochemischer Behandlung unterlagen die in den Miniemulsionen eingebrachten Wirkstoffe moderaten Abbauvorgängen. Markant war deren Sensitivität gegenüber dem basischen Milieu. Im Rahmen der Rezepturentwicklung des NEMs war hier die Empfehlung, eine Miniemulsion mit einem leicht saurem pH-Milieu zum Schutz des Wirkstoffes durch kontrollierte Zugabe weiterer Inhaltstoffe zu gestalten.
Im weiteren Entwicklungsprozess des NEMs wurden Fertigrezepturen mit dem Wirkstoff Luteinester aufgestellt. Die alleinige Anwendung des Emulgators Biozate 1 zeigte sich dabei als ungeeignet. Die weiterhin zur Verfügung stehenden Fertigrezepturen enthielten in der Öl-phase neben dem Wirkstoff das MCT-ÖL oder Rapsöl sowie a-Tocopherol zur Stabilisierung. Die Wasserphase bestand aus dem Emulgator Tween 80 oder einer Kombination aus Tween 80 und Biozate 1. Zusatzstoffe waren zudem als mikrobiologischer Schutz Ascorbinsäure und Kaliumsorbat sowie für sensorische Effekte Xylitol und Orangenaroma. Die Anordnung der Basisrezeptur und das angewendete Emulgierverfahren lieferten stabile Miniemulsionen. Weiterhin zeigten langfristige Lagerungsversuche mit den Fertigrezepturen bei 4°C, dass eine Aufrechterhaltung der geforderten Luteinestermenge im Produkt gewährleistet war. Analoge Untersuchungen an einem luteinhaltigen, marktgängigen Präparat bestätigten dagegen eine bereits bei kurzfristiger Lagerung auftretende Instabilität von Lutein.
Abschließend wurde durch Resorptions- und Absorptionsstudien in vitro mit den Präemulsionen und Fertigrezepturen die Bioverfügbarkeit von Luteinestern geprüft. Nach Behandlung in einem etablierten in vitro Verdaumodell konnte eine geringfügige Resorptionsverfügbarkeit der Luteinester definiert werden. Limitiert war eine Micellarisierung des Wirkstoffes aus den konzipierten Formulierungen zu beobachten. Eine enzymatische Spaltung der Luteinester zu freiem Lutein wurde nur begrenzt festgestellt. Spezifität und Aktivität von entsprechenden hydrolytischen Lipasen sind als äußerst gering gegenüber Luteinestern zu bewerten. In sich anschließenden Zellkulturversuchen mit der Zelllinie Caco-2 wurden keine zytotoxischen Effekte durch die relevanten Inhaltsstoffe in den Präemulsionen gezeigt. Dagegen konnten eine Sensibilität gegenüber den Fertigrezepturen beobachtet werden. Diese sollte im Zusammenhang mit Irritationen der Schleimhäute des Magen-Darm-Traktes bedacht werden. Eine weniger komplexe Rezeptur könnte die beobachteten Einschränkungen möglicherweise minimieren. Abschließende Absorptionsstudien zeigten, dass grundsätzlich eine geringfügige Aufnahme von vorrangig Lutein, aber auch Luteinmonoestern in den Enterocyten aus Miniemulsionen erfolgen kann. Dabei hatte weder Tween 80 noch Biozate 1 einen förderlichen Einfluss auf die Absorptionsrate von Lutein oder Luteinestern. Die Metabolisierung der Wirkstoffe durch vorherigen in vitro-Verdau steigerte die zelluläre Aufnahme von Wirkstoffen aus Formulierungen mit Lutein und Luteinestern gleichermaßen. Die beobachtete Aufnahme von Lutein und Luteinmonoestern in den Enterocyten scheint über passive Diffusion zu erfolgen, wobei auch der aktive Transport nicht ausgeschlossen werden kann. Dagegen können Luteindiester aufgrund ihrer Molekülgröße nicht über den Weg der Micellarisierung und einfachen Diffusion in die Enterocyten gelangen. Ihre Aufnahme in die Dünndarmepithelzellen bedarf einer vorherigen hydrolytischen Spaltung durch spezifische Lipasen. Dieser Schritt limitiert wiederum die effektive Aufnahme der Luteinester in die Zellen bzw. stellt eine Einschränkung in ihrer Bioverfügbarkeit im Vergleich zu freiem Lutein dar.
Zusammenfassend konnte für die physikochemisch stabilen Luteinester eine geringe Bioverfügbarkeit aus kolloidalen Formulierungen gezeigt werden. Dennoch ist die Verwendung als Wirkstoffquelle für den sekundären Pflanzenstoff Lutein in einem NEM zu empfehlen. Im Zusammenhang mit der Aufnahme von luteinreichen, pflanzlichen Lebensmitteln kann trotz der zu erwartenden geringen Bioverfügbarkeit der Luteinester aus dem NEM ein Beitrag zur Verbesserung des Luteinstatus erreicht werden. Entsprechende Publikationen zeigten eindeutige Korrelationen zwischen der Aufnahme von luteinesterhaltigen Präparaten und einem Anstieg der Luteinkonzentration im Serum bzw. der Makulapigmentdichte in vivo. Die geringfügig bessere Bioverfügbarkeit von freiem Lutein steht im kritischen Zusammenhang mit seiner Instabilität und Kostenintensität. Bilanzierend wurde im Rahmen dieser Arbeit das marktgängige Produkt Vita Culus® konzipiert. Im Ausblick sollten humane Interventionsstudien mit dem NEM die abschließende Bewertung der Bioverfügbarkeit von Luteinestern aus dem Präparat möglich machen.
N2  - Secondary plant metabolites and their health-promoting properties have been studied and pub-lished over the past two decades. Their specificity with regard to positive properties and effects in the human organism has been described precisely. Among the carotenoids, the secondary plant metabolite lutein has become the focus of research, particularly in the prevention of ophthalmic diseases. The xanthophyll, which is synthesized exclusively by plants (incl. some algae), is absorbed into the human organism through plant food especially green leafy vegetables. There it accumulates preferentially in the macular pigment of the retina of the human eye and is important in the process of maintaining the functionality of the photoreceptors. As the aging progresses, the decrease in the density of the macular pigment and the depletion of lutein can be observed. The resulting destabilization of the photoreceptors in connection with a changed metabolism in the aging organism can lead to the development of age-related macular degeneration (AMD). The pathological symptoms of AMD range from loss of visual acuity to irreversible blindness. Since therapeutic agents only enable the disease to be decelerated or come to a standstill, research approaches exist to find preventive measures. The supplementation of preparations containing lutein offers a starting point to have a targeted positive effect on the stability of the macular pigment density and thus to maintain the quality of vision even in old age. Dietary supplements (DS) with lutein in various applications are available on the market. Limiting is the stability and bioavailability of lutein, which can be expensive and acquired with unknown purity. For this reason, the use of the storage form of lutein in plants, the lutein esters within the framework of a DS would be advantageous. In addition to their natural, higher stability, lutein esters can be used sustainably and inexpensively.
In this thesis, physicochemical and nutritionally relevant aspects in the product development process of a DS with lutein esters in a colloidal formulation were investigated. The hitherto unique use of lutein esters in oral spray applications should facilitate and improve the absorption of the active ingredient especially for older people. Taking into account the results and the nutritional assessment, recommendations for the recipe compositions of a miniemulsions (emulsion with particle sizes <1.0 µm) are given. An assessment of the bioavailability of the lutein esters from the developed colloidal formulations was realized by means of studies on the absorption accessibility and availability in vitro.
In physical investigations, the basic components for the colloidal formulations to be developed were first specified. In the first active ingredient-free sample emulsions selected oils as carrier phase as well as emulsifiers and solubilizers (peptizers) could be physically tested with regard to their suitability for providing a miniemulsion. The best stability and optimal properties of a miniemulsion were found when using MCT oil (medium chain triglyceride) or rapeseed oil in the carrier phase and the emulsifier Tween® 80 (Tween 80) alone or in combination with the whey protein hydrolyzate Biozate® 1 (Biozate 1) in the aqueous phase.
The pre-emulsions were developed as prototypes from the physical examinations of the basic recipes. These contained the active ingredient lutein in various forms. Pre-emulsions with lutein, with lutein esters or with lutein and lutein esters were prepared. They contained the emulsifier Tween 80 or the combination with Biozate 1. In the preparation of the pre-emulsions the use of ultrasound emulsification techniques with subsequent high-pressure homogenization led to the postulated miniemulsions. Both emulsifiers used offered optimal stabilization effects. This was followed by the physicochemical characterization of the active substances in the pre-emulsions. In particular, lutein esters from oleoresin were found to be stable against various storage conditions. A short-term treatment of the active ingredients under specific mechanical, thermal, acidic and basic conditions also demonstrated the stability of lutein and lutein esters. The addition of Biozate 1 offered further protection for lutein. In the case of prolonged physico-chemical treatment, the active substances incorporated in the miniemulsions were subject to moderate degradation processes. The sensitivity of the active ingredients in the formulations to a basic environment was striking. As part of the formulation development of the DS, the recommendation was given to design a miniemulsion with a slightly acidic environment by the controlled addition of further ingredients to protect the active ingredient.
In the further development process of the DS, refined formulations with the active ingredient lutein ester and modifications of the emulsifiers were then set up. The sole use of the emulsifier Biozate 1 turned out to be unsuitable and these formulations were rejected. The refined formulations that were still available contained the carriers MCT oil or rapeseed oil as well as a-tocopherol for stabilization. The water phase consisted of the emulsifier Tween 80 or a combination of Tween 80 and Biozate 1. Additives were ascorbic acid and potassium sorbate for microbial protection such as xylitol and orange aroma for sensory effects. The arrangement of the basic recipe and the emulsifying process used provided stable miniemulsions. Long-term storage tests with the ready formulations at 4°C showed that the required amount of lutein ester is maintained in the product. Analogous tests on a preparation containing lutein confirmed the instability of lutein, which occurs even in the case of short-term storage.
Finally, the bioavailability of the lutein esters was investigated using the pre-emulsions and refined formulations in studies of absorption accessibility and availability in vitro. For these studies an in vitro digestion model was confirmed. After treatment of the formulations in this model a slight absorption accessibility of the lutein esters could be classified. Micellarization process and enzymatic cleavage of the lutein esters to free lutein has only been found to a limited extent. The specificity and activity of corresponding hydrolytic lipases to lutein esters can be rated as extremely low. In subsequent cell culture experiments with the Caco-2 cell line, no cytotoxic effects were shown by the relevant ingredients in the pre-emulsions. In contrast, sensitivity to the refined formulations could be observed. This should be considered in connection with irritation of the mucous membranes of the gastrointestinal tract. A less complex formulation could possibly prevent the observed restrictions. In studies of absorption availability in vitro a low uptake of primarily free lutein, but also lutein monoesters in the enterocytes from miniemulsions could be observed. Neither Tween 80 nor Biozate 1 have a beneficial influence on the absorption rate of lutein or lutein esters. But micellarization of the active ingredients through previous in vitro digestion increased the cellular uptake of lutein and lutein esters from the formulations. This gives an evidence of the relevance of micellarization in absorption of lipophilic substances. The uptake of lutein and lutein monoesters in the enterocytes seems to be possible via passive diffusion, although active transport cannot be ruled out either. On the other hand, due to their molecular size, lutein diesters cannot enter into the enterocytes via micellarization or simple diffusion. Their absorption in the small intestine epithelial cells requires prior hydrolytic cleavage by specific lipases. This step in turn limits the effective absorption of the lutein esters into the cells or represents a restriction in their bioavailability in comparison to free lutein.
In summary, a low bioavailability for the physicochemically stable lutein esters from colloidal formulations was shown. Nevertheless, the use as a source of active ingredients for the xanthophyll lutein in a DS is recommended. In connection with the intake of plant foods rich in lutein, a contribution to improving the lutein status can be achieved despite the expected low bioavailability of the lutein esters from the DS. Corresponding publications showed clear correlations between the intake of preparations containing lutein ester and an increase in serum lutein concentrations or the macular pigment density in vivo. The slightly better bioavailability of free lutein is critically linked to its instability and cost intensity. On the basis of this work, the product Vita Culus® was designed and is available on the market. As a prospect of future research, human intervention studies with the DS should be conducted to assess the total bio-availability of lutein esters from miniemulsions in detail.
T2  - Product development of a lutein-containing, colloidal dietary supplement: physicochemical and nutritional aspects
KW  - Luteinester
KW  - Emulsion
KW  - Nahrunsgergänzungsmittel
KW  - Bioverfügbarkeit
KW  - lutein esters
KW  - emulsion
KW  - dietary supplements
KW  - bioavailability
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-487743
ER  - 
TY  - GEN
A1  - Figueroa Campos, Gustavo A.
A1  - Sagu Tchewonpi, Sorel
A1  - Saravia Celis, Pedro
A1  - Rawel, Harshadrai Manilal
T1  - Comparison of batch and continuous wet-processing of coffee
BT  - changes in the main compounds in beans, by-products and wastewater
T2  - Postprints der Universität Potsdam : Mathematisch Naturwissenschaftliche Reihe
N2  - Many technical challenges still need to be overcome to improve the quality of the green coffee beans. In this work, the wet Arabica coffee processing in batch and continuous modus were investigated. Coffee beans samples as well as by-products and wastewaters collected at different production steps were analyzed in terms of their content in total phenols, antioxidant capacity, caffeine content, organic acids, reducing sugars, free amino group and protein content. The results showed that 40% of caffeine was removed with pulp. Green coffee beans showed highest concentration of organic acids and sucrose (4.96 ± 0.25 and 5.07 ± 0.39 g/100 g DW for the batch and continuous processing). Batch green coffee beans contained higher amount of phenols. 5-caffeoylquinic Acid (5-CQA) was the main constituent (67.1 and 66.0% for the batch and continuous processing, respectively). Protein content was 15 and 13% in the green coffee bean in batch and continuous processing, respectively. A decrease of 50 to 64% for free amino groups during processing was observed resulting in final amounts of 0.8 to 1.4% in the processed beans. Finally, the batch processing still revealed by-products and wastewater with high nutrient content encouraging a better concept for valorization.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1010 
KW  - Arabica coffee beans
KW  - coffee by-products
KW  - batch process
KW  - continuous process
KW  - nutritional characteristics
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-481691
SN  - 1866-8372
IS  - 1010
ER  - 
TY  - GEN
A1  - Li, Chen
A1  - Stoma, Svetlana
A1  - Lotta, Luca A.
A1  - Warner, Sophie
A1  - Albrecht, Eva
A1  - Allione, Alessandra
A1  - Arp, Pascal P.
A1  - Broer, Linda
A1  - Buxton, Jessica L.
A1  - Boeing, Heiner
A1  - Langenberg, Claudia
A1  - Codd, Veryan
T1  - Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1 , PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1205 
KW  - Mendelian randomization
KW  - risk
KW  - variants
KW  - disease
KW  - cancer
KW  - loci
KW  - database
KW  - genes
KW  - heart
KW  - gwas
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-526843
SN  - 1866-8372
IS  - 3
ER  - 
TY  - GEN
A1  - Boekstegers, Felix
A1  - Marcelain, Katherine
A1  - Barahona Ponce, Carol
A1  - Baez Benavides, Pablo F.
A1  - Müller, Bettina
A1  - de Toro, Gonzalo
A1  - Retamales, Javier
A1  - Barajas, Olga
A1  - Ahumada, Monica
A1  - Aleksandrova, Krasimira
A1  - Bermejo, Justo Lorenzo
T1  - ABCB1/4 gallbladder cancer risk variants identified in India also show strong effects in Chileans
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Background: The first large-scale genome-wide association study of gallbladder cancer (GBC) recently identified and validated three susceptibility variants in the ABCB1 and ABCB4 genes for individuals of Indian descent. We investigated whether these variants were also associated with GBC risk in Chileans, who show the highest incidence of GBC worldwide, and in Europeans with a low GBC incidence.
Methods: This population-based study analysed genotype data from retrospective Chilean case-control (255 cases, 2042 controls) and prospective European cohort (108 cases, 181 controls) samples consistently with the original publication.
Results: Our results confirmed the reported associations for Chileans with similar risk effects. Particularly strong associations (per-allele odds ratios close to 2) were observed for Chileans with high Native American (=Mapuche) ancestry. No associations were noticed for Europeans, but the statistical power was low.
Conclusion: Taking full advantage of genetic and ethnic differences in GBC risk may improve the efficiency of current prevention programs.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1204 
KW  - gallbladder cancer
KW  - population-specific risk marker
KW  - cancer epidemiology
KW  - native American ancestry
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-526833
SN  - 1866-8372
ER  - 
TY  - GEN
A1  - Christakoudi, Sofa
A1  - Tsilidis, Konstantinos K.
A1  - Muller, David C.
A1  - Freisling, Heinz
A1  - Weiderpass, Elisabete
A1  - Overvad, Kim
A1  - Söderberg, Stefan
A1  - Häggström, Christel
A1  - Pischon, Tobias
A1  - Dahm, Christina C.
A1  - Zhang, Jie
A1  - Tjønneland, Anne
A1  - Schulze, Matthias Bernd
T1  - A Body Shape Index (ABSI) achieves better mortality risk stratification than alternative indices of abdominal obesity: results from a large European cohort
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - 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.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1200 
KW  - all-cause mortality
KW  - anthropometric measures
KW  - mass index
KW  - overweight
KW  - cancer
KW  - prediction
KW  - adiposity
KW  - size
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-525827
SN  - 1866-8372
IS  - 1
ER  - 
TY  - JOUR
A1  - Klaus, Susanne
A1  - Ost, Mario
T1  - Mitochondrial uncoupling and longevity
BT  - a role for mitokines?
JF  - Experimental gerontology
N2  - Aging has been viewed both as a random process due to accumulation of molecular and cellular damage over time and as a programmed process linked to cellular pathway important for growth and maturation. These views converge on mitochondria as both the major producer of damaging reactive oxidant species (ROS) and as signaling organelles. A finite proton leak across the inner mitochondrial membrane leading to a slight uncoupling of oxidative phosphorylation and respiration is an intrinsic property of all mitochondria and according to the "uncoupling to survive" hypothesis it has evolved to protect against ROS production to minimize oxidative damage. This hypothesis is supported by evidence linking an increased endogenous, uncoupling protein (UCP1) mediated, as well as experimentally induced mitochondrial uncoupling to an increased lifespan in rodents. This is possibly due to the synergistic activation of molecular pathways linked to life extending effects of caloric restriction as well as a mitohormetic response. Mitohormesis is an adaptive stress response through mitonuclear signaling which increases stress resistance resulting in health promoting effects. Part of this response is the induction of fibroblast growth factor 21 (FGF21) and growth and differentiation factor 15 (GDF15), two stress-induced mitokines which elicit beneficial systemic metabolic effects via endocrine action.
KW  - Uncoupling proteins
KW  - Energy metabolism
KW  - Skeletal muscle
KW  - Mitohormesis
KW  - GDF15
KW  - FGF21
Y1  - 2019
U6  - https://doi.org/10.1016/j.exger.2019.110796
SN  - 0531-5565
SN  - 1873-6815
VL  - 130
PB  - Elsevier Science
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Ouni, Meriem
A1  - Schürmann, Annette
T1  - Epigenetic contribution to obesity
JF  - Mammalian genome
N2  - Obesity is a worldwide epidemic and contributes to global morbidity and mortality mediated via the development of nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), cardiovascular (CVD) and other diseases. It is a consequence of an elevated caloric intake, a sedentary lifestyle and a genetic as well as an epigenetic predisposition. This review summarizes changes in DNA methylation and microRNAs identified in blood cells and different tissues in obese human and rodent models. It includes information on epigenetic alterations which occur in response to fat-enriched diets, exercise and metabolic surgery and discusses the potential of interventions to reverse epigenetic modifications.
Y1  - 2020
U6  - https://doi.org/10.1007/s00335-020-09835-3
SN  - 0938-8990
SN  - 1432-1777
VL  - 31
IS  - 5-6
SP  - 134
EP  - 145
PB  - Springer
CY  - New York, NY ; Berlin ; Heidelberg [u.a.]
ER  - 
TY  - JOUR
A1  - Stadion, Mandy
A1  - Schürmann, Annette
T1  - Intermittierendes Fasten
BT  - was gibt es Neues aus der Wissenschaft?
BT  - what’s new from science?
JF  - Der Diabetologe
N2  - Obesity increases the risk of metabolic disorders and can lead to type 2 diabetes. Therefore, the treatment and prevention of obesity represent important medical challenges. Increased physical activity and a reduction in daily caloric intake of 25-30% are often recommended. Another possibility is intermittent fasting, by limiting dietary caloric content over certain times, i.e. one or more days a week or for more than 14 h a day. Animal and human studies provide evidence that intermittent fasting in obesity leads to a reduction in body fat mass as well as to improvements of metabolic parameters and insulin sensitivity. These positive effects are mediated not only by the decrease in body mass, but also by the activation of metabolic pathways and cellular processes that are specific for fasting conditions. In this article, we describe the current knowledge about the mechanisms induced by intermittent fasting and present results from randomized controlled human trials.
N2  - Übergewicht und Adipositas erhöhen die Risiken für Stoffwechselstörungen und können zu einem Typ-2-Diabetes führen. Deshalb stellen die Behandlung und Prävention von Fettleibigkeit eine große medizinische Herausforderung dar. Häufig werden eine erhöhte körperliche Aktivität und die Reduktion der täglichen Kalorienaufnahme um 25–30 % angeraten. Eine andere Möglichkeit bietet intermittierendes Fasten, also eine Kalorieneinschränkung über bestimmte Zeiten, d. h. an einem oder mehreren Tagen pro Woche oder über mehr als 14 h pro Tag. Tier- und Humanstudien lieferten Hinweise darauf, dass intermittierendes Fasten bei Adipositas zu einer Verringerung der Körperfettmasse sowie zu Verbesserungen der Stoffwechselparameter und der Insulinsensitivität führt. Diese positiven Effekte werden nicht nur allein durch die Abnahme der Körpermasse, sondern auch durch die Aktivierung von Stoffwechselwegen und zellulären Prozessen ausgelöst, die für Fastenbedingungen spezifisch sind. In diesem Artikel beschreiben wir die derzeit bekannten Mechanismen, die durch intermittierendes Fasten induziert werden, und stellen Ergebnisse aus randomisierten kontrollierten Studien am Menschen vor.
T2  - Intermittent fasting
KW  - Glucose metabolism disorders
KW  - Lipid metabolism
KW  - Insulin sensitivity
KW  - Energy metabolism
KW  - Circadian rhythm
KW  - Glukosestoffwechselstörungen
KW  - Fettstoffwechsel
KW  - Insulinsensitivität
KW  - Energiestoffwechsel
KW  - Zirkadianer Rhythmus
Y1  - 2020
U6  - https://doi.org/10.1007/s11428-020-00666-z
SN  - 1860-9716
SN  - 1860-9724
VL  - 16
IS  - 7
SP  - 641
EP  - 646
PB  - Springer Medizin
CY  - Berlin
ER  - 
TY  - JOUR
A1  - Borremans, An
A1  - Bußler, Sara
A1  - Sagu Tchewonpi, Sorel
A1  - Rawel, Harshadrai Manilal
A1  - Schlüter, Oliver K.
A1  - Leen, Van Campenhout
T1  - Effect of blanching plus fermentation on selected functional properties of mealworm (Tenebrio molitor) powders
JF  - Foods : open access journal
N2  - The aim of this study was to determine the effect of blanching followed by fermentation of mealworms (Tenebrio molitor) with commercial meat starter cultures on the functional properties of powders produced from the larvae. Full fat and defatted powder samples were prepared from non-fermented and fermented mealworm pastes. Then the crude protein, crude fat, and dry matter contents, pH, bulk density, colour, water and oil binding capacity, foaming capacity and stability, emulsion capacity and stability, protein solubility, quantity of free amino groups, and protein composition of the powders were evaluated. Regardless of the starter culture used, the blanching plus fermentation process reduced the crude and soluble protein contents of the full fat powders and in general impaired their water and oil binding, foaming, and emulsifying properties. Defatting of the powders improved most functional properties studied. The o-phthaldialdehyde assay revealed that the amount of free amino groups was higher in the fermented powders while sodium dodecyl sulfate polyacrylamide gel electrophoresis demonstrated that the soluble proteins of the fermented powders were composed of molecules of lower molecular mass compared to non-fermented powders. As molecular sizes of the soluble proteins decreased, it was clear that the protein structure was also modified by the fermentation process, which in turn led to changes in functional properties. In general, it was concluded that fermentation of mealworms with blanching as a pre-treatment does not contribute to the functional properties studied in this work. Nevertheless, the results confirmed that the properties of non-fermented powders are comparable to other food protein sources.
KW  - mealworm
KW  - fermentation
KW  - functional properties
KW  - insect proteins
KW  - SDS-PAGE
Y1  - 2020
U6  - https://doi.org/10.3390/foods9070917
SN  - 2304-8158
VL  - 9
IS  - 7
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Wright, Stephanie L.
A1  - Ulke, Jannis
A1  - Font, Anna
A1  - Chan, Ka Lung Andrew
A1  - Kelly, Frank J.
T1  - Atmospheric microplastic deposition in an urban environment and an evaluation of transport
JF  - Environment international
N2  - Microplastics are a global environmental issue contaminating aquatic and terrestrial environments. They have been reported in atmospheric deposition, and indoor and outdoor air, raising concern for public health due to the potential for exposure. Moreover, the atmosphere presents a new vehicle for microplastics to enter the wider environment, yet our knowledge of the quantities, characteristics and pathways of airborne microplastics is sparse. Here we show microplastics in atmospheric deposition in a major population centre, central London. Microplastics were found in all samples, with deposition rates ranging from 575 to 1008 microplastics/m(2)/d. They were found in various shapes, of which fibrous microplastics accounted for the great majority (92%). Across all samples, 15 different petrochemical-based polymers were identified. Bivariate polar plots indicated dependency on wind, with different source areas for fibrous and non-fibrous airborne microplastics. This is the first evidence of airborne microplastics in London and confirms the need to include airborne pathways when consolidating microplastic impacts on the wider environment and human health.
KW  - microplastics
KW  - atmospheric deposition
KW  - air pollution
KW  - urban
Y1  - 2020
U6  - https://doi.org/10.1016/j.envint.2019.105411
SN  - 0160-4120
SN  - 1873-6750
VL  - 136
PB  - Elsevier, Pergamon Press
CY  - New York, NY [u.a.]
ER  - 
TY  - JOUR
A1  - Schedlbauer, Carola
A1  - Blaue, Dominique
A1  - Raila, Jens
A1  - Vervuert, Ingrid
T1  - Alterations of serum vitamin E and vitamin A concentrations of ponies and horses during experimentally induced obesity
JF  - Journal of animal physiology and animal nutrition
JF  - Zeitschrift für Tierphysiologie, Tierernährung und Futtermittelkunde
N2  - 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.
KW  - body weight gain
KW  - equine
KW  - laminitis
KW  - retinol-binding protein 4
KW  - alpha-tocopherol
Y1  - 2020
U6  - https://doi.org/10.1111/jpn.13385
SN  - 0931-2439
SN  - 1439-0396
VL  - 104
IS  - 5
SP  - 1501
EP  - 1508
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Dünkelberg, Sophie
A1  - Maywald, Martina
A1  - Schmitt, Anne Kristina
A1  - Schwerdtle, Tanja
A1  - Meyer, Sören
A1  - Rink, Lothar
T1  - The interaction of sodium and zinc in the priming of T cell subpopulations regarding Th17 and Treg cells
JF  - Molecular nutrition & food research : bioactivity, chemistry, immunology, microbiology, safety, technology
N2  - Scope:
Nutrition is a critical determinant of a functional immune system. The aim of this study is to investigate the molecular mechanisms by which immune cells are influenced by zinc and sodium.

Methods and Results:
 Mixed lymphocyte cultures and Jurkat cells are generated and incubated with zinc, sodium, or a combination of both for further tests. Zinc induces the number of regulatory T cells (Treg) and decreases T helper 17 cells (Th17), and sodium has the opposite effect. The transforming growth factor beta receptor signaling pathway is also enhanced by zinc and reduced by sodium as indicated by contrary phosphoSmad 2/3 induction. Antagonistic effects can also be seen on zinc transporter and metallothionein-1 (MT-1) mRNA expression: zinc declines Zip10 mRNA expression while sodium induces it, whereas MT-1 mRNA expression is induced by zinc while it is reduced by sodium. 

Conclusion:
This data indicate that zinc and sodium display opposite effects regarding Treg and Th17 induction in MLC, respectively, resulting in a contrary effect on the immune system. Additionally, it reveals a direct interaction of zinc and sodium in the priming of T cell subpopulations and shows that Zip10 and MT-1 play a significant role in those differentiation pathways.
KW  - Foxp3
KW  - regulatory T cells
KW  - sodium
KW  - T helper 17 cells
KW  - zinc
Y1  - 2020
U6  - https://doi.org/10.1002/mnfr.201900245
SN  - 1613-4133
VL  - 64
IS  - 2
PB  - Wiley-VCH
CY  - Weinheim
ER  - 
TY  - JOUR
A1  - Sagu Tchewonpi, Sorel
A1  - Zimmermann, Lynn
A1  - Landgräber, Eva
A1  - Homann, Thomas
A1  - Huschek, Gerd
A1  - Özpinar, Haydar
A1  - Schweigert, Florian J.
A1  - Rawel, Harshadrai Manilal
T1  - Comprehensive Characterization and Relative Quantification of α-Amylase/Trypsin Inhibitors from Wheat Cultivars by Targeted HPLC-MS/MS
JF  - Foods
N2  - The α-amylase/trypsin inhibitors (ATIs) are discussed as being responsible for non-celiac wheat sensitivity (NCWS), besides being known as allergenic components for baker’s asthma. Different approaches for characterization and quantification including proteomics-based methods for wheat ATIs have been documented. In these studies generally the major ATIs have been addressed. The challenge of current study was then to develop a more comprehensive workflow encompassing all reviewed wheat-ATI entries in UniProt database. To substantially test proof of concept, 46 German and Turkish wheat samples were used. Two extractions systems based on chloroform/methanol mixture (CM) and under buffered denaturing conditions were evaluated. Three aspects were optimized, tryptic digestion, chromatographic separation, and targeted tandem mass spectrometric analysis (HPLC-MS/MS). Preliminary characterization with sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) documented the purity of the extracted ATIs with CM mixture and the amylase (60–80%)/trypsin (10–20%) inhibition demonstrated the bifunctional activity of ATIs. Thirteen (individual/common) biomarkers were established. Major ATIs (7–34%) were differently represented in samples. Finally, to our knowledge, the proposed HPLC-MS/MS method allowed for the first time so far the analysis of all 14 reviewed wheat ATI entries reported.
KW  - α-amylase/trypsin inhibitors
KW  - wheat cultivars
KW  - SDS-PAGE
KW  - peptides markers
KW  - relative quantification
KW  - mass spectrometry
KW  - LC-MRM-MS
Y1  - 2020
U6  - https://doi.org/10.3390/foods9101448
SN  - 2304-8158
VL  - 9
IS  - 10
PB  - MDPI
CY  - Basel
ER  - 
TY  - GEN
A1  - Sagu Tchewonpi, Sorel
A1  - Zimmermann, Lynn
A1  - Landgräber, Eva
A1  - Homann, Thomas
A1  - Huschek, Gerd
A1  - Özpinar, Haydar
A1  - Schweigert, Florian J.
A1  - Rawel, Harshadrai Manilal
T1  - Comprehensive Characterization and Relative Quantification of α-Amylase/Trypsin Inhibitors from Wheat Cultivars by Targeted HPLC-MS/MS
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - The α-amylase/trypsin inhibitors (ATIs) are discussed as being responsible for non-celiac wheat sensitivity (NCWS), besides being known as allergenic components for baker’s asthma. Different approaches for characterization and quantification including proteomics-based methods for wheat ATIs have been documented. In these studies generally the major ATIs have been addressed. The challenge of current study was then to develop a more comprehensive workflow encompassing all reviewed wheat-ATI entries in UniProt database. To substantially test proof of concept, 46 German and Turkish wheat samples were used. Two extractions systems based on chloroform/methanol mixture (CM) and under buffered denaturing conditions were evaluated. Three aspects were optimized, tryptic digestion, chromatographic separation, and targeted tandem mass spectrometric analysis (HPLC-MS/MS). Preliminary characterization with sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) documented the purity of the extracted ATIs with CM mixture and the amylase (60–80%)/trypsin (10–20%) inhibition demonstrated the bifunctional activity of ATIs. Thirteen (individual/common) biomarkers were established. Major ATIs (7–34%) were differently represented in samples. Finally, to our knowledge, the proposed HPLC-MS/MS method allowed for the first time so far the analysis of all 14 reviewed wheat ATI entries reported.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1028 
KW  - α-amylase/trypsin inhibitors
KW  - wheat cultivars
KW  - SDS-PAGE
KW  - peptides markers
KW  - relative quantification
KW  - mass spectrometry
KW  - LC-MRM-MS
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-486118
SN  - 1866-8372
IS  - 1028
ER  - 
TY  - JOUR
A1  - Cencetti, Francesca
A1  - Bruno, Gennaro
A1  - Bernacchioni, Caterina
A1  - Japtok, Lukasz
A1  - Puliti, Elisa
A1  - Donati, Chiara
A1  - Bruni, Paola
T1  - Sphingosine 1-phosphate lyase blockade elicits myogenic differentiation of murine myoblasts acting via Spns2/S1P(2) receptor axis
JF  - Biochimica et biophysica acta : Molecular and cell biology of lipids
N2  - The bioactive sphingolipid sphingosine 1-phosphate (S1P) has emerged in the last three decades as main regulator of key cellular processes including cell proliferation, survival, migration and differentiation. A crucial role for this sphingolipid has been recognized in skeletal muscle cell biology both in vitro and in vivo. S1P lyase (SPL) is responsible for the irreversible degradation of S1P and together with sphingosine kinases, the S1P producing enzymes, regulates cellular S1P levels. In this study is clearly showed that the blockade of SPL by pharmacological or RNA interference approaches induces myogenic differentiation of C2C12 myoblasts. Moreover, down-regulation of the specific S1P transporter spinster homolog 2 (Spns2) abrogates myogenic differentiation brought about by SPL inhibition or down-regulation, pointing at a role of extracellular S1P in the pro-myogenic action induced by SPL blockade. Furthermore, also S1P(2) receptor down-regulation was found to abrogate the pro-myogenic effect of SPL blockade. These results provide further proof that inside-out S1P signaling is critically implicated in skeletal muscle biology and provide support to the concept that the specific targeting of SPL could represent an exploitable strategy to treat skeletal muscle disorders.
KW  - Sphingosine 1-phosphate
KW  - Myogenic differentiation
Y1  - 2020
U6  - https://doi.org/10.1016/j.bbalip.2020.158759
SN  - 1388-1981
SN  - 1879-2618
VL  - 1865
IS  - 9
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - GEN
A1  - Sagu Tchewonpi, Sorel
A1  - Landgräber, Eva
A1  - Rackiewicz, Michal
A1  - Huschek, Gerd
A1  - Rawel, Harshadrai Manilal
T1  - Relative Abundance of Alpha-Amylase/Trypsin Inhibitors in Selected Sorghum Cultivars
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Sorghum is of growing interest and considered as a safe food for wheat related disorders. Besides the gluten, α-amylase/trypsin-inhibitors (ATIs) have been identified as probable candidates for these disorders. Several studies focused on wheat-ATIs although there is still a lack of data referring to the relative abundance of sorghum-ATIs. The objective of this work was therefore to contribute to the characterization of sorghum ATI profiles by targeted proteomics tools. Fifteen sorghum cultivars from different regions were investigated with raw proteins ranging from 7.9 to 17.0 g/100 g. Ammonium bicarbonate buffer in combination with urea was applied for protein extraction, with concentration from 0.588 ± 0.047 to 4.140 ± 0.066 mg/mL. Corresponding electrophoresis data showed different protein profiles. UniProtKB data base research reveals two sorghum ATIs, P81367 and P81368; both reviewed and a targeted LC–MS/MS method was developed to analyze these. Quantifier peptides ELAAVPSR (P81367) and TYMVR (P81368) were identified and retained as biomarkers for relative quantification. Different reducing and alkylating agents were assessed and combination of tris (2 carboxyethyl) phosphine/iodoacetamide gave the best response. Linearity was demonstrated for the quantifier peptides with standard recovery between 92.2 and 107.6%. Nine sorghum cultivars presented up to 60 times lower ATI contents as compared to wheat samples. This data suggests that sorghum can effectively be considered as a good alternative to wheat.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1068 
KW  - sorghum
KW  - α-amylase/trypsin inhibitors
KW  - reducing agents
KW  - cysteine alkylation
KW  - SDS PAGE
KW  - targeted proteomics
KW  - LC–MS/MS
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-488096
SN  - 1866-8372
IS  - 1068
ER  - 
TY  - JOUR
A1  - Sagu Tchewonpi, Sorel
A1  - Landgräber, Eva
A1  - Rackiewicz, Michal
A1  - Huschek, Gerd
A1  - Rawel, Harshadrai Manilal
T1  - Relative Abundance of Alpha-Amylase/Trypsin Inhibitors in Selected Sorghum Cultivars
JF  - Molecules
N2  - Sorghum is of growing interest and considered as a safe food for wheat related disorders. Besides the gluten, α-amylase/trypsin-inhibitors (ATIs) have been identified as probable candidates for these disorders. Several studies focused on wheat-ATIs although there is still a lack of data referring to the relative abundance of sorghum-ATIs. The objective of this work was therefore to contribute to the characterization of sorghum ATI profiles by targeted proteomics tools. Fifteen sorghum cultivars from different regions were investigated with raw proteins ranging from 7.9 to 17.0 g/100 g. Ammonium bicarbonate buffer in combination with urea was applied for protein extraction, with concentration from 0.588 ± 0.047 to 4.140 ± 0.066 mg/mL. Corresponding electrophoresis data showed different protein profiles. UniProtKB data base research reveals two sorghum ATIs, P81367 and P81368; both reviewed and a targeted LC–MS/MS method was developed to analyze these. Quantifier peptides ELAAVPSR (P81367) and TYMVR (P81368) were identified and retained as biomarkers for relative quantification. Different reducing and alkylating agents were assessed and combination of tris (2 carboxyethyl) phosphine/iodoacetamide gave the best response. Linearity was demonstrated for the quantifier peptides with standard recovery between 92.2 and 107.6%. Nine sorghum cultivars presented up to 60 times lower ATI contents as compared to wheat samples. This data suggests that sorghum can effectively be considered as a good alternative to wheat.
KW  - sorghum
KW  - α-amylase/trypsin inhibitors
KW  - reducing agents
KW  - cysteine alkylation
KW  - SDS PAGE
KW  - targeted proteomics
KW  - LC–MS/MS
Y1  - 2020
U6  - https://doi.org/10.3390/molecules25245982
SN  - 1420-3049
VL  - 25
IS  - 24
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Xiong, Chan
A1  - Stiboller, Michael
A1  - Glabonjat, Ronald A.
A1  - Rieger, Jaqueline
A1  - Paton, Lhiam
A1  - Francesconi, Kevin A.
T1  - Transport of arsenolipids to the milk of a nursing mother after consuming salmon fish
JF  - Journal of trace elements in medicine and biology
N2  - Objective: 
We address two questions relevant to infants' exposure to potentially toxic arsenolipids, namely, are the arsenolipids naturally present in fish transported intact to a mother's milk, and what is the efficiency of this transport.

Methods: 
We investigated the transport of arsenolipids and other arsenic species present in fish to mother's milk by analyzing the milk of a single nursing mother at 15 sampling times over a 3-day period after she had consumed a meal of salmon. Total arsenic values were obtained by elemental mass spectrometry, and arsenic species were measured by HPLC coupled to both elemental and molecular mass spectrometry.

Results: 
Total arsenic increased from background levels (0.1 mu g As kg(-1)) to a peak value of 1.72 lig As kg(-1) eight hours after the fish meal. The pattern for arsenolipids was similar to that of total arsenic, increasing from undetectable background levels (< 0.01 mu g As kg(-1)) to a peak after eight hours of 0.45 mu g As kg(-1). Most of the remaining total arsenic in the milk was accounted for by arsenobetaine. The major arsenolipids in the salmon were arsenic hydrocarbons (AsHCs; 55 % of total arsenolipids), and these compounds were also the dominant arsenolipids in the milk where they contributed over 90 % of the total arsenolipids. 

Conclusions:
Our study has shown that ca 2-3 % of arsenic hydrocarbons, natural constituents of fish, can be directly transferred unchanged to the milk of a nursing mother. In view of the potential neurotoxicity of AsHCs, the effects of these compounds on the brain developmental stage of infants need to be investigated.
KW  - human milk
KW  - arsenolipids
KW  - salmon fish
KW  - HPLC/ICPMS
KW  - HPLC/HR-ESMS
Y1  - 2020
U6  - https://doi.org/10.1016/j.jtemb.2020.126502
SN  - 0946-672X
VL  - 61
PB  - Elsevier
CY  - München
ER  - 
TY  - GEN
A1  - Rodríguez Sillke, Yasmina
A1  - Schumann, Michael
A1  - Lissner, Donata
A1  - Branchi, Frederica
A1  - Glauben, Rainer
A1  - Siegmund, Britta
T1  - Small intestinal inflammation but not colitis drives pro-inflammatory nutritional antigen-specific T-cell response
T2  - Journal of Crohn's and Colitis
N2  - Background: 
Inflammatory bowel disease (IBD) represents a dysregulation of the mucosal immune system. The pathogenesis of Crohn’s disease (CD) and ulcerative colitis (UC) is linked to the loss of intestinal tolerance and barrier function. The healthy mucosal immune system has previously been shown to be inert against food antigens. Since the small intestine is the main contact surface for antigens and therefore the immunological response, the present study served to analyse food-antigen-specific T cells in the peripheral blood of IBD patients.

Methods: 
Peripheral blood mononuclear cells of CD, with an affected small intestine, and UC (colitis) patients, either active or in remission, were stimulated with the following food antigens: gluten, soybean, peanut and ovalbumin. Healthy controls and celiac disease patients were included as controls. Antigen-activated CD4+ T cells in the peripheral blood were analysed by a magnetic enrichment of CD154+ effector T cells and a cytometric antigen-reactive T-cell analysis (‘ARTE’ technology) followed by characterisation of the ef- fector response.

Results:
The effector T-cell response of antigen-specific T cells were compared between CD with small intestinal inflammation and UC where inflammation was restricted to the colon. Among all tested food antigens, the highest frequency of antigen-specific T cells (CD4+CD154+) was found for gluten. Celiac disease patients were included as control, since gluten has been identified as the disease- causing antigen. The highest frequency of gluten antigen-specific T cells was revealed in active CD when compared with UC, celiac disease on a gluten-free diet (GFD) and healthy controls. Ovalbuminspecific T cells were almost undetectable, whereas the reaction to soybean and peanut was slightly higher. But again, the strong- est reaction was observed in CD with small intestinal involvement compared with UC. Remarkably, in celiac disease on a GFD only
antigen-specific cells for gluten were detected. These gluten-specific T cells were characterised by up-regulation of the pro-inflammatory cytokines IFN-γ, IL-17A and TNF-α. IFN-g was exclusively elevated in CD patients with active disease. Gluten-specific T-cells expressing IL-17A were increased in all IBD patients. Furthermore, T cells of CD patients, independent of disease activity, revealed a high expression of the pro-inflammatory cytokine TNF-α.

Conclusion:
The ‘ARTE’-technique allows to analyse and quantify food antigen specific T cells in the peripheral blood of IBD patients indicating a potential therapeutic insight. These data provide evidence that small intestinal inflammation in CD is key for the development of a systemic pro-inflammatory effector T-cell response driven by food antigens.
Y1  - 2020
U6  - https://doi.org/10.1093/ecco-jcc/jjz203.172
SN  - 1873-9946
SN  - 1876-4479
VL  - 14
SP  - S154
EP  - S155
PB  - Oxford Univ. Press
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Stepanovska, Bisera
A1  - Zivkovic, Aleksandra
A1  - Enzmann, Gaby
A1  - Tietz, Silvia
A1  - Homann, Thomas
A1  - Kleuser, Burkhard
A1  - Engelhardt, Britta
A1  - Stark, Holger
A1  - Huwiler, Andrea
T1  - Morpholino analogues of fingolimod as novel and selective S1P1 ligands with in vivo efficacy in a mouse model of experimental antigen-induced encephalomyelitis
JF  - International journal of molecular sciences
N2  - Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the central nervous system (CNS) which is associated with lower life expectancy and disability. The experimental antigen-induced encephalomyelitis (EAE) in mice is a useful animal model of MS, which allows exploring the etiopathogenetic mechanisms and testing novel potential therapeutic drugs. A new therapeutic paradigm for the treatment of MS was introduced in 2010 through the sphingosine 1-phosphate (S1P) analogue fingolimod (FTY720, Gilenya(R)), which acts as a functional S1P(1) antagonist on T lymphocytes to deplete these cells from the blood. In this study, we synthesized two novel structures, ST-1893 and ST-1894, which are derived from fingolimod and chemically feature a morpholine ring in the polar head group. These compounds showed a selective S1P(1) activation profile and a sustained S1P(1) internalization in cultures of S1P(1)-overexpressing Chinese hamster ovary (CHO)-K1 cells, consistent with a functional antagonism. In vivo, both compounds induced a profound lymphopenia in mice. Finally, these substances showed efficacy in the EAE model, where they reduced clinical symptoms of the disease, and, on the molecular level, they reduced the T-cell infiltration and several inflammatory mediators in the brain and spinal cord. In summary, these data suggest that S1P(1)-selective compounds may have an advantage over fingolimod and siponimod, not only in MS but also in other autoimmune diseases.
KW  - ST-1893
KW  - ST-1894
KW  - morpholino analogues of fingolimod
KW  - sphingosine
KW  - 1-phosphate
KW  - immunomodulator
KW  - lymphopenia
KW  - multiple sclerosis
KW  - experimental antigen-induced encephalomyelitis
Y1  - 2020
U6  - https://doi.org/10.3390/ijms21186463
SN  - 1422-0067
VL  - 21
IS  - 18
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Ost, Mario
A1  - Igual Gil, Carla
A1  - Coleman, Verena
A1  - Keipert, Susanne
A1  - Efstathiou, Sotirios
A1  - Vidic, Veronika
A1  - Weyers, Miriam
A1  - Klaus, Susanne
T1  - Muscle-derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress
JF  - EMBO reports
N2  - Mitochondrial dysfunction promotes metabolic stress responses in a cell-autonomous as well as organismal manner. The wasting hormone growth differentiation factor 15 (GDF15) is recognized as a biomarker of mitochondrial disorders, but its pathophysiological function remains elusive. To test the hypothesis that GDF15 is fundamental to the metabolic stress response during mitochondrial dysfunction, we investigated transgenic mice (Ucp1-TG) with compromised muscle-specific mitochondrial OXPHOS capacity via respiratory uncoupling. Ucp1-TG mice show a skeletal muscle-specific induction and diurnal variation of GDF15 as a myokine. Remarkably, genetic loss of GDF15 in Ucp1-TG mice does not affect muscle wasting or transcriptional cell-autonomous stress response but promotes a progressive increase in body fat mass. Furthermore, muscle mitochondrial stress-induced systemic metabolic flexibility, insulin sensitivity, and white adipose tissue browning are fully abolished in the absence of GDF15. Mechanistically, we uncovered a GDF15-dependent daytime-restricted anorexia, whereas GDF15 is unable to suppress food intake at night. Altogether, our evidence suggests a novel diurnal action and key pathophysiological role of mitochondrial stress-induced GDF15 in the regulation of systemic energy metabolism.
KW  - anorexia
KW  - GDF15
KW  - integrated stress response
KW  - mitochondrial dysfunction
KW  - muscle wasting
Y1  - 2020
U6  - https://doi.org/10.15252/embr.201948804
SN  - 1469-221X
SN  - 1469-3178
VL  - 21
IS  - 3
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Volk, Christin
A1  - Brandsch, Corinna
A1  - Schlegelmilch, Ulf
A1  - Wensch-Dorendorf, Monika
A1  - Hirche, Frank
A1  - Simm, Andreas
A1  - Gargum, Osama
A1  - Wiacek, Claudia
A1  - Braun, Peggy G.
A1  - Kopp, Johannes F.
A1  - Schwerdtle, Tanja
A1  - Treede, Hendrik
A1  - Stangl, Gabriele I.
T1  - Postprandial metabolic response to rapeseed protein in healthy subjects
JF  - Nutrients
N2  - Plant proteins have become increasingly important for ecological reasons. Rapeseed is a novel source of plant proteins with high biological value, but its metabolic impact in humans is largely unknown. A randomized, controlled intervention study including 20 healthy subjects was conducted in a crossover design. All participants received a test meal without additional protein or with 28 g of rapeseed protein isolate or soy protein isolate (control). Venous blood samples were collected over a 360-min period to analyze metabolites; satiety was assessed using a visual analog scale. Postprandial levels of lipids, urea, and amino acids increased following the intake of both protein isolates. The postprandial insulin response was lower after consumption of the rapeseed protein than after intake of the soy protein (p< 0.05), whereas the postmeal responses of glucose, lipids, interleukin-6, minerals, and urea were comparable between the two protein isolates. Interestingly, the rapeseed protein exerted stronger effects on postprandial satiety than the soy protein (p< 0.05). The postmeal metabolism following rapeseed protein intake is comparable with that of soy protein. The favorable effect of rapeseed protein on postprandial insulin and satiety makes it a valuable plant protein for human nutrition.
KW  - rapeseed protein
KW  - soy protein
KW  - postprandial study
KW  - metabolic response
KW  - healthy subjects
Y1  - 2020
U6  - https://doi.org/10.3390/nu12082270
SN  - 2072-6643
VL  - 12
IS  - 8
PB  - MDPI
CY  - Basel
ER  - 
TY  - GEN
A1  - Lang, Judith
A1  - Bohn, Patrick
A1  - Bhat, Hilal
A1  - Jastrow, Holger
A1  - Walkenfort, Bernd
A1  - Cansiz, Feyza
A1  - Fink, Julian
A1  - Bauer, Michael
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Lang, Karl S.
T1  - Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Macrophages have important protective functions during infection with herpes simplex virus type 1 (HSV-1). However, molecular mechanisms that restrict viral propagation and protect from severe disease are unclear. Here we show that macrophages take up HSV-1 via endocytosis and transport the virions into multivesicular bodies (MVBs). In MVBs, acid ceramidase (aCDase) converts ceramide into sphingosine and increases the formation of sphingosine-rich intraluminal vesicles (ILVs). Once HSV-1 particles reach MVBs, sphingosine-rich ILVs bind to HSV-1 particles, which restricts fusion with the limiting endosomal membrane and prevents cellular infection. Lack of aCDase in macrophage cultures or in Asah1(-/-) mice results in replication of HSV-1 and Asah1(-/-) mice die soon after systemic or intravaginal inoculation. The treatment of macrophages with sphingosine enhancing compounds blocks HSV-1 propagation, suggesting a therapeutic potential of this pathway. In conclusion, aCDase loads ILVs with sphingosine, which prevents HSV-1 capsids from penetrating into the cytosol.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1400 
KW  - immunology
KW  - infection
KW  - membrane fusion
KW  - phagocytosis
KW  - sphingolipids
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-515661
SN  - 1866-8372
IS  - 1
ER  - 
TY  - JOUR
A1  - Samaha, Doaa
A1  - Hamdo, Housam H.
A1  - Cong, Xiaojing
A1  - Schumacher, Fabian
A1  - Banhart, Sebastian
A1  - Aglar, Öznur
A1  - Möller, Heiko Michael
A1  - Heuer, Dagmar
A1  - Kleuser, Burkhard
A1  - Saied, Essa M.
A1  - Arenz, Christoph
T1  - Liposomal FRET assay identifies potent drug-like inhibitors of the Ceramide Transport Protein (CERT)
JF  - Chemistry - a European journal
N2  - Ceramide transfer protein (CERT) mediates non-vesicular transfer of ceramide from endoplasmic reticulum to Golgi apparatus and thus catalyzes the rate-limiting step of sphingomyelin biosynthesis. Usually, CERT ligands are evaluated in tedious binding assays or non-homogenous transfer assays using radiolabeled ceramides. Herein, a facile and sensitive assay for CERT, based on Forster resonance energy transfer (FRET), is presented. To this end, we mixed donor and acceptor vesicles, each containing a different fluorescent ceramide species. By CERT-mediated transfer of fluorescent ceramide, a FRET system was established, which allows readout in 96-well plate format, despite the high hydrophobicity of the components. Screening of a 2 000 compound library resulted in two new potent CERT inhibitors. One is approved for use in humans and one is approved for use in animals. Evaluation of cellular activity by quantitative mass spectrometry and confocal microscopy showed inhibition of ceramide trafficking and sphingomyelin biosynthesis.
KW  - enzyme assays
KW  - Forster resonance energy transfer (FRET)
KW  - liposomes
KW  - sphingolipids
KW  - transport proteins
Y1  - 2020
U6  - https://doi.org/10.1002/chem.202003283
SN  - 0947-6539
SN  - 1521-3765
VL  - 26
IS  - 70
SP  - 16616
EP  - 16621
PB  - Wiley-VCH
CY  - Weinheim
ER  - 
TY  - JOUR
A1  - Lang, Judith
A1  - Bohn, Patrick
A1  - Bhat, Hilal
A1  - Jastrow, Holger
A1  - Walkenfort, Bernd
A1  - Cansiz, Feyza
A1  - Fink, Julian
A1  - Bauer, Michael
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Lang, Karl S.
T1  - Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease
JF  - Nature Communications
N2  - Macrophages have important protective functions during infection with herpes simplex virus type 1 (HSV-1). However, molecular mechanisms that restrict viral propagation and protect from severe disease are unclear. Here we show that macrophages take up HSV-1 via endocytosis and transport the virions into multivesicular bodies (MVBs). In MVBs, acid ceramidase (aCDase) converts ceramide into sphingosine and increases the formation of sphingosine-rich intraluminal vesicles (ILVs). Once HSV-1 particles reach MVBs, sphingosine-rich ILVs bind to HSV-1 particles, which restricts fusion with the limiting endosomal membrane and prevents cellular infection. Lack of aCDase in macrophage cultures or in Asah1(-/-) mice results in replication of HSV-1 and Asah1(-/-) mice die soon after systemic or intravaginal inoculation. The treatment of macrophages with sphingosine enhancing compounds blocks HSV-1 propagation, suggesting a therapeutic potential of this pathway. In conclusion, aCDase loads ILVs with sphingosine, which prevents HSV-1 capsids from penetrating into the cytosol.
KW  - immunology
KW  - infection
KW  - membrane fusion
KW  - phagocytosis
KW  - sphingolipids
Y1  - 2020
U6  - https://doi.org/10.1038/s41467-020-15072-8
SN  - 2041-1723
VL  - 11
IS  - 1
SP  - 1
EP  - 15
PB  - Nature Publishing Group UK
CY  - London
ER  - 
TY  - JOUR
A1  - Aga-Barfknecht, Heja
A1  - Hallahan, Nicole
A1  - Gottmann, Pascal
A1  - Jähnert, Markus
A1  - Osburg, Sophie
A1  - Schulze, Gunnar
A1  - Kamitz, Anne
A1  - Arends, Danny
A1  - Brockmann, Gudrun
A1  - Schallschmidt, Tanja
A1  - Lebek, Sandra
A1  - Chadt, Alexandra
A1  - Al-Hasani, Hadi
A1  - Joost, Hans-Georg
A1  - Schürmann, Annette
A1  - Vogel, Heike
T1  - Identification of novel potential type 2 diabetes genes mediating beta-cell loss and hyperglycemia using positional cloning
JF  - Frontiers in genetics
N2  - Type 2 diabetes (T2D) is a complex metabolic disease regulated by an interaction of genetic predisposition and environmental factors. To understand the genetic contribution in the development of diabetes, mice varying in their disease susceptibility were crossed with the obese and diabetes-prone New Zealand obese (NZO) mouse. Subsequent whole-genome sequence scans revealed one major quantitative trait loci (QTL),Nidd/DBAon chromosome 4, linked to elevated blood glucose and reduced plasma insulin and low levels of pancreatic insulin. Phenotypical characterization of congenic mice carrying 13.6 Mbp of the critical fragment of DBA mice displayed severe hyperglycemia and impaired glucose clearance at week 10, decreased glucose response in week 13, and loss of beta-cells and pancreatic insulin in week 16. To identify the responsible gene variant(s), further congenic mice were generated and phenotyped, which resulted in a fragment of 3.3 Mbp that was sufficient to induce hyperglycemia. By combining transcriptome analysis and haplotype mapping, the number of putative responsible variant(s) was narrowed from initial 284 to 18 genes, including gene models and non-coding RNAs. Consideration of haplotype blocks reduced the number of candidate genes to four (Kti12,Osbpl9,Ttc39a, andCalr4) as potential T2D candidates as they display a differential expression in pancreatic islets and/or sequence variation. In conclusion, the integration of comparative analysis of multiple inbred populations such as haplotype mapping, transcriptomics, and sequence data substantially improved the mapping resolution of the diabetes QTLNidd/DBA. Future studies are necessary to understand the exact role of the different candidates in beta-cell function and their contribution in maintaining glycemic control.
KW  - type 2 diabetes
KW  - beta-cell loss
KW  - insulin
KW  - positional cloning
KW  - transcriptomics
KW  - haplotype
Y1  - 2020
U6  - https://doi.org/10.3389/fgene.2020.567191
SN  - 1664-8021
VL  - 11
PB  - Frontiers Media
CY  - Lausanne
ER  - 
TY  - JOUR
A1  - Olayide, Priscilla
A1  - Large, Annabel
A1  - Stridh, Linnea
A1  - Rabbi, Ismail
A1  - Baldermann, Susanne
A1  - Stavolone, Livia
A1  - Alexandersson, Erik
T1  - Gene expression and metabolite profiling of thirteen Nigerian cassava landraces to elucidate starch and carotenoid composition
JF  - Agronomy
N2  - The prevalence of vitamin A deficiency in sub-Saharan Africa necessitates effective approaches to improve provitamin A content of major staple crops. Cassava holds much promise for food security in sub-Saharan Africa, but a negative correlation between beta-carotene, a provitamin A carotenoid, and dry matter content has been reported, which poses a challenge to cassava biofortification by conventional breeding. To identify suitable material for genetic transformation in tissue culture with the overall aim to increase beta-carotene and maintain starch content as well as better understand carotenoid composition, root and leaf tissues from thirteen field-grown cassava landraces were analyzed for agronomic traits, carotenoid, chlorophyll, and starch content. The expression of five genes related to carotenoid biosynthesis were determined in selected landraces. Analysis revealed a weak negative correlation between starch and beta-carotene content, whereas there was a strong positive correlation between root yield and many carotenoids including beta-carotene. Carotenoid synthesis genes were expressed in both white and yellow cassava roots, but phytoene synthase 2 (PSY2), lycopene-epsilon-cyclase (LCY epsilon), and beta-carotenoid hydroxylase (CHY beta) expression were generally higher in yellow roots. This study identified lines with reasonably high content of starch and beta-carotene that could be candidates for biofortification by further breeding or plant biotechnological means.
KW  - carotenoid biosynthesis
KW  - ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS)
KW  - provitamin A
KW  - biofortification
Y1  - 2020
U6  - https://doi.org/10.3390/agronomy10030424
SN  - 2073-4395
VL  - 10
IS  - 3
SP  - 1
EP  - 16
PB  - MDPI
CY  - Basel
ER  - 
TY  - GEN
A1  - Olayide, Priscilla
A1  - Large, Annabel
A1  - Stridh, Linnea
A1  - Rabbi, Ismail
A1  - Baldermann, Susanne
A1  - Stavolone, Livia
A1  - Alexandersson, Erik
T1  - Gene expression and metabolite profiling of thirteen Nigerian cassava landraces to elucidate starch and carotenoid composition
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - The prevalence of vitamin A deficiency in sub-Saharan Africa necessitates effective approaches to improve provitamin A content of major staple crops. Cassava holds much promise for food security in sub-Saharan Africa, but a negative correlation between beta-carotene, a provitamin A carotenoid, and dry matter content has been reported, which poses a challenge to cassava biofortification by conventional breeding. To identify suitable material for genetic transformation in tissue culture with the overall aim to increase beta-carotene and maintain starch content as well as better understand carotenoid composition, root and leaf tissues from thirteen field-grown cassava landraces were analyzed for agronomic traits, carotenoid, chlorophyll, and starch content. The expression of five genes related to carotenoid biosynthesis were determined in selected landraces. Analysis revealed a weak negative correlation between starch and beta-carotene content, whereas there was a strong positive correlation between root yield and many carotenoids including beta-carotene. Carotenoid synthesis genes were expressed in both white and yellow cassava roots, but phytoene synthase 2 (PSY2), lycopene-epsilon-cyclase (LCY epsilon), and beta-carotenoid hydroxylase (CHY beta) expression were generally higher in yellow roots. This study identified lines with reasonably high content of starch and beta-carotene that could be candidates for biofortification by further breeding or plant biotechnological means.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1415 
KW  - carotenoid biosynthesis
KW  - ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS)
KW  - provitamin A
KW  - biofortification
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-517834
SN  - 1866-8372
IS  - 3
ER  - 
TY  - GEN
A1  - Zoicas, Iulia
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Reichel, Martin
A1  - Gulbins, Erich
A1  - Fejtova, Anna
A1  - Kornhuber, Johannes
A1  - Rhein, Cosima
T1  - The forebrain-specific overexpression of acid sphingomyelinase induces depressive-like symptoms in mice
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Human and murine studies identified the lysosomal enzyme acid sphingomyelinase (ASM) as a target for antidepressant therapy and revealed its role in the pathophysiology of major depression. In this study, we generated a mouse model with overexpression of Asm (Asm-tg(fb)) that is restricted to the forebrain to rule out any systemic effects of Asm overexpression on depressive-like symptoms. The increase in Asm activity was higher in male Asm-tg(fb) mice than in female Asm-tg(fb) mice due to the breeding strategy, which allows for the generation of wild-type littermates as appropriate controls. Asm overexpression in the forebrain of male mice resulted in a depressive-like phenotype, whereas in female mice, Asm overexpression resulted in a social anxiogenic-like phenotype. Ceramides in male Asm-tg(fb) mice were elevated specifically in the dorsal hippocampus. mRNA expression analyses indicated that the increase in Asm activity affected other ceramide-generating pathways, which might help to balance ceramide levels in cortical brain regions. This forebrain-specific mouse model offers a novel tool for dissecting the molecular mechanisms that play a role in the pathophysiology of major depression.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1186 
KW  - Smpd1
KW  - acid sphingomyelinase
KW  - forebrain
KW  - depressive-like behavior
KW  - anxiety-like behavior
KW  - ceramide
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-524368
SN  - 1866-8372
IS  - 5
ER  - 
TY  - JOUR
A1  - Zoicas, Iulia
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Reichel, Martin
A1  - Gulbins, Erich
A1  - Fejtova, Anna
A1  - Kornhuber, Johannes
A1  - Rhein, Cosima
T1  - The forebrain-specific overexpression of acid sphingomyelinase induces depressive-like symptoms in mice
JF  - Cells
N2  - Human and murine studies identified the lysosomal enzyme acid sphingomyelinase (ASM) as a target for antidepressant therapy and revealed its role in the pathophysiology of major depression. In this study, we generated a mouse model with overexpression of Asm (Asm-tg(fb)) that is restricted to the forebrain to rule out any systemic effects of Asm overexpression on depressive-like symptoms. The increase in Asm activity was higher in male Asm-tg(fb) mice than in female Asm-tg(fb) mice due to the breeding strategy, which allows for the generation of wild-type littermates as appropriate controls. Asm overexpression in the forebrain of male mice resulted in a depressive-like phenotype, whereas in female mice, Asm overexpression resulted in a social anxiogenic-like phenotype. Ceramides in male Asm-tg(fb) mice were elevated specifically in the dorsal hippocampus. mRNA expression analyses indicated that the increase in Asm activity affected other ceramide-generating pathways, which might help to balance ceramide levels in cortical brain regions. This forebrain-specific mouse model offers a novel tool for dissecting the molecular mechanisms that play a role in the pathophysiology of major depression.
KW  - Smpd1
KW  - acid sphingomyelinase
KW  - forebrain
KW  - depressive-like behavior
KW  - anxiety-like behavior
KW  - ceramide
Y1  - 2020
VL  - 9
IS  - 5
PB  - MDPI
CY  - Basel
ER  - 
TY  - GEN
A1  - Dwi Putra, Sulistyo Emantoko
A1  - Reichetzeder, Christoph
A1  - Hasan, Ahmed Abdallah Abdalrahman Mohamed
A1  - Slowinski, Torsten
A1  - Chu, Chang
A1  - Krämer, Bernhard K.
A1  - Kleuser, Burkhard
A1  - Hocher, Berthold
T1  - Being born large for gestational age is associated with increased global placental DNA methylation
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Being born small (SGA) or large for gestational age (LGA) is associated with adverse birth outcomes and metabolic diseases in later life of the offspring. It is known that aberrations in growth during gestation are related to altered placental function. Placental function is regulated by epigenetic mechanisms such as DNA methylation. Several studies in recent years have demonstrated associations between altered patterns of DNA methylation and adverse birth outcomes. However, larger studies that reliably investigated global DNA methylation are lacking. The aim of this study was to characterize global placental DNA methylation in relationship to size for gestational age. Global DNA methylation was assessed in 1023 placental samples by LC-MS/MS. LGA offspring displayed significantly higher global placental DNA methylation compared to appropriate for gestational age (AGA; p<0.001). ANCOVA analyses adjusted for known factors impacting on DNA methylation demonstrated an independent association between placental global DNA methylation and LGA births (p<0.001). Tertile stratification according to global placental DNA methylation levels revealed a significantly higher frequency of LGA births in the third tertile. Furthermore, a multiple logistic regression analysis corrected for known factors influencing birth weight highlighted an independent positive association between global placental DNA methylation and the frequency of LGA births (p=0.001).
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1405 
KW  - fetal origins hypothesis
KW  - birth weight
KW  - repetitive elements
KW  - glucocorticoid receptor
KW  - nutrient transport
KW  - growth restriction
KW  - later health
KW  - pregnancy
KW  - genes
KW  - patterns
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-516289
SN  - 1866-8372
IS  - 1
ER  - 
TY  - JOUR
A1  - Dwi Putra, Sulistyo Emantoko
A1  - Reichetzeder, Christoph
A1  - Hasan, Ahmed Abdallah Abdalrahman Mohamed
A1  - Slowinski, Torsten
A1  - Chu, Chang
A1  - Krämer, Bernhard K.
A1  - Kleuser, Burkhard
A1  - Hocher, Berthold
T1  - Being born large for gestational age is associated with increased global placental DNA methylation
JF  - Scientific Reports
N2  - Being born small (SGA) or large for gestational age (LGA) is associated with adverse birth outcomes and metabolic diseases in later life of the offspring. It is known that aberrations in growth during gestation are related to altered placental function. Placental function is regulated by epigenetic mechanisms such as DNA methylation. Several studies in recent years have demonstrated associations between altered patterns of DNA methylation and adverse birth outcomes. However, larger studies that reliably investigated global DNA methylation are lacking. The aim of this study was to characterize global placental DNA methylation in relationship to size for gestational age. Global DNA methylation was assessed in 1023 placental samples by LC-MS/MS. LGA offspring displayed significantly higher global placental DNA methylation compared to appropriate for gestational age (AGA; p<0.001). ANCOVA analyses adjusted for known factors impacting on DNA methylation demonstrated an independent association between placental global DNA methylation and LGA births (p<0.001). Tertile stratification according to global placental DNA methylation levels revealed a significantly higher frequency of LGA births in the third tertile. Furthermore, a multiple logistic regression analysis corrected for known factors influencing birth weight highlighted an independent positive association between global placental DNA methylation and the frequency of LGA births (p=0.001).
KW  - fetal origins hypothesis
KW  - birth weight
KW  - repetitive elements
KW  - glucocorticoid receptor
KW  - nutrient transport
KW  - growth restriction
KW  - later health
KW  - pregnancy
KW  - genes
KW  - patterns
Y1  - 2020
U6  - https://doi.org/10.1038/s41598-020-57725-0
SN  - 2045-2322
VL  - 10
IS  - 1
SP  - 1
EP  - 10
PB  - Springer Nature
CY  - London
ER  - 
TY  - GEN
A1  - Harms, Laura M.
A1  - Scalbert, Augustin
A1  - Zamora-Ros, Raul
A1  - Rinaldi, Sabina
A1  - Jenab, Mazda
A1  - Murphy, Neil
A1  - Achaintre, David
A1  - Tjønneland, Anne
A1  - Olsen, Anja
A1  - Overvad, Kim
A1  - Aleksandrova, Krasimira
T1  - Plasma polyphenols associated with lower high-sensitivity C-reactive protein concentrations
BT  - a cross-sectional study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - 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.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1404 
KW  - polyphenols
KW  - plasma measurements
KW  - C-reactive protein
KW  - inflammation
KW  - chronic diseases
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-515774
SN  - 1866-8372
IS  - 2
ER  - 
TY  - GEN
A1  - Schedlbauer, Carola
A1  - Blaue, Dominique
A1  - Raila, Jens
A1  - Vervuert, Ingrid
T1  - Alterations of serum vitamin E and vitamin A concentrations of ponies and horses during experimentally induced obesity
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - 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.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1429 
KW  - body weight gain
KW  - equine
KW  - laminitis
KW  - retinol-binding protein 4
KW  - α-tocophero
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-519515
SN  - 1866-8372
IS  - 5
ER  - 
TY  - JOUR
A1  - McNulty, Margaret A.
A1  - Goupil, Brad A.
A1  - Albarado, Diana C.
A1  - Castaño-Martinez, Teresa
A1  - Ambrosi, Thomas H.
A1  - Puh, Spela
A1  - Schulz, Tim Julius
A1  - Schürmann, Annette
A1  - Morrison, Christopher D.
A1  - Laeger, Thomas
T1  - FGF21, not GCN2, influences bone morphology due to dietary protein restrictions
JF  - Bone Reports
N2  - 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.
KW  - dietary restriction
KW  - protein restriction
KW  - FGF21
KW  - GCN2
KW  - microcomputed tomography
Y1  - 2020
U6  - https://doi.org/10.1016/j.bonr.2019.100241
SN  - 2352-1872
VL  - 12
SP  - 1
EP  - 10
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - GEN
A1  - McNulty, Margaret A.
A1  - Goupil, Brad A.
A1  - Albarado, Diana C.
A1  - Castaño-Martinez, Teresa
A1  - Ambrosi, Thomas H.
A1  - Puh, Spela
A1  - Schulz, Tim Julius
A1  - Schürmann, Annette
A1  - Morrison, Christopher D.
A1  - Laeger, Thomas
T1  - FGF21, not GCN2, influences bone morphology due to dietary protein restrictions
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - 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.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1406 
KW  - dietary restriction
KW  - protein restriction
KW  - FGF21
KW  - GCN2
KW  - microcomputed tomography
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-516297
SN  - 1866-8372
ER  - 
TY  - CHAP
A1  - Schenke, Maren
A1  - Schjeide, Brit-Maren
A1  - Püschel, Gerhard
A1  - Seeger, Bettina
T1  - Human motor neurons diffentiated from plutipotent stem cells as superior traged cells for botulinum neuotoxin potency testing
BT  - In: German Pharm-Tox Summit 2020: abstracts of the 86th Annual Meeting of the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT)
T2  - Naunyn-Schmiedeberg's archives of pharmacology
Y1  - 2020
U6  - https://doi.org/10.1007/s00210-020-01828-y
SN  - 0028-1298
SN  - 1432-1912
VL  - 393
IS  - SUPPL 1
SP  - 10
EP  - 10
PB  - Springer
CY  - Berlin ; Heidelberg
ER  - 
TY  - GEN
A1  - Winkelbeiner, Nicola Lisa
A1  - Wandt, Viktoria Klara Veronika
A1  - Ebert, Franziska
A1  - Lossow, Kristina
A1  - Bankoglu, Ezgi E.
A1  - Martin, Maximilian
A1  - Mangerich, Aswin
A1  - Stopper, Helga
A1  - Bornhorst, Julia
A1  - Kipp, Anna Patricia
A1  - Schwerdtle, Tanja
T1  - A Multi-Endpoint Approach to Base Excision Repair Incision Activity Augmented by PARylation and DNA Damage Levels in Mice
BT  - Impact of Sex and Age
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - 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.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1021 
KW  - maintenance of genomic integrity
KW  - ageing
KW  - sex
KW  - DNA damage
KW  - base excision repair (incision activity)
KW  - DNA damage response
KW  - poly(ADP-ribosyl)ation
KW  - liver
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-484831
SN  - 1866-8372
IS  - 1021
ER  - 
TY  - JOUR
A1  - Bornhorst, Julia
A1  - Ebert, Franziska
A1  - Meyer, Sören
A1  - Ziemann, Vanessa
A1  - Xiong, Chan
A1  - Guttenberger, Nikolaus
A1  - Raab, Andrea
A1  - Baesler, Jessica
A1  - Aschner, Michael
A1  - Feldmann, Jörg
A1  - Francesconi, Kevin
A1  - Raber, Georg
A1  - Schwerdtle, Tanja
T1  - Toxicity of three types of arsenolipids
BT  - species-specific effects in Caenorhabditis elegans
JF  - Metallomics
N2  - Although fish and seafood are well known for their nutritional benefits, they contain contaminants that might affect human health. Organic lipid-soluble arsenic species, so called arsenolipids, belong to the emerging contaminants in these food items; their toxicity has yet to be systematically studied. Here, we apply the in vivo model Caenorhabditis elegans to assess the effects of two arsenic-containing hydrocarbons (AsHC), a saturated arsenic-containing fatty acid (AsFA), and an arsenic-containing triacylglyceride (AsTAG) in a whole organism. Although all arsenolipids were highly bioavailable in Caenorhabditis elegans, only the AsHCs were substantially metabolized to thioxylated or shortened metabolic products and induced significant toxicity, affecting both survival and development. Furthermore, the AsHCs were several fold more potent as compared to the toxic reference arsenite. This study clearly indicates the need for a full hazard identification of subclasses of arsenolipids to assess whether they pose a risk to human health.
Y1  - 2020
U6  - https://doi.org/https://doi.org/10.1039/d0mt00039f
SN  - 1756-591X
SN  - 1756-5901
VL  - 12
IS  - 5
SP  - 794
EP  - 798
PB  - Oxford University Press
CY  - Cambridge
ER  - 
TY  - JOUR
A1  - Nicolai, Merle Marie
A1  - Baesler, Jessica
A1  - Aschner, Michael
A1  - Schwerdtle, Tanja
A1  - Bornhorst, Julia
T1  - Consequences of manganese overload in C. elegans
BT  - oxidative stress and DNA damage
JF  - Naunyn-Schmiedeberg's archives of pharmacology / ed. for the Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie
Y1  - 2020
U6  - https://doi.org/10.1007/s00210-020-01828-y
SN  - 0028-1298
SN  - 1432-1912
VL  - 393
IS  - SUPPL 1
SP  - 9
EP  - 9
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Winkelbeiner, Nicola Lisa
A1  - Wandt, Viktoria Klara Veronika
A1  - Ebert, Franziska
A1  - Lossow, Kristina
A1  - Bankoglu, Ezgi E.
A1  - Martin, Maximilian
A1  - Mangerich, Aswin
A1  - Stopper, Helga
A1  - Bornhorst, Julia
A1  - Kipp, Anna Patricia
A1  - Schwerdtle, Tanja
T1  - A Multi-Endpoint Approach to Base Excision Repair Incision Activity Augmented by PARylation and DNA Damage Levels in Mice
BT  - Impact of Sex and Age
JF  - International Journal of Molecular Sciences
N2  - 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.
KW  - maintenance of genomic integrity
KW  - ageing
KW  - sex
KW  - DNA damage
KW  - base excision repair (incision activity)
KW  - DNA damage response
KW  - poly(ADP-ribosyl)ation
KW  - liver
Y1  - 2020
U6  - https://doi.org/10.3390/ijms21186600
SN  - 1422-0067
VL  - 21
IS  - 18
PB  - Molecular Diversity Preservation International
CY  - Basel
ER  - 
TY  - GEN
A1  - Weber, Daniela
A1  - Kochlik, Bastian
A1  - Demuth, Ilja
A1  - Steinhagen-Thiessen, Elisabeth
A1  - Grune, Tilman
A1  - Norman, Kristina
T1  - Plasma carotenoids, tocopherols and retinol
BT  - Association with age in the Berlin Aging Study II
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - 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.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1409 
KW  - carotenoids
KW  - tocopherols
KW  - micronutrients
KW  - age
KW  - plasma
KW  - food frequency questionnaire
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-515996
SN  - 1866-8372
ER  - 
TY  - GEN
A1  - Kessler, Katharina
A1  - Hornemann, Silke
A1  - Rudovich, Natalia
A1  - Weber, Daniela
A1  - Grune, Tilman
A1  - Kramer, Achim
A1  - Pfeiffer, Andreas F. H.
A1  - Pivovarova-Ramich, Olga
T1  - Saliva samples as a tool to study the effect of meal timing on metabolic and inflammatory biomarkers
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - 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.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1425 
KW  - meal timing
KW  - saliva
KW  - circadian clock
KW  - adiponectin
KW  - resistin
KW  - visfatin
KW  - insulin
KW  - melatonin
KW  - cortisol
KW  - cytokines
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-512079
SN  - 1866-8372
IS  - 2
ER  - 
TY  - GEN
A1  - Raupbach, Jana
A1  - Ott, Christiane
A1  - König, Jeannette
A1  - Grune, Tilman
T1  - Proteasomal degradation of glycated proteins depends on substrate unfolding
BT  - preferred degradation of moderately modified myoglobin
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - 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.
KW  - glycation
KW  - myoglobin
KW  - heme
KW  - advanced glycation endproducts
KW  - 20S proteasome
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-527570
SN  - 1866-8372
SP  - 516
EP  - 524
ER  - 
TY  - JOUR
A1  - Wiedmer, Petra
A1  - Jung, Tobias
A1  - Castro, Jose Pedro
A1  - Pomatto, Laura C. D.
A1  - Sun, Patrick Y.
A1  - Davies, Kelvin J. A.
A1  - Grune, Tilman
T1  - Sarcopenia
BT  - molecular mechanisms and open questions
JF  - Ageing research reviews : ARR
N2  - Sarcopenia represents a muscle-wasting syndrome characterized by progressive and generalized degenerative loss of skeletal muscle mass, quality, and strength occurring during normal aging. Sarcopenia patients are mainly suffering from the loss in muscle strength and are faced with mobility disorders reducing their quality of life and are, therefore, at higher risk for morbidity (falls, bone fracture, metabolic diseases) and mortality. <br /> Several molecular mechanisms have been described as causes for sarcopenia that refer to very different levels of muscle physiology. These mechanisms cover e. g. function of hormones (e. g. IGF-1 and Insulin), muscle fiber composition and neuromuscular drive, myo-satellite cell potential to differentiate and proliferate, inflammatory pathways as well as intracellular mechanisms in the processes of proteostasis and mitochondrial function. <br /> In this review, we describe sarcopenia as a muscle-wasting syndrome distinct from other atrophic diseases and summarize the current view on molecular causes of sarcopenia development as well as open questions provoking further research efforts for establishing efficient lifestyle and therapeutic interventions.
KW  - molecular pathways
KW  - proteostasis
KW  - proteasome
KW  - autophagy
KW  - mitochondria,
KW  - muscle fibre composition
Y1  - 2020
U6  - https://doi.org/10.1016/j.arr.2020.101200
SN  - 1568-1637
SN  - 1872-9649
VL  - 65
PB  - Elsevier
CY  - Clare
ER  - 
TY  - JOUR
A1  - Grune, Tilman
T1  - Oxidized protein aggregates
BT  - formation and biological effects
JF  - Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research
N2  - The study of protein aggregates has a long history. While in the first decades until the 80ies of the 20th century only the observation of the presence of such aggregates was reported, later the biochemistry of the formation and the biological effects of theses aggregates were described. 
This review focusses on the complexity of the biological effects of protein aggregates and its potential role in the aging process.
Y1  - 2020
U6  - https://doi.org/10.1016/j.freeradbiomed.2020.02.014
SN  - 0891-5849
SN  - 1873-4596
VL  - 150
SP  - 120
EP  - 124
PB  - Elsevier
CY  - New York
ER  - 
TY  - JOUR
A1  - Kehm, Richard
A1  - Jähnert, Markus
A1  - Deubel, Stefanie
A1  - Flore, Tanina
A1  - König, Jeannette
A1  - Jung, Tobias
A1  - Stadion, Mandy
A1  - Jonas, Wenke
A1  - Schürmann, Annette
A1  - Grune, Tilman
A1  - Höhn, Annika
T1  - Redox homeostasis and cell cycle activation mediate beta-cell mass expansion in aged, diabetes-prone mice under metabolic stress conditions: role of thioredoxin-interacting protein (TXNIP)
JF  - Redox Biology
N2  - Overnutrition contributes to insulin resistance, obesity and metabolic stress, initiating a loss of functional beta-cells and diabetes development. Whether these damaging effects are amplified in advanced age is barely investigated. Therefore, New Zealand Obese (NZO) mice, a well-established model for the investigation of human obesity-associated type 2 diabetes, were fed a metabolically challenging diet with a high-fat, carbohydrate restricted period followed by a carbohydrate intervention in young as well as advanced age. Interestingly, while young NZO mice developed massive hyperglycemia in response to carbohydrate feeding, leading to beta-cell dysfunction and cell death, aged counterparts compensated the increased insulin demand by persistent beta-cell function and beta-cell mass expansion. Beta-cell loss in young NZO islets was linked to increased expression of thioredoxin-interacting protein (TXNIP), presumably initiating an apoptosis-signaling cascade via caspase-3 activation. In contrast, islets of aged NZOs exhibited a sustained redox balance without changes in TXNIP expression, associated with higher proliferative potential by cell cycle activation. These findings support the relevance of a maintained proliferative potential and redox homeostasis for preserving islet functionality under metabolic stress, with the peculiarity that this adaptive response emerged with advanced age in diabetesprone NZO mice.
KW  - aging
KW  - redox homeostasis
KW  - metabolic stress
KW  - beta-cells
KW  - cell cycle
KW  - thioredoxin-interacting protein
Y1  - 2020
U6  - https://doi.org/10.1016/j.redox.2020.101748
SN  - 2213-2317
VL  - 37
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Häseli, Steffen
A1  - Deubel, Stefanie
A1  - Jung, Tobias
A1  - Grune, Tilman
A1  - Ott, Christiane
T1  - Cardiomyocyte contractility and autophagy in a premature senescence model of cardiac aging
JF  - Oxidative medicine and cellular longevity
N2  - Globally, cardiovascular diseases are the leading cause of death in the aging population. While the clinical pathology of the aging heart is thoroughly characterized, underlying molecular mechanisms are still insufficiently clarified. The aim of the present study was to establish an in vitro model system of cardiomyocyte premature senescence, culturing heart muscle cells derived from neonatal C57Bl/6J mice for 21 days. Premature senescence of neonatal cardiac myocytes was induced by prolonged culture time in an oxygen-rich postnatal environment. Age-related changes in cellular function were determined by senescence-associated beta-galactosidase activity, increasing presence of cell cycle regulators, such as p16, p53, and p21, accumulation of protein aggregates, and restricted proteolysis in terms of decreasing (macro-)autophagy. Furthermore, the culture system was functionally characterized for alterations in cell morphology and contractility. An increase in cellular size associated with induced expression of atrial natriuretic peptides demonstrated a stress-induced hypertrophic phenotype in neonatal cardiomyocytes. Using the recently developed analytical software tool Myocyter, we were able to show a spatiotemporal constraint in spontaneous contraction behavior during cultivation. Within the present study, the 21-day culture of neonatal cardiomyocytes was defined as a functional model system of premature cardiac senescence to study age-related changes in cardiomyocyte contractility and autophagy.
Y1  - 2020
U6  - https://doi.org/10.1155/2020/8141307
SN  - 1942-0994
VL  - 2020
IS  - Special Issue
PB  - Landes Bioscience
CY  - Austin, Tex.
ER  - 
TY  - JOUR
A1  - Raupbach, Jana
A1  - Ott, Christiane
A1  - König, Jeannette
A1  - Grune, Tilman
T1  - Proteasomal degradation of glycated proteins depends on substrate unfolding: Preferred degradation of moderately modified myoglobin
JF  - Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research
N2  - 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.
KW  - Glycation
KW  - Myoglobin
KW  - Heme
KW  - Advanced glycation endproducts
KW  - 20S
KW  - proteasome
Y1  - 2020
U6  - https://doi.org/10.1016/j.freeradbiomed.2019.11.024
SN  - 0891-5849
SN  - 1873-4596
VL  - 152
SP  - 516
EP  - 524
PB  - Elsevier
CY  - New York
ER  - 
TY  - JOUR
A1  - Kessler, Katharina
A1  - Hornemann, Silke
A1  - Rudovich, Natalia
A1  - Weber, Daniela
A1  - Grune, Tilman
A1  - Kramer, Achim
A1  - Pfeiffer, Andreas F. H.
A1  - Pivovarova-Ramich, Olga
T1  - Saliva samples as a tool to study the effect of meal timing on metabolic and inflammatory biomarkers
JF  - Nutrients
N2  - 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.
KW  - meal timing
KW  - saliva
KW  - circadian clock
KW  - adiponectin
KW  - resistin
KW  - visfatin
KW  - insulin
KW  - melatonin
KW  - cortisol
KW  - cytokines
Y1  - 2020
U6  - https://doi.org/10.3390/nu12020340
SN  - 2072-6643
IS  - 2
SP  - 1
EP  - 12
PB  - MDPI
CY  - Basel
ER  -