TY - JOUR
A1 - Baesler, Jessica
A1 - Kopp, Johannes Florian
A1 - Pohl, Gabriele
A1 - Aschner, Michael
A1 - Haase, Hajo
A1 - Schwerdtle, Tanja
A1 - Bornhorst, Julia
T1 - Zn homeostasis in genetic models of Parkinson’s disease in Caenorhabditis elegans
JF - Journal of Trace Elements in Medicine and Biology
N2 - While the underlying mechanisms of Parkinson’s disease (PD) are still insufficiently studied, a complex interaction between genetic and environmental factors is emphasized. Nevertheless, the role of the essential trace element zinc (Zn) in this regard remains controversial. In this study we altered Zn balance within PD models of the versatile model organism Caenorhabditis elegans (C. elegans) in order to examine whether a genetic predisposition in selected genes with relevance for PD affects Zn homeostasis. Protein-bound and labile Zn species act in various areas, such as enzymatic catalysis, protein stabilization pathways and cell signaling. Therefore, total Zn and labile Zn were quantitatively determined in living nematodes as individual biomarkers of Zn uptake and bioavailability with inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) or a multi-well method using the fluorescent probe ZinPyr-1. Young and middle-aged deletion mutants of catp-6 and pdr-1, which are orthologues of mammalian ATP13A2 (PARK9) and parkin (PARK2), showed altered Zn homeostasis following Zn exposure compared to wildtype worms. Furthermore, age-specific differences in Zn uptake were observed in wildtype worms for total as well as labile Zn species. These data emphasize the importance of differentiation between Zn species as meaningful biomarkers of Zn uptake as well as the need for further studies investigating the role of dysregulated Zn homeostasis in the etiology of PD.
KW - Caenorhabditis elegans
KW - Zinc
KW - Zinc homeostasis
KW - Parkinson disease
KW - Labile zinc
Y1 - 2019
U6 - https://doi.org/10.1016/j.jtemb.2019.05.005
VL - 55
SP - 44
EP - 49
PB - Elsevier
CY - München
ER -
TY - JOUR
A1 - Schjeide, Brit-Maren
A1 - Schenke, Maren
A1 - Seeger, Bettina
A1 - Püschel, Gerhard
T1 - Validation of a novel double control quantitative copy number PCR method to quantify off-target transgene integration after CRISPR-induced DNA modification
JF - Methods and protocols : M&Ps
N2 - In order to improve a recently established cell-based assay to assess the potency of botulinum neurotoxin, neuroblastoma-derived SiMa cells and induced pluripotent stem-cells (iPSC) were modified to incorporate the coding sequence of a reporter luciferase into a genetic safe harbor utilizing CRISPR/Cas9. A novel method, the double-control quantitative copy number PCR (dc-qcnPCR), was developed to detect off-target integrations of donor DNA. The donor DNA insertion success rate and targeted insertion success rate were analyzed in clones of each cell type. The dc-qcnPCR reliably quantified the copy number in both cell lines. The probability of incorrect donor DNA integration was significantly increased in SiMa cells in comparison to the iPSCs. This can possibly be explained by the lower bundled relative gene expression of a number of double-strand repair genes (BRCA1, DNA2, EXO1, MCPH1, MRE11, and RAD51) in SiMa clones than in iPSC clones. The dc-qcnPCR offers an efficient and cost-effective method to detect off-target CRISPR/Cas9-induced donor DNA integrations.
KW - CRISPR editing validation
KW - copy number analyses
KW - homology-directed repair
KW - homologous recombination deficiency
Y1 - 2022
U6 - https://doi.org/10.3390/mps5030043
SN - 2409-9279
VL - 5
IS - 3
SP - 1
EP - 14
PB - MDPI
CY - Basel, Schweiz
ER -
TY - JOUR
A1 - Knebel, Constanze
A1 - Neeb, Jannika
A1 - Zahn, Elisabeth
A1 - Schmidt, Flavia
A1 - Carazo, Alejandro
A1 - Holas, Ondej
A1 - Pavek, Petr
A1 - Püschel, Gerhard Paul
A1 - Zanger, Ulrich M.
A1 - Süssmuth, Roderich
A1 - Lampen, Alfonso
A1 - Marx-Stoelting, Philip
A1 - Braeuning, Albert
T1 - Unexpected Effects of Propiconazole, Tebuconazole, and Their Mixture on the Receptors CAR and PXR in Human Liver Cells
JF - Toxicological sciences
N2 - Analyzing mixture toxicity requires an in-depth understanding of the mechanisms of action of its individual components. Substances with the same target organ, same toxic effect and same mode of action (MoA) are believed to cause additive effects, whereas substances with different MoAs are assumed to act independently. Here, we tested 2 triazole fungicides, propiconazole, and tebuconazole (Te), for individual and combined effects on liver toxicity-related endpoints. Both triazoles are proposed to belong to the same cumulative assessment group and are therefore thought to display similar and additive behavior. Our data show that Te is an antagonist of the constitutive androstane receptor (CAR) in rats and humans, while propiconazole is an agonist of this receptor. Both substances activate the pregnane X-receptor (PXR) and further induce mRNA expression of CYP3A4. CYP3A4 enzyme activity, however, is inhibited by propiconazole. For common targets of PXR and CAR, the activation of PXR by Te overrides CAR inhibition. In summary, propiconazole and Te affect different hepatotoxicity-relevant cellular targets and, depending on the individual endpoint analyzed, act via similar or dissimilar mechanisms. The use of molecular data based on research in human cell systems extends the picture to refine cumulative assessment group grouping and substantially contributes to the understanding of mixture effects of chemicals in biological systems.
KW - triazole fungicides
KW - constitutive androstane receptor
KW - pregnane X-receptor
KW - enzyme induction
KW - liver toxicity
KW - mixtures
Y1 - 2018
U6 - https://doi.org/10.1093/toxsci/kfy026
SN - 1096-6080
SN - 1096-0929
VL - 163
IS - 1
SP - 170
EP - 181
PB - Oxford Univ. Press
CY - Oxford
ER -
TY - JOUR
A1 - 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 - JOUR
A1 - Johann, Kornelia
A1 - Kleinert, Maximilian
A1 - Klaus, Susanne
T1 - The role of GDF15 as a myomitokine
JF - Cells
N2 - Growth differentiation factor 15 (GDF15) is a cytokine best known for affecting systemic energy metabolism through its anorectic action. GDF15 expression and secretion from various organs and tissues is induced in different physiological and pathophysiological states, often linked to mitochondrial stress, leading to highly variable circulating GDF15 levels.
In skeletal muscle and the heart, the basal expression of GDF15 is very low compared to other organs, but GDF15 expression and secretion can be induced in various stress conditions, such as intense exercise and acute myocardial infarction, respectively. GDF15 is thus considered as a myokine and cardiokine. GFRAL, the exclusive receptor for GDF15, is expressed in hindbrain neurons and activation of the GDF15-GFRAL pathway is linked to an increased sympathetic outflow and possibly an activation of the hypothalamic-pituitary-adrenal (HPA) stress axis.
There is also evidence for peripheral, direct effects of GDF15 on adipose tissue lipolysis and possible autocrine cardiac effects. Metabolic and behavioral outcomes of GDF15 signaling can be beneficial or detrimental, likely depending on the magnitude and duration of the GDF15 signal.
This is especially apparent for GDF15 production in muscle, which can be induced both by exercise and by muscle disease states such as sarcopenia and mitochondrial myopathy.
KW - anorexia
KW - appetite regulation
KW - cardiokine
KW - cytokine
KW - exercise
KW - mitochondria
KW - muscle
KW - myokine
KW - myopathy
KW - sarcopenia
Y1 - 2021
U6 - https://doi.org/10.3390/cells10112990
SN - 2073-4409
VL - 10
IS - 11
PB - MDPI
CY - Basel
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 - JOUR
A1 - Cramer, Sandra
A1 - Tacke, Sebastian
A1 - Bornhorst, Julia
A1 - Klingauf, Jürgen
A1 - Schwerdtle, Tanja
A1 - Galla, Hans-Joachim
T1 - The Influence of Silver Nanoparticles on the Blood-Brain and the Blood-Cerebrospinal Fluid Barrier in vitro
JF - Journal of Nanomedicine & Nanotechnology
N2 - The use of silver nanoparticles in medical and consumer products such as wound dressings, clothing and cosmetic has increased significantly in recent years. Still, the influence of these particles on our health and especially on our brain, has not been examined adequately up to now. We studied the influence of AgEO- (Ethylene Oxide) and AgCitrate-Nanoparticles (NPs) on the protective barriers of the brain, namely the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (blood-CSF) barrier in vitro. The NPs toxicity was evaluated by examining changes in membrane integrity, cell morphology, barrier properties, oxidative stress and inflammatory reactions. AgNPs decreased cell viability, disturbed barrier integrity and tight junctions and triggered oxidative stress and DNA strand breaks. However, all mentioned effects were, at least partly, suppressed by a Citrate-coating and were most pronounced in the cells of the BBB as compared to the epithelial cells representing the blood-CSF barrier. AgEO- but not AgCitrate-NPs also triggered an inflammatory reaction in porcine brain capillary endothelial cells (PBCEC), which represent the BBB.
Our data indicate that AgNPs may cause adverse effects within the barriers of the brain, but their toxicity can be reduced by choosing an appropriate coating material.
Y1 - 2014
U6 - https://doi.org/10.4172/2157-7439.1000225
SN - 2157-7439
VL - 5
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 - 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 - 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 - 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 - Rohn, Isabelle
A1 - Kroepfl, Nina
A1 - Bornhorst, Julia
A1 - Kühnelt, Doris
A1 - Schwerdtle, Tanja
T1 - Side-directed transfer and presystemic metabolism of selenoneine in a human intestinal barrier model
JF - Molecular nutrition & food research : bioactivity, chemistry, immunology, microbiology, safety, technology
N2 - Scope: Selenoneine, a recently discovered selenium (Se) species mainly present in marine fish, is the Se analogue of ergothioneine, a sulfur-containing purported antioxidant. Although similar properties have been proposed for selenoneine, data on its relevance to human health are yet scarce. Here, the transfer and presystemic metabolism of selenoneine in an in vitro model of the human intestinal barrier are investigated. Methods and results: Selenoneine and the reference species Se-methylselenocysteine (MeSeCys) and selenite are applied to the Caco-2 intestinal barrier model. Selenoneine is transferred in higher amounts, but with similar kinetics as selenite, while MeSeCys shows the highest permeability. In contrast to the reference species, transfer of selenoneine is directed toward the blood side. Cellular Se contents demonstrate that selenoneine is efficiently taken up by Caco-2 cells. Moreover, HPLC/MS-based Se speciation studies reveal a partial metabolism to Se-methylselenoneine, a metabolite previously detected in human blood and urine. Conclusions: Selenoneine is likely to pass the intestinal barrier via transcellular, carrier-mediated transport, is highly bioavailable to Caco-2 cells and undergoes metabolic transformations. Therefore, further studies are needed to elucidate its possible health effects and to characterize the metabolism of selenoneine in humans.
KW - bioavailability
KW - Caco-2 intestinal barrier model
KW - presystemic metabolism
KW - selenoneine
KW - Se-methylselenoneine
Y1 - 2019
U6 - https://doi.org/10.1002/mnfr.201900080
SN - 1613-4125
SN - 1613-4133
VL - 63
IS - 12
PB - Wiley
CY - Hoboken
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.
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.
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 - 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 -
TY - JOUR
A1 - Schenk, Matthew
A1 - Eichelmann, Fabian
A1 - Schulze, Matthias Bernd
A1 - Rudovich, Natalia
A1 - Pfeiffer, Andreas F. H.
A1 - di Giuseppe, Romina
A1 - Böing, Heiner
A1 - Aleksandrova, Krasimira
T1 - Reproducibility of novel immune-inflammatory biomarkers over 4 months
BT - an analysis with repeated measures design
JF - Biomarkers in medicine
N2 - Aim: Assessment of the feasibility and reliability of immune-inflammatory biomarker measurements. Methods: The following biomarkers were assessed in 207 predominantly healthy participants at baseline and after 4 months: MMF, TGF-beta, suPAR and clusterin. Results: Intraclass correlation coefficients (95% CIs) ranged from good for TGF-beta (0.75 [95% CI: 0.33-0.90]) to excellent for MMF (0.81 [95% CI: 0.64-0.90]), clusterin (0.83 [95% CI: 0.78-0.87]) and suPAR (0.91 [95% CI: 0.88-0.93]). Measurement of TGF-beta was challenged by the large number of values below the detection limit. Conclusion: Single measurements of suPAR, clusterin and MMF could serve as feasible and reliable biomarkers of immune-inflammatory pathways in biomedical research.
KW - clusterin
KW - immune-inflammatory biomarkers
KW - MMF
KW - repeated measures design
KW - reproducibility
KW - suPAR
KW - TGF-beta
Y1 - 2019
U6 - https://doi.org/10.2217/bmm-2018-0351
SN - 1752-0363
SN - 1752-0371
VL - 13
IS - 8
SP - 639
EP - 648
PB - Future Medicine
CY - London
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 - 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 - 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 - Figueroa Campos, Gustavo Adolfo
A1 - Perez, Jeffrey Paulo H.
A1 - Block, Inga
A1 - Sagu Tchewonpi, 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
JF - Processes : open access journal
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.
KW - coffee by-products
KW - spent coffee grounds
KW - parchment
KW - valorization
KW - calcination
KW - activated carbon
KW - organic compounds adsorption
Y1 - 2021
U6 - https://doi.org/10.3390/pr9081396
SN - 2227-9717
VL - 9
IS - 8
PB - MDPI
CY - Basel
ER -
TY - JOUR
A1 - Schiborn, Catarina
A1 - Schulze, Matthias Bernd
T1 - Precision prognostics for the development of complications in diabetes
JF - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
N2 - Individuals with diabetes face higher risks for macro- and microvascular complications than their non-diabetic counterparts. The concept of precision medicine in diabetes aims to optimise treatment decisions for individual patients to reduce the risk of major diabetic complications, including cardiovascular outcomes, retinopathy, nephropathy, neuropathy and overall mortality. In this context, prognostic models can be used to estimate an individual's risk for relevant complications based on individual risk profiles. This review aims to place the concept of prediction modelling into the context of precision prognostics. As opposed to identification of diabetes subsets, the development of prediction models, including the selection of predictors based on their longitudinal association with the outcome of interest and their discriminatory ability, allows estimation of an individual's absolute risk of complications. As a consequence, such models provide information about potential patient subgroups and their treatment needs. This review provides insight into the methodological issues specifically related to the development and validation of prediction models for diabetes complications. We summarise existing prediction models for macro- and microvascular complications, commonly included predictors, and examples of available validation studies. The review also discusses the potential of non-classical risk markers and omics-based predictors. Finally, it gives insight into the requirements and challenges related to the clinical applications and implementation of developed predictions models to optimise medical decision making.
KW - Cardiovascular diseases
KW - Complications in diabetes
KW - Macrovascular
KW - complications
KW - Microvascular complications
KW - Personalised medicine
KW - Precision medicine
KW - Precision prognostics
KW - Review
KW - Risk prediction
KW - Risk
KW - scores
Y1 - 2022
U6 - https://doi.org/10.1007/s00125-022-05731-4
SN - 0012-186X
SN - 1432-0428
PB - Springer
CY - New York
ER -
TY - JOUR
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
JF - British Journal of Nutrition
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.
KW - polyphenols
KW - plasma measurements
KW - C-reactive protein
KW - inflammation
KW - chronic diseases
Y1 - 2019
U6 - https://doi.org/10.1017/S0007114519002538
SN - 0007-1145
SN - 1475-2662
VL - 123
IS - 2
SP - 198
EP - 208
PB - Cambridge University Press
CY - Cambridge
ER -
TY - JOUR
A1 - Lu, Yong-Ping
A1 - Hasan, Ahmed A.
A1 - Zeng, Shufei
A1 - Hocher, Berthold
T1 - Plasma ET-1 concentrations are elevated in pregnant women with hypertension - meta-analysis of clinical studies
JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie ; official organ of the Deutsche Liga zur Bekämpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft
N2 - Background/Aims:
The ET system might be involved in the pathogenesis of hypertensive disorders during pregnancy. The objective is to analyse the impact of ET-1 in hypertensive pregnant women by a strict meta-analysis of published human clinical studies.
Methods:
Based on the principle of Cochrane systematic reviews, Cohort studies in PubMed (Medline), Google Scholar and China Biological Medicine Database (CBM-disc) designed to identify the role of endothelin-1 (ET-1) in the pathophysiology of gestational hypertension and preeclampsia were screened. Review Manager Version 5.0 (Rev-Man 5.0) was applied for statistical analysis. Mean difference and 95% confidence interval (CI) were shown in inverse variance (IV) fixed-effects model or IV random-effects model.
Results:
Sixteen published cohort studies including 1739 hypertensive cases and 409 controls were used in the meta-analysis. ET-1 plasma concentrations were higher in hypertensive pregnant women as compared to the controls (mean difference between groups: 19.02 [15.60~22.44], P < 0.00001,). These finding were driven by severity of hypertension and/or degree of proteinuria.
Conclusion:
Plasma ET-1 concentrations are elevated in hypertensive disorders during human pregnancy. In particular women with preeclampsia (hypertensive pregnant women with proteinuria) have substantially elevated plasma ET-1 concentration as compared to pregnant women with normal blood pressure.
KW - Et-1
KW - Pregnancy
KW - Hypertension
KW - Meta-analysis
Y1 - 2017
U6 - https://doi.org/10.1159/000482004
SN - 1420-4096
SN - 1423-0143
VL - 42
IS - 4
SP - 654
EP - 663
PB - Karger
CY - Basel
ER -
TY - JOUR
A1 - Weber, Daniela
A1 - Kochlik, Bastian Max
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
JF - Redox Biology
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.
KW - carotenoids
KW - tocopherols
KW - micronutrients
KW - age
KW - plasma
KW - food frequency questionnaire
Y1 - 2020
U6 - https://doi.org/10.1016/j.redox.2020.101461
SN - 2213-2317
VL - 32
SP - 1
EP - 8
PB - Elsevier
CY - Amsterdam
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 - 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 - JOUR
A1 - Schwiebs, Anja
A1 - Thomas, Dominique Jeanette
A1 - Kleuser, Burkhard
A1 - Pfeilschifter, Josef
A1 - Radeke, Heinfried H.
T1 - Nuclear translocation of SGPP-1 and decrease of SGPL-1 activity contribute to sphingolipid rheostat regulation of inflammatory dendritic cells
JF - Mediators of inflammation
N2 - A balanced sphingolipid rheostat is indispensable for dendritic cell function and survival and thus initiation of an immune response. Sphingolipid levels are dynamically maintained by the action of sphingolipid enzymes of which sphingosine kinases, S1P phosphatases (SGPP-1/2) and S1P lyase (SGPL-1), are pivotal in the balance of S1P and sphingosine levels. In this study, we present that SGPP-1 and SGPL-1 are regulated in inflammatory dendritic cells and contribute to S1P fate. TLR-dependent activation caused SGPL-1 protein downregulation with subsequent decrease of enzymatic activity by two-thirds. In parallel, confocal fluorescence microscopy revealed that endogenous SGPP-1 was expressed in nuclei of naive dendritic cells and was translocated into the cytoplasmatic compartment upon inflammatory stimulation resulting in dephosphorylation of S1P. Mass spectrometric determination showed that a part of the resulting sphingosine was released from the cell, increasing extracellular levels. Another route of diminishing intracellular S1P was possibly taken by its export via ATP-binding cassette transporter C1 which was upregulated in array analysis, while the S1P transporter, spinster homolog 2, was not relevant in dendritic cells. These investigations newly describe the sequential expression and localization of the endogenous S1P regulators SGPP-1 and SGPL-1 and highlight their contribution to the sphingolipid rheostat in inflammation.
Y1 - 2017
U6 - https://doi.org/10.1155/2017/5187368
SN - 0962-9351
SN - 1466-1861
PB - Hindawi Publishing Corp.
CY - London
ER -
TY - JOUR
A1 - Castro, Jose Pedro
A1 - Fernando, Raquel
A1 - Reeg, Sandra
A1 - Meinl, Walter
A1 - Almeida, Henrique
A1 - Grune, Tilman
T1 - Non-enzymatic cleavage of Hsp90 by oxidative stress leads to actin aggregate formation
BT - A novel gain-of-function mechanism
JF - Redox Biology
N2 - Aging is accompanied by the accumulation of oxidized proteins. To remove them, cells employ the proteasomal and autophagy-lysosomal systems; however, if the clearance rate is inferior to its formation, protein aggregates form as a hallmark of proteostasis loss. In cells, during stress conditions, actin aggregates accumulate leading to impaired proliferation and reduced proteasomal activity, as observed in cellular senescence. The heat shock protein 90 (Hsp90) is a molecular chaperone that binds and protects the proteasome from oxidative inactivation. We hypothesized that in oxidative stress conditions a malfunction of Hsp90 occurs resulting in the aforementioned protein aggregates. Here, we demonstrate that upon oxidative stress Hsp90 loses its function in a highly specific non-enzymatic iron-catalyzed oxidation event and its breakdown product, a cleaved form of Hsp90 (Hsp90cl), acquires a new function in mediating the accumulation of actin aggregates. Moreover, the prevention of Hsp90 cleavage reduces oxidized actin accumulation, whereas transfection of the cleaved form of Hsp90 leads to an enhanced accumulation of oxidized actin. This indicates a clear role of the Hsp90cl in the aggregation of oxidized proteins.
KW - Oxidative stress
KW - Protein oxidation
KW - Heat shock protein 90
KW - Proteasome
KW - Protein aggregates
Y1 - 2019
U6 - https://doi.org/10.1016/j.redox.2019.101108
SN - 2213-2317
VL - 21
PB - Elsevier
CY - Amsterdam
ER -
TY - JOUR
A1 - Bernacchioni, Caterina
A1 - Ghini, Veronica
A1 - Cencetti, Francesca
A1 - Japtok, Lukasz
A1 - Donati, Chiara
A1 - Bruni, Paola
A1 - Turano, Paola
T1 - NMR metabolomics highlights sphingosine kinase-1 as a new molecular switch in the orchestration of aberrant metabolic phenotype in cancer cells
JF - Molecular oncology / Federation of European Biochemical Societies
N2 - Strong experimental evidence in animal and cellular models supports a pivotal role of sphingosine kinase-1 (SK1) in oncogenesis. In many human cancers, SK1 levels are upregulated and these increases are linked to poor prognosis in patients. Here, by employing untargeted NMR- based metabolomic profiling combined with functional validations, we report the crucial role of SK1 in the metabolic shift known as the Warburg effect in A2780 ovarian cancer cells. Indeed, expression of SK1 induced a high glycolytic rate, characterized by increased levels of lactate along with increased expression of the proton/monocarboxylate symporter MCT1, and decreased oxidative metabolism, associated with the accumulation of intermediates of the tricarboxylic acid cycle and reduction in CO2 production. Additionally, SK1-expressing cells displayed a significant increase in glucose uptake paralleled by GLUT3 transporter upregulation. The role of SK1 is not limited to the induction of aerobic glycolysis, affecting metabolic pathways that appear to support the biosynthesis of macromolecules. These findings highlight the role of SK1 signaling axis in cancer metabolic reprogramming, pointing out innovative strategies for cancer therapies.
KW - NMR-based metabolomics
KW - ovarian cancer
KW - sphingosine kinase-1
KW - Warburg effect
Y1 - 2017
U6 - https://doi.org/10.1002/1878-0261.12048
SN - 1878-0261
VL - 11
SP - 517
EP - 533
PB - Wiley
CY - Hoboken
ER -
TY - JOUR
A1 - Drobyshev, Evgenii J.
A1 - Kybarskaya, Larisa
A1 - Dagaev, Sergey
A1 - Solovyev, Nikolay
T1 - New insight in beryllium toxicity excluding exposure to beryllium-containing dust
BT - accumulation patterns, target organs, and elimination
JF - Archives of toxicology : official journal of EUROTOX
N2 - There is much contradiction between different experimental studies on beryllium (Be) toxicity. The majority of studies focus on occupational pathologies, caused by the exposure to Be dust. However, Be pollution may affect wide population groups through other exposure routes. The discrepancies between experimental studies may be attributed to the lack of adequate Be toxicity model since conventional administration routes are hampered by high acidity and low solubility of Be compounds. This study was aimed to develop a novel way to implement Be toxicity avoiding side effects, related to high acidity or low solubility of Be salts. Intraperitoneal injection of Be-glycine composition (containing BeSO4, glycine, purified water, pH adjusted to 5.5 with NaOH) was tested in the dose range 238-7622 mu molBekg(-1) (body weight, b/w) in full-grown Wistar male rats. The model provided reliable uptake of Be from the peritoneum into general circulation for at least 48h. LD50 was found to be 687 mu molBekg(-1) (b/w). The established LD50 value differed from previous data on gastrointestinal, intramuscular or intravenous administration of Be compounds. The liver was found to act as a primary elimination route for Be and related to the highest Be content in the animal. However, it had no signs of morphological damage, which was observed only in the testes (deterioration of germinal epithelium). At the same time, the lungs, stated as a primary target tissue for Be in the models of chronic beryllium disease, did not show strong Be accumulation nor morphological changes. Survived animals showed behavioral changes, including increased motor activity and aggressive reactions in some cases, and complete spasticity in other. The obtained data show the applicability of the established modeling protocol and testified for the independence of chronic beryllium disease on Be2+ ion toxicity per se.
KW - Beryllium
KW - Intraperitoneal administration
KW - Testicle
KW - Rats
KW - Excretion
Y1 - 2019
U6 - https://doi.org/10.1007/s00204-019-02432-7
SN - 0340-5761
SN - 1432-0738
VL - 93
IS - 4
SP - 859
EP - 869
PB - Springer
CY - Heidelberg
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 - Wigger, Dominik
A1 - Gulbins, Erich
A1 - Kleuser, Burkhard
A1 - Schumacher, Fabian
T1 - Monitoring the Sphingolipid de novo Synthesis by Stable-Isotope Labeling and Liquid Chromatography-Mass Spectrometry
JF - Frontiers in Cell and Developmental Biology
N2 - Sphingolipids are a class of lipids that share a sphingoid base backbone. They exert various effects in eukaryotes, ranging from structural roles in plasma membranes to cellular signaling. De novo sphingolipid synthesis takes place in the endoplasmic reticulum (ER), where the condensation of the activated C₁₆ fatty acid palmitoyl-CoA and the amino acid L-serine is catalyzed by serine palmitoyltransferase (SPT). The product, 3-ketosphinganine, is then converted into more complex sphingolipids by additional ER-bound enzymes, resulting in the formation of ceramides. Since sphingolipid homeostasis is crucial to numerous cellular functions, improved assessment of sphingolipid metabolism will be key to better understanding several human diseases. To date, no assay exists capable of monitoring de novo synthesis sphingolipid in its entirety. Here, we have established a cell-free assay utilizing rat liver microsomes containing all the enzymes necessary for bottom-up synthesis of ceramides. Following lipid extraction, we were able to track the different intermediates of the sphingolipid metabolism pathway, namely 3-ketosphinganine, sphinganine, dihydroceramide, and ceramide. This was achieved by chromatographic separation of sphingolipid metabolites followed by detection of their accurate mass and characteristic fragmentations through high-resolution mass spectrometry and tandem-mass spectrometry. We were able to distinguish, unequivocally, between de novo synthesized sphingolipids and intrinsic species, inevitably present in the microsome preparations, through the addition of stable isotope-labeled palmitate-d₃ and L-serine-d₃. To the best of our knowledge, this is the first demonstration of a method monitoring the entirety of ER-associated sphingolipid biosynthesis. Proof-of-concept data was provided by modulating the levels of supplied cofactors (e.g., NADPH) or the addition of specific enzyme inhibitors (e.g., fumonisin B₁). The presented microsomal assay may serve as a useful tool for monitoring alterations in sphingolipid de novo synthesis in cells or tissues. Additionally, our methodology may be used for metabolism studies of atypical substrates – naturally occurring or chemically tailored – as well as novel inhibitors of enzymes involved in sphingolipid de novo synthesis.
KW - sphingolipid de novo synthesis
KW - serine palmitoyltransferase
KW - mass spectrometry
KW - stable-isotope labeling
KW - ceramides
Y1 - 2019
U6 - https://doi.org/10.3389/fcell.2019.00210
SN - 2296-634X
VL - 7
PB - Frontiers Media
CY - Lausanne
ER -
TY - JOUR
A1 - Shi, Jiang
A1 - Xie, Dongchao
A1 - Qi, Dandan
A1 - Peng, Qunhua
A1 - Chen, Zongmao
A1 - Schreiner, Monika
A1 - Lin, Zhi
A1 - Baldermann, Susanne
T1 - Methyl jasmonate-induced changes of flavor profiles during the processing of Green, Oolong, and Black Tea
JF - Frontiers in plant science
N2 - Tea aroma is one of the most important factors affecting the character and quality of tea. Here we describe the practical application of methyl jasmonate (MeJA) to improve the aroma quality of teas. The changes of selected metabolites during crucial tea processing steps, namely, withering, fixing and rolling, and fermentation, were analyzed. MeJA treatment of tea leaves (12, 24, 48, and 168 h) greatly promotes the aroma quality of green, oolong, and black tea products when comparing with untreated ones (0 h) and as confirmed by sensory evaluation. MeJA modulates the aroma profiles before, during, and after processing. Benzyl alcohol, benzaldehyde, 2-phenylethyl alcohol, phenylacetaldehyde, and trans-2-hexenal increased 1.07- to 3-fold in MeJA-treated fresh leaves and the first two maintained at a higher level in black tea and the last two in green tea. This correlates with a decrease in aromatic amino acids by more than twofold indicating a direct relation to tryptophan- and phenylalanine-derived volatiles. MeJA-treated oolong tea was characterized by a more pleasant aroma. Especially the terpenoids linalool and oxides, geraniol, and carvenol increased by more than twofold.
KW - methyl jasmonate
KW - aroma quality
KW - volatile compounds
KW - amino acids
KW - tea processing
Y1 - 2019
U6 - https://doi.org/10.3389/fpls.2019.00781
SN - 1664-462X
VL - 10
PB - Frontiers Research Foundation
CY - Lausanne
ER -
TY - JOUR
A1 - Rothwell, Joseph A.
A1 - Murphy, Neil
A1 - Aleksandrova, Krasimira
A1 - Schulze, Matthias Bernd
A1 - Bešević, Jelena
A1 - Kliemann, Nathalie
A1 - Jenab, Mazda
A1 - Ferrari, Pietro
A1 - Achaintre, David
A1 - Gicquiau, Audrey
A1 - Vozar, Béatrice
A1 - Scalbert, Augustin
A1 - Huybrechts, Inge
A1 - Freisling, Heinz
A1 - Prehn, Cornelia
A1 - Adamski, Jerzy
A1 - Cross, Amanda J.
A1 - Pala, Valeria Maria
A1 - Boutron-Ruault, Marie-Christine
A1 - Dahm, Christina C.
A1 - Overvad, Kim
A1 - Gram, Inger Torhild
A1 - Sandanger, Torkjel M.
A1 - Skeie, Guri
A1 - Jakszyn, Paula
A1 - Tsilidis, Kostas K.
A1 - Hughes, David J.
A1 - van Guelpen, Bethany
A1 - Bodén, Stina
A1 - Sánchez, Maria-José
A1 - Schmidt, Julie A.
A1 - Katzke, Verena
A1 - Kühn, Tilman
A1 - Colorado-Yohar, Sandra
A1 - Tumino, Rosario
A1 - Bueno-de-Mesquita, Bas
A1 - Vineis, Paolo
A1 - Masala, Giovanna
A1 - Panico, Salvatore
A1 - Eriksen, Anne Kirstine
A1 - Tjønneland, Anne
A1 - Aune, Dagfinn
A1 - Weiderpass, Elisabete
A1 - Severi, Gianluca
A1 - Chajès, Véronique
A1 - Gunter, Marc J.
T1 - Metabolic signatures of healthy lifestyle patterns and colorectal cancer risk in a European cohort
JF - Clinical gastroenterology and hepatology
N2 - BACKGROUND & AIMS: Colorectal cancer risk can be lowered by adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines. We derived metabolic signatures of adherence to these guidelines and tested their associations with colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort.
METHODS: Scores reflecting adherence to the WCRF/AICR recommendations (scale, 1-5) were calculated from participant data on weight maintenance, physical activity, diet, and alcohol among a discovery set of 5738 cancer-free European Prospective Investigation into Cancer and Nutrition participants with metabolomics data. Partial least-squares regression was used to derive fatty acid and endogenous metabolite signatures of the WCRF/AICR score in this group. In an independent set of 1608 colorectal cancer cases and matched controls, odds ratios (ORs) and 95% CIs were calculated for colorectal cancer risk per unit increase in WCRF/AICR score and per the corresponding change in metabolic signatures using multivariable conditional logistic regression.
RESULTS: Higher WCRF/AICR scores were characterized by metabolic signatures of increased odd-chain fatty acids, serine, glycine, and specific phosphatidylcholines. Signatures were inversely associated more strongly with colorectal cancer risk (fatty acids: OR, 0.51 per unit increase; 95% CI, 0.29-0.90; endogenous metabolites: OR, 0.62 per unit change; 95% CI, 0.50-0.78) than the WCRF/AICR score (OR, 0.93 per unit change; 95% CI, 0.86-1.00) overall. Signature associations were stronger in male compared with female participants.
CONCLUSIONS: Metabolite profiles reflecting adherence to WCRF/AICR guidelines and additional lifestyle or biological risk factors were associated with colorectal cancer. Measuring a specific panel of metabolites representative of a healthy or unhealthy lifestyle may identify strata of the population at higher risk of colorectal cancer.
KW - colorectal neoplasm
KW - risk factors
KW - World Cancer Research Fund/American Institute for Cancer Research Recommendations
KW - targeted metabolomics
Y1 - 2020
U6 - https://doi.org/10.1016/j.cgh.2020.11.045
SN - 1542-3565
SN - 1542-7714
VL - 20
SP - E1061
EP - E1082
PB - Elsevier
CY - New York, NY
ER -
TY - JOUR
A1 - Yadav, Heena
A1 - Dreher, Dorothée
A1 - Athmer, Benedikt
A1 - Porzel, Andrea
A1 - Gavrin, Aleksandr
A1 - Baldermann, Susanne
A1 - Tissier, Alain
A1 - Hause, Bettina
T1 - Medicago TERPENE SYNTHASE 10 is involved in defense against an oomycete root pathogen
JF - Plant physiology : an international journal devoted to physiology, biochemistry, cellular and molecular biology, biophysics and environmental biology of plants
N2 - In nature, plants interact with numerous beneficial or pathogenic soil-borne microorganisms. Plants have developed various defense strategies to expel pathogenic microbes, some of which function soon after pathogen infection. We used Medicago truncatula and its oomycete pathogen Aphanomyces euteiches to elucidate early responses of the infected root. A. euteiches causes root rot disease in legumes and is a limiting factor in legume production. Transcript profiling of seedlings and adult plant roots inoculated with A. euteiches zoospores for 2 h revealed specific upregulation of a gene encoding a putative sesquiterpene synthase (M. truncatula TERPENE SYNTHASE 10 [MtTPS10]) in both developmental stages. MtTPS10 was specifically expressed in roots upon oomycete infection. Heterologous expression of MtTPS10 in yeast led to production of a blend of sesquiterpenes and sesquiterpene alcohols, with NMR identifying a major peak corresponding to himalachol. Moreover, plants carrying a tobacco (Nicotiana tabacum) retrotransposon Tnt1 insertion in MtTPS10 lacked the emission of sesquiterpenes upon A. euteiches infection, supporting the assumption that the identified gene encodes a multiproduct sesquiterpene synthase. Mttps10 plants and plants with reduced MtTPS10 transcript levels created by expression of an MtTPS10-artificial microRNA in roots were more susceptible to A. euteiches infection than were the corresponding wild-type plants and roots transformed with the empty vector, respectively. Sesquiterpenes produced by expression of MtTPS10 in yeast also inhibited mycelial growth and A. euteiches zoospore germination. These data suggest that sesquiterpene production in roots by MtTPS10 plays a previously unrecognized role in the defense response of M. truncatula against A. euteiches.
Y1 - 2019
U6 - https://doi.org/10.1104/pp.19.00278
SN - 0032-0889
SN - 1532-2548
VL - 180
IS - 3
SP - 1598
EP - 1613
PB - American Society of Plant Physiologists
CY - Rockville
ER -
TY - JOUR
A1 - Fayyaz, Susann
A1 - Japtok, Lukasz
A1 - Schumacher, Fabian
A1 - Wigger, Dominik
A1 - Schulz, Tim Julius
A1 - Haubold, Kathrin
A1 - Gulbins, Erich
A1 - Völler, Heinz
A1 - Kleuser, Burkhard
T1 - Lysophosphatidic acid inhibits insulin signaling in primary rat hepatocytes via the LPA(3) receptor subtype and is increased in obesity
JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology
N2 - Background/Aims:
Obesity is a main risk factor for the development of hepatic insulin resistance and it is accompanied by adipocyte hypertrophy and an elevated expression of different adipokines such as autotaxin (ATX). ATX converts lysophosphatidylcholine to lysophosphatidic acid (LPA) and acts as the main producer of extracellular LPA. This bioactive lipid regulates a broad range of physiological and pathological responses by activation of LPA receptors (LPA1-6).
Methods:
The activation of phosphatidylinositide 3-kinases (PI3K) signaling (Akt and GSK-3ß) was analyzed via western blotting in primary rat hepatocytes. Incorporation of glucose into glycogen was measured by using radio labeled glucose. Real-time PCR analysis and pharmacological modulation of LPA receptors were performed. Human plasma LPA levels of obese (BMI > 30, n = 18) and normal weight individuals (BMI 18.5-25, n = 14) were analyzed by liquid chromatography tandem-mass spectrometry (LC-MS/MS).
Results:
Pretreatment of primary hepatocytes with LPA resulted in an inhibition of insulin-mediated Gck expression, PI3K activation and glycogen synthesis. Pharmacological approaches revealed that the LPA3-receptor subtype is responsible for the inhibitory effect of LPA on insulin signaling. Moreover, human plasma LPA concentrations (16: 0 LPA) of obese participants (BMI > 30) are significantly elevated in comparison to normal weight individuals (BMI 18.5-25).
Conclusion:
LPA is able to interrupt insulin signaling in primary rat hepatocytes via the LPA3 receptor subtype. Moreover, the bioactive lipid LPA (16: 0) is increased in obesity.
KW - Lysophosphatidic acid
KW - Insulin signaling
KW - Adipose tissue
KW - Autotaxin
KW - Hepatic insulin resistance
KW - LPA(3) receptor subtype
Y1 - 2017
U6 - https://doi.org/10.1159/000480470
SN - 1015-8987
SN - 1421-9778
VL - 43
SP - 445
EP - 456
PB - Karger
CY - Basel
ER -
TY - JOUR
A1 - Gohlke, Sabrina
A1 - Mancini, Carola
A1 - Garcia-Carrizo, Francisco
A1 - Schulz, Tim J.
T1 - Loss of the ciliary gene Bbs4 results in defective thermogenesis due to metabolic inefficiency and impaired lipid metabolism
JF - The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology
N2 - Adipose tissue is central to the regulation of energy balance. While white adipose tissue (WAT) is responsible for triglyceride storage, brown adipose tissue specializes in energy expenditure. Deterioration of brown adipocyte function contributes to the development of metabolic complications like obesity and diabetes. These disorders are also leading symptoms of the Bardet-Biedl syndrome (BBS), a hereditary disorder in humans which is caused by dysfunctions of the primary cilium and which therefore belongs to the group of ciliopathies. The cilium is a hair-like organelle involved in cellular signal transduction. The BBSome, a supercomplex of several Bbs gene products, localizes to the basal body of cilia and is thought to be involved in protein sorting to and from the ciliary membrane. The effects of a functional BBSome on energy metabolism and lipid mobilization in brown and white adipocytes were tested in whole-body Bbs4 knockout mice that were subjected to metabolic challenges. Chronic cold exposure reveals cold-intolerance of knockout mice but also ameliorates the markers of metabolic pathology detected in knockouts prior to cold. Hepatic triglyceride content is markedly reduced in knockout mice while circulating lipids are elevated, altogether suggesting that defective lipid metabolism in adipose tissue creates increased demand for systemic lipid mobilization to meet energetic demands of reduced body temperatures. These findings taken together suggest that Bbs4 is essential for the regulation of adipose tissue lipid metabolism, representing a potential target to treat metabolic disorders.
KW - adipose tissue
KW - Bbs4
KW - BBsome
KW - browning
KW - cilium
KW - lipid metabolism
Y1 - 2021
U6 - https://doi.org/10.1096/fj.202100772RR
SN - 1530-6860
VL - 35
IS - 11
PB - Wiley
CY - Hoboken
ER -
TY - JOUR
A1 - Frede, Katja
A1 - Schreiner, Monika
A1 - Baldermann, Susanne
T1 - Light quality-induced changes of carotenoid composition in pak choi Brassica rapa ssp. chinensis
N2 - Carotenoids as part of the photosystems are crucial for their assembly, light-harvesting, and photoprotection. Light of different wavelengths impacts the composition and structure of photosystems, thus offering the possibility to influence the carotenoid concentrations and composition in photosystems by illumination with specific narrow-banded light spectra. Key components involved in the regulation of gene transcription are still poorly characterized, particularly in leafy vegetables as compared to model plants. In particular, the effect of different light qualities and its connection to redox control mechanisms, which also determine the photosystem composition and structure, is not yet well understood. Furthermore, light quality effects are species-dependent, and thus, increase the need to perform research on individual vegetable species such as pak choi Brassica rapa ssp. chinensis. Here, we investigated the carotenoid concentrations and composition of pak choi sprouts grown for 6 days under blue, red, or white light emitting diodes (LEDs) as light source. After 6 days, the total carotenoid content was the highest under white and slightly reduced under blue or red LEDs. Blue, red, and white light differently affected the carotenoid composition mainly due to variations of the beta-carotene content which could be correlated to changes in the transcript levels of beta-carotene hydroxylase 1 (beta-OHASE1). Further investigations implied a redox controlled gene expression of beta-OHASE1. In addition, transcription factors related to light signaling and the circadian clock differed in their transcriptional abundance after exposure to blue and red light. RNA-Seq analysis also revealed increased transcript levels of genes encoding the outer antenna complex of photosystem II under red compared to blue light, indicating an adjustment of the photosystems to the different light qualities which possibly contributed to the alternations in the carotenoid content and composition.
KW - Brassica rapa ssp. chinensis
KW - beta-carotene hydroxylase
KW - Carotenoids
KW - LEDs
KW - Light quality
KW - Redox control
Y1 - 2019
U6 - https://doi.org/10.1016/j.jphotobiol.2019.02.001
SN - 1011-1344
VL - 193
SP - 18
EP - 30
PB - Elsevier
CY - Lausanne
ER -
TY - JOUR
A1 - Knoche, Lisa
A1 - Lisec, Jan
A1 - Schwerdtle, Tanja
A1 - Koch, Matthias
T1 - LC-HRMS-Based identification of transformation products of the drug salinomycin generated by electrochemistry and liver microsome
JF - Antibiotics
N2 - The drug salinomycin (SAL) is a polyether antibiotic and used in veterinary medicine as coccidiostat and growth promoter. Recently, SAL was suggested as a potential anticancer drug. However, transformation products (TPs) resulting from metabolic and environmental degradation of SAL are incompletely known and structural information is missing. In this study, we therefore systematically investigated the formation and identification of SAL derived TPs using electrochemistry (EC) in an electrochemical reactor and rat and human liver microsome incubation (RLM and HLM) as TP generating methods. Liquid chromatography (LC) coupled to high-resolution mass spectrometry (HRMS) was applied to determine accurate masses in a suspected target analysis to identify TPs and to deduce occurring modification reactions of derived TPs. A total of 14 new, structurally different TPs were found (two EC-TPs, five RLM-TPs, and 11 HLM-TPs). The main modification reactions are decarbonylation for EC-TPs and oxidation (hydroxylation) for RLM/HLM-TPs. Of particular interest are potassium-based TPs identified after liver microsome incubation because these might have been overlooked or declared as oxidated sodium adducts in previous, non-HRMS-based studies due to the small mass difference between K and O + Na of 21 mDa. The MS fragmentation pattern of TPs was used to predict the position of identified modifications in the SAL molecule. The obtained knowledge regarding transformation reactions and novel TPs of SAL will contribute to elucidate SAL-metabolites with regards to structural prediction.
KW - salinomycin
KW - ionophore antibiotics
KW - transformation product
KW - electrochemistry
KW - rat
KW - human liver microsomes
KW - HRMS
Y1 - 2022
U6 - https://doi.org/10.3390/antibiotics11020155
SN - 2079-6382
VL - 11
IS - 2
PB - MDPI
CY - Basel
ER -
TY - JOUR
A1 - Eggert, Kai
A1 - Rawel, Harshadrai Manilal
A1 - Nikfardjam, Martin S. Pour
A1 - Kroll, Jürgen
T1 - Interactions between lysozyme and wine components
JF - Deutsche Lebensmittel-Rundschau : DLR
N2 - The addition of lysozyme amounting to 1000 mg/l wine does neither effect its total phenol content (Folin-Ciocalteu-Method), nor wine colour (measured by extinction at 512 nm) nor its antioxidative capacity (TEAC-Assay). No covalent binding of wine phenols to the enzyme was observed during lysozyme addition, although non-covalent interactions are possible. Lysozyme activity is not influenced by the presence of malvidin-3-glucoside and resveratrol in model experiments, whereas pH and ethanol content produce a corresponding alteration in lysozyme activity. With regard to red wine, a significant effect was noted in the presence of wine components.
KW - lysozyme
KW - red wine
KW - total phenol content
KW - colour
KW - antioxidative capacity
KW - lysozyme activity
Y1 - 2006
SN - 0012-0413
VL - 102
IS - 10
SP - 472
EP - 478
PB - Behr
CY - Stuttgart
ER -
TY - JOUR
A1 - Folkesson, Maggie
A1 - Vorkapic, Emina
A1 - Gulbins, Erich
A1 - Japtok, Lukasz
A1 - Kleuser, Burkhard
A1 - Welander, Martin
A1 - Länne, Toste
A1 - Wågsäter, Dick
T1 - Inflammatory cells, ceramides, and expression of proteases in perivascular adipose tissue adjacent to human abdominal aortic aneurysms
JF - Journal of vascular surgery
N2 - Background: Abdominal aortic aneurysm (AAA) is a deadly irreversible weakening and distension of the abdominal aortic wall. The pathogenesis of AAA remains poorly understood. Investigation into the physical and molecular characteristics of perivascular adipose tissue (PVAT) adjacent to AAA has not been done before and is the purpose of this study.
Methods and Results: Human aortae, periaortic PVAT, and fat surrounding peripheral arteries were collected from patients undergoing elective surgical repair of AAA. Control aortas were obtained from recently deceased healthy organ donors with no known arterial disease. Aorta and PVAT was found in AAA to larger extent compared with control aortas. Immunohistochemistry revealed neutrophils, macrophages, mast cells, and T-cells surrounding necrotic adipocytes. Gene expression analysis showed that neutrophils, mast cells, and T-cells were found to be increased in PVAT compared with AAA as well as cathepsin K and S. The concentration of ceramides in PVAT was determined using mass spectrometry and correlated with content of T-cells in the PVAT.
Conclusions: Our results suggest a role for abnormal necrotic, inflamed, proteolytic adipose tissue to the adjacent aneurysmal aortic wall in ongoing vascular damage.
Y1 - 2016
U6 - https://doi.org/10.1016/j.jvs.2015.12.056
SN - 0741-5214
VL - 65
IS - 4
SP - 1171
EP - 1179
PB - Elsevier
CY - New York
ER -
TY - JOUR
A1 - Maares, Maria
A1 - Keil, Claudia
A1 - Koza, Jenny
A1 - Straubing, Sophia
A1 - Schwerdtle, Tanja
A1 - Haase, Hajo
T1 - In Vitro Studies on Zinc Binding and Buffering by Intestinal Mucins
JF - International Journal of Molecular Sciences
N2 - The investigation of luminal factors influencing zinc availability and accessibility in the intestine is of great interest when analyzing parameters regulating intestinal zinc resorption. Of note, intestinal mucins were suggested to play a beneficial role in the luminal availability of zinc. Their exact zinc binding properties, however, remain unknown and the impact of these glycoproteins on human intestinal zinc resorption has not been investigated in detail. Thus, the aim of this study is to elucidate the impact of intestinal mucins on luminal uptake of zinc into enterocytes and its transfer into the blood. In the present study, in vitro zinc binding properties of mucins were analyzed using commercially available porcine mucins and secreted mucins of the goblet cell line HT-29-MTX. The molecular zinc binding capacity and average zinc binding affinity of these glycoproteins demonstrates that mucins contain multiple zinc-binding sites with biologically relevant affinity within one mucin molecule. Zinc uptake into the enterocyte cell line Caco-2 was impaired by zinc-depleted mucins. Yet this does not represent their form in the intestinal lumen in vivo under zinc adequate conditions. In fact, zinc-uptake studies into enterocytes in the presence of mucins with differing degree of zinc saturation revealed zinc buffering by these glycoproteins, indicating that mucin-bound zinc is still available for the cells. Finally, the impact of mucins on zinc resorption using three-dimensional cultures was studied comparing the zinc transfer of a Caco-2/HT-29-MTX co-culture and conventional Caco-2 monoculture. Here, the mucin secreting co-cultures yielded higher fractional zinc resorption and elevated zinc transport rates, suggesting that intestinal mucins facilitate the zinc uptake into enterocytes and act as a zinc delivery system for the intestinal epithelium.
KW - intestinal zinc resorption
KW - zinc binding
KW - mucus layer
KW - intestinal mucins
KW - in vitro intestinal model
KW - goblet cells
KW - Caco-2/HT-29-MTX-model
Y1 - 2018
U6 - https://doi.org/10.3390/ijms19092662
SN - 1422-0067
VL - 19
IS - 9
ER -
TY - JOUR
A1 - Jonas, Wenke
A1 - Kluth, Oliver
A1 - Helms, Anett
A1 - Voss, Sarah
A1 - Jahnert, Markus
A1 - Gottmann, Pascal
A1 - Speckmann, Thilo
A1 - Knebel, Birgit
A1 - Chadt, Alexandra
A1 - Al-Hasani, Hadi
A1 - Schürmann, Annette
A1 - Vogel, Heike
T1 - Identification of novel genes involved in hyperglycemia in mice
JF - International journal of molecular sciences
N2 - Current attempts to prevent and manage type 2 diabetes have been moderately effective, and a better understanding of the molecular roots of this complex disease is important to develop more successful and precise treatment options.
Recently, we initiated the collective diabetes cross, where four mouse inbred strains differing in their diabetes susceptibility were crossed with the obese and diabetes-prone NZO strain and identified the quantitative trait loci (QTL) Nidd13/NZO, a genomic region on chromosome 13 that correlates with hyperglycemia in NZO allele carriers compared to B6 controls.
Subsequent analysis of the critical region, harboring 644 genes, included expression studies in pancreatic islets of congenic Nidd13/NZO mice, integration of single-cell data from parental NZO and B6 islets as well as haplotype analysis.
Finally, of the five genes (Acot12, S100z, Ankrd55, Rnf180, and Iqgap2) within the polymorphic haplotype block that are differently expressed in islets of B6 compared to NZO mice, we identified the calcium-binding protein S100z gene to affect islet cell proliferation as well as apoptosis when overexpressed in MINE cells. In summary, we define S100z as the most striking gene to be causal for the diabetes QTL Nidd13/NZO by affecting beta-cell proliferation and apoptosis. Thus, S100z is an entirely novel diabetes gene regulating islet cell function.
KW - beta-cell
KW - diabetes
KW - proliferation
KW - apoptosis
KW - QTL
Y1 - 2022
U6 - https://doi.org/10.3390/ijms23063205
SN - 1661-6596
SN - 1422-0067
VL - 23
IS - 6
PB - MDPI
CY - Basel
ER -
TY - JOUR
A1 - Wardelmann, Kristina
T1 - Hormonal regulation of neuronal mitochondrial unfolded protein response and its impact on metabolism
N2 - The hypothalamus is the main brain area of central regulation of whole body metabolism through impacting food intake and energy expenditure. For the complex regulation, high amounts of energy are needed and mainly provided by mitochondria. Hence, mitochondrial function is crucial for cell homeostasis and modulates central insulin sensitivity. Thus, mitochondrial dysfunction is associated with insulin resistance in the brain and therefore is involved in the pathogenesis of type-2 diabetes (T2D). Mitochondrial health and protein homeostasis is propagated by mitochondrial stress responses like e.g. mitochondrial unfolded protein response (UPRmt). Therefore, studies regarding the regulation of mitochondrial homeostasis are crucial for understanding its effects on the central nervous system (CNS) for the progression of metabolic and nutrition-dependent disorders.
One main aim of this thesis was to investigate the metabolic regulation of mitochondrial stress responsiveness in the hypothalamus. The observed results showed that functional ERK-dependent insulin signaling is needed for regulation of mitochondrial stress response (MSR) genes and positively impacted the metabolism by controlling mitochondrial proteostasis without affecting mitochondrial biogenesis.
To further explore the role of MSR genes for brain cell homeostasis and its consequences for the metabolism, one of the key players - the mitochondrial chaperone heat shock protein 10 (Hsp10) – was studied in detail. Hsp10 expression was decreased in insulin-resistant, hyperglycemic db/db mice brains along with increased protein oxidation. Leptin, another key hormone in regulating metabolism, was able to induce Hsp10 in neurons. Appropriately, lentiviral-mediated knock down (KD) of Hsp10 introduced into hypothalamic CLU-183 cells induced mitochondrial dysfunction, altered mitochondrial dynamics and increased contact sites between mitochondria and endoplasmic reticulum (ER). In addition, Hsp10 KD caused cellular insulin resistance along with increasing oxidative stress specifically in mitochondrial fraction.
Interestingly, acute Hsp10 KD in the arcuate nucleus of the hypothalamus in C57BL/6N male mice did not change body weight or food intake, but it increased plasma leptin concentrations suggesting an effect on global leptin signaling. It increased hepatic markers of gluconeogenesis and hepatic insulin resistance along with features of low-grade inflammation.
Long-term studies of hypothalamic Hsp10 KD mice revealed unaltered systemic insulin sensitivity. The demonstrated increase in markers of hepatic gluconeogenesis of acute Hsp10 KD was still exhibited after 13 weeks, but insulin resistance in the liver was no longer observed.
In conclusion, hypothalamic insulin action regulates MSR and ensures proper mitochondrial function which positively affects metabolism. In addition, hypothalamic Hsp10 acts as a modulator of both insulin and leptin signaling and is identified as pivotal for the regulation of central mitochondrial function as well as insulin sensitivity in the brain and it impacts liver function. It may present a regulator of brain-liver crosstalk influencing hepatic gluconeogenesis and insulin sensitivity through a novel regulatory signaling mechanism.
N2 - Die zentrale Regulation des Metabolismus wird vom Hypothalamus gesteuert, indem diese Hirnregion die Nahrungsaufnahme sowie den Energieverbrauch reguliert. Dieser komplexe Regulations-Mechanismus benötigt eine enorme Menge an Energie, die hauptsächlich von Mitochondrien produziert wird. Somit ist die mitochondriale Funktion existenziell für die Zell-Homöostase und in einigen Studien konnte gezeigt werden, dass diese Funktion ebenfalls mit der zentralen Insulin-Sensitivität zusammenhängt. Mitochondriale Dysfunktion hingegen ist mit Insulin-Resistenz im Gehirn assoziiert und damit an der Pathogenese und Progression von Diabetes Typ 2 beteiligt. Mitochondriale Stressantworten wie zum Beispiel die mitochondriale ungefaltete Proteinantwort (mitochondrial unfolded stress response) ermöglichen die Protein-Homöostase und einwandfreie Funktion der Mitochondrien. Folglich sind Untersuchungen der Regulation der mitochondrialen Funktion von großer Bedeutung für das Verständnis der zentralnervösen Auswirkungen auf die Entwicklung ernährungsbedingter Störungen des Metabolismus.
Eine der Zielstellungen dieser Doktorarbeit war die Untersuchung der metabolischen Regulation der hypothalamische Stressantwort der Mitochondrien. Die hier durchgeführten Studien zeigten, dass die funktionelle Insulin Signalkaskade für die Regulierung der mitochondrialen Stressantwort (MSR) benötigt wird und dies durch die Kontrolle der Proteostase der Mitochondrien positive Effekte auf den Metabolismus hat.
Zur genaueren Klärung der Aufgabe der mitochondrialen Stressantwort für die Homöostase der Gehirnzelle und dessen Auswirkungen für den Metabolismus wurde eines der Mitglieder dieser Stressantwort, das mitochondriale Chaperon Hitzeschock-Protein 10 (Hsp10), näher untersucht. Zunächst konnte dargelegt werden, dass die Expression von Hsp10 in Gehirnen von Insulin-resistenten, hyperglykämischen db/db Mäusen verringert ist. Diese Mäuse zeigen zusätzlich eine Erhöhung der Oxidation von Proteinen im Gehirn, ein weiteres Merkmal des Krankheitsbildes von Diabetes Typ 2. Darüber hinaus zeigten die vorliegenden Studien, dass Leptin, ein weiteres für die Regulation des Metabolismus wichtiges Hormon, die Expression von Hsp10 in Neuronen induzieren konnte. Der lentiviral-vermittelte knockdown von Hsp10 in der hypothalamischen, neuronalen Zelllinie CLU 183 hingegen verursacht mitochondriale Dysfunktion, sowie eine veränderte mitochondriale Dynamik einhergehend mit erhöhtem Kontakt von Mitochondrien mit dem endoplasmatischen Retikulum. Zusätzlich wurde Mitochondrien-spezifischer oxidativer Stress von der Reduzierung von Hsp10 verursacht und eine Insulin-Resistenz ausgelöst.
Interessanterweise beeinflusste der akute knockdown der Hsp10 Expression im Nucleus Arcuatus des Hypothalamus in männlichen C57BL/6N Mäusen weder das Körpergewicht noch die Futteraufnahme, jedoch war die Plasma-Konzentration von Leptin erhöht. Dies deutet auf einen Effekt von zentralem Hsp10 auf die systemische Leptin-Signalwirkung hin. Außerdem wurde durch die akute Verringerung von hypothalamischen Hsp10 PEPCK in der Leber induziert, ein wichtiges Protein der Gluconeogenese, sowie eine hepatische Insulin-Resistenz ausgelöst, verbunden mit Anzeichen einer schwachen Inflammation dieses Gewebes. Bei verlängerter Reduktion der Expression von Hsp10 im Hypothalamus wurde die systemische Insulin-Sensitivität der Mäuse nicht verändert. Die hepatische Insulin-Resistenz war nach 13 Wochen des hypothalamischen knockdown von Hsp10 in C57BL/6N Mäusen nicht mehr zu beobachten, aber die Induktion des Gluconeogenese-Gens PEPCK in der Leber war weiterhin existent.
Zusammenfassend zeigt diese Dissertation, dass die hypothalamische Insulin-Signalwirkung die mitochondriale Stressantwort reguliert und somit die Funktion der Mitochondrien gewährleistet, was den Metabolismus positiv beeinflusst. Des Weiteren deuten die diskutierten Ergebnisse darauf hin, dass Hsp10 im Hypothalamus ein Modulator der Insulin- sowie Leptinsignalwirkung des Körpers ist. Hsp10 ist entscheidend für die Regulierung der zentralen Funktion der Mitochondrien sowie der Insulin-Sensitivität in Gehirn und beeinflusst die Leberfunktion. Die Konsequenzen der Verringerung von Hsp10 im Hypothalamus modulieren die hepatische Gluconeogenese und Insulin-Sensitivität. Daraus folgend wird Hsp10 als neuer Regulator der Kommunikation zwischen Gehirn und Leber identifiziert, mit einem in diesem Falle noch unbekannten Mechanismus der Signalweiterleitung zwischen den beiden Organen.
Y1 - 2019
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 - 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 - JOUR
A1 - Rund, Katharina M.
A1 - Heylmann, Daniel
A1 - Seiwert, Nina
A1 - Wecklein, Sabine
A1 - Oger, Camille
A1 - Galano, Jean-Marie
A1 - Durand, Thierry
A1 - Chen, Rongjun
A1 - Güler, Faikah
A1 - Fahrer, Jörg
A1 - Bornhorst, Julia
A1 - Schebb, Nils Helge
T1 - Formation of trans-epoxy fatty acids correlates with formation of isoprostanes and could serve as biomarker of oxidative stress
JF - Prostaglandins & Other Lipid Mediators
N2 - In mammals, epoxy-polyunsaturated fatty acids (epoxy-PUFA) are enzymatically formed from naturally occurring all-cis PUFA by cytochrome P450 monooxygenases leading to the generation of cis-epoxy-PUFA (mixture of R,S- and S,R-enantiomers). In addition, also non-enzymatic chemical peroxidation gives rise to epoxy-PUFA leading to both, cis- and trans-epoxy-PUFA (mixture of R,R- and S,S-enantiomers). Here, we investigated for the first time trans-epoxy-PUFA and the trans/cis-epoxy-PUFA ratio as potential new biomarker of lipid peroxidation. Their formation was analyzed in correlation with the formation of isoprostanes (IsoP), which are commonly used as biomarkers of oxidative stress. Five oxidative stress models were investigated including incubations of three human cell lines as well as the in vivo model Caenorhabditis elegans with tert-butyl hydroperoxide (t-BOOH) and analysis of murine kidney tissue after renal ischemia reperfusion injury (IRI). A comprehensive set of IsoP and epoxy-PUFA derived from biologically relevant PUFA (ARA, EPA and DHA) was simultaneously quantified by LC-ESI(-)-MS/MS. Following renal IRI only a moderate increase in the kidney levels of IsoP and no relevant change in the trans/cis-epoxy-PUFA ratio was observed. In all investigated cell lines (HCT-116, HepG2 and Caki-2) as well as C. elegans a dose dependent increase of both, IsoP and the trans/cis-epoxy-PUFA ratio in response to the applied t-BOOH was observed. The different cell lines showed a distinct time dependent pattern consistent for both classes of autoxidatively formed oxylipins. Clear and highly significant correlations of the trans/cisepoxy-PUFA ratios with the IsoP levels were found in all investigated cell lines and C. elegans. Based on this, we suggest the trans/cis-epoxy-PUFA ratio as potential new biomarker of oxidative stress, which warrants further investigation.
KW - Isoprostane
KW - Trans-epoxy-fatty acid
KW - Oxidative stress
KW - Biomarker
KW - Oxylipin
KW - Eicosanoid
Y1 - 2019
U6 - https://doi.org/10.1016/j.prostaglandins.2019.04.004
SN - 1098-8823
SN - 2212-196X
VL - 144
PB - Elsevier
CY - New York
ER -
TY - JOUR
A1 - Fruscalzo, Arrigo
A1 - Frommer, Julia-Marie
A1 - Londero, Ambrogio P.
A1 - Henze, Andrea
A1 - Schweigert, Florian J.
A1 - Nofer, Jerzy-Roch
A1 - Steinhard, Johannes
A1 - Klockenbusch, Walter
A1 - Schmitz, Ralf
A1 - Raila, Jens
T1 - First trimester TTR-RBP4-ROH complex and angiogenic factors in the prediction of small for gestational age infant’s outcome
JF - Archives of gynecology and obstetrics
N2 - To study the role of the TTR-RBP4-ROH complex components (transthyretin, serum retinol binding protein, retinol) and of angiogenic factors PlGF (placental growth factor) and sFlt-1 (soluble fms-like tyrosine kinase-1) in pregnancies complicated by small for gestational age infants (SGA). Case control study conducted on maternal serum collected between 11 + 0 to 13 + 6 weeks of gestation. TTR, RBP4, ROH, PlGF and sFlt-1 were measured in SGA patients (birth weight < 10%) who delivered at term (n = 37) and before 37 weeks of gestation (n = 17) and in a matched control group with uneventful pregnancies (n = 37). We found decreased RBP4 in SGA patients that delivered fetuses < 3% and in fetuses delivered after the 37 weeks of gestation compared to controls [1.50 (95% CI 1.40-1.75) vs 1.62 (95% CI 1.47-1.98), p < 0.05]. Further, we found lower PlGF and sFlt-1 concentrations in SGA that delivered before 37 weeks of gestation compared to controls (respectively, PIGF and sFlt-1: 39.7 pg/ml (95% CI 32.3-66.3) vs 62.9 pg/ml (95% CI 45.2-78.4) and 906 pg/ml (95% CI 727-1626) vs 1610 pg/ml (95% CI 1088-212), p < 0.05). First trimester maternal serum RBP4 and angiogenic factors PlGF and sFlt-1 can differently predict the timing of delivery of pregnancies complicated by SGA fetuses.
KW - Low birth weight
KW - Small for gestational age
KW - Pregnancy
KW - First trimester
KW - Marker
KW - RBP4
KW - TTR
KW - Retinol
KW - Vitamin A
KW - sFlt-1
KW - PlGF
Y1 - 2017
U6 - https://doi.org/10.1007/s00404-017-4338-4
SN - 0932-0067
SN - 1432-0711
VL - 295
SP - 1157
EP - 1165
PB - Springer
CY - Heidelberg
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 - JOUR
A1 - Wetzel, Alexandra Nicole
A1 - Scholtka, Bettina
A1 - Schumacher, Fabian
A1 - Rawel, Harshadrai Manilal
A1 - Geisendörfer, Birte
A1 - Kleuser, Burkhard
T1 - Epigenetic DNA methylation of EBI3 modulates human interleukin-35 formation via NFkB signaling
BT - a promising therapeutic option in ulcerative colitis
JF - International journal of molecular sciences
N2 - Ulcerative colitis (UC), a severe chronic disease with unclear etiology that is associated with increased risk for colorectal cancer, is accompanied by dysregulation of cytokines. Epstein-Barr virus-induced gene 3 (EBI3) encodes a subunit in the unique heterodimeric IL-12 cytokine family of either pro- or anti-inflammatory function. After having recently demonstrated that upregulation of EBI3 by histone acetylation alleviates disease symptoms in a dextran sulfate sodium (DSS)-treated mouse model of chronic colitis, we now aimed to examine a possible further epigenetic regulation of EBI3 by DNA methylation under inflammatory conditions. Treatment with the DNA methyltransferase inhibitor (DNMTi) decitabine (DAC) and TNF alpha led to synergistic upregulation of EBI3 in human colon epithelial cells (HCEC). Use of different signaling pathway inhibitors indicated NF kappa B signaling was necessary and proportional to the synergistic EBI3 induction. MALDI-TOF/MS and HPLC-ESIMS/MS analysis of DAC/TNF alpha-treated HCEC identified IL-12p35 as the most probable binding partner to form a functional protein. EBI3/IL-12p35 heterodimers (IL-35) induce their own gene upregulation, something that was indeed observed in HCEC cultured with media from previously DAC/TNF alpha-treated HCEC. These results suggest that under inflammatory and demethylating conditions the upregulation of EBI3 results in the formation of anti-inflammatory IL-35, which might be considered as a therapeutic target in colitis.
KW - decitabine
KW - DNMT inhibitor
KW - EBI3
KW - inhibitory cytokines
KW - interleukin-35
KW - TNF alpha
KW - Ulcerative colitis
Y1 - 2021
U6 - https://doi.org/10.3390/ijms22105329
SN - 1422-0067
VL - 22
IS - 10
PB - MDPI
CY - Basel
ER -
TY - JOUR
A1 - Henkel-Oberländer, Janin
A1 - Klauder, Julia
A1 - Statz, Meike
A1 - Wohlenberg, Anne-Sophie
A1 - Kuipers, Sonja
A1 - Vahrenbrink, Madita
A1 - Püschel, Gerhard
T1 - Enhanced Palmitate-Induced Interleukin-8 Formation in Human Macrophages by Insulin or Prostaglandin E₂
JF - Biomedicines : open access journal
N2 - Macrophages in pathologically expanded dysfunctional white adipose tissue are exposed to a mix of potential modulators of inflammatory response, including fatty acids released from insulin-resistant adipocytes, increased levels of insulin produced to compensate insulin resistance, and prostaglandin E₂ (PGE₂) released from activated macrophages. The current study addressed the question of how palmitate might interact with insulin or PGE₂ to induce the formation of the chemotactic pro-inflammatory cytokine interleukin-8 (IL-8). Human THP-1 cells were differentiated into macrophages. In these macrophages, palmitate induced IL-8 formation. Insulin enhanced the induction of IL-8 formation by palmitate as well as the palmitate-dependent stimulation of PGE₂ synthesis. PGE₂ in turn elicited IL-8 formation on its own and enhanced the induction of IL-8 release by palmitate, most likely by activating the EP4 receptor. Since IL-8 causes insulin resistance and fosters inflammation, the increase in palmitate-induced IL-8 formation that is caused by hyperinsulinemia and locally produced PGE₂ in chronically inflamed adipose tissue might favor disease progression in a vicious feed-forward cycle.
KW - macrophages
KW - insulin
KW - prostaglandin E2
KW - interleukin-8
KW - inflammation
Y1 - 2021
U6 - https://doi.org/10.3390/biomedicines9050449
SN - 2227-9059
VL - 9
IS - 5
PB - MDPI
CY - Basel
ER -
TY - JOUR
A1 - Müller, Sandra Marie
A1 - Ebert, Franziska
A1 - Raber, Georg
A1 - Meyer, Sören
A1 - Bornhorst, Julia
A1 - Hüwel, Stephan
A1 - Galla, Hans-Joachim
A1 - Francesconi, Kevin A.
A1 - Schwerdtle, Tanja
T1 - Effects of arsenolipids on in vitro blood-brain barrier model
JF - Archives of toxicology : official journal of EUROTOX
N2 - Arsenic-containing hydrocarbons (AsHCs), a subgroup of arsenolipids (AsLs) occurring in fish and edible algae, possess a substantial neurotoxic potential in fully differentiated human brain cells. Previous in vivo studies indicating that AsHCs cross the blood–brain barrier of the fruit fly Drosophila melanogaster raised the question whether AsLs could also cross the vertebrate blood–brain barrier (BBB). In the present study, we investigated the impact of several representatives of AsLs (AsHC 332, AsHC 360, AsHC 444, and two arsenic-containing fatty acids, AsFA 362 and AsFA 388) as well as of their metabolites (thio/oxo-dimethylpropionic acid, dimethylarsinic acid) on porcine brain capillary endothelial cells (PBCECs, in vitro model for the blood–brain barrier). AsHCs exerted the strongest cytotoxic effects of all investigated arsenicals as they were up to fivefold more potent than the toxic reference species arsenite (iAsIII). In our in vitro BBB-model, we observed a slight transfer of AsHC 332 across the BBB after 6 h at concentrations that do not affect the barrier integrity. Furthermore, incubation with AsHCs for 72 h led to a disruption of the barrier at sub-cytotoxic concentrations. The subsequent immunocytochemical staining of three tight junction proteins revealed a significant impact on the cell membrane. Because AsHCs enhance the permeability of the in vitro blood–brain barrier, a similar behavior in an in vivo system cannot be excluded. Consequently, AsHCs might facilitate the transfer of accompanying foodborne toxicants into the brain.
KW - Arsenolipids
KW - Arsenic-containing hydrocarbons
KW - Arsenic-containing fatty acids
KW - In vitro blood-brain barrier model
Y1 - 2017
SN - 0340-5761
SN - 1432-0738
VL - 92
IS - 2
SP - 823
EP - 832
PB - Springer
CY - Heidelberg
ER -
TY - JOUR
A1 - Odongo, Grace Akinyi
A1 - Schlotz, Nina
A1 - Baldermann, Susanne
A1 - Neugart, Susanne
A1 - Ngwene, Benard
A1 - Schreiner, Monika
A1 - Lamy, Evelyn
T1 - Effects of Amaranthus cruentus L. on aflatoxin B1- and oxidative stress-induced DNA damage in human liver (HepG2) cells
JF - Food bioscience
N2 - Amaranth is presently an underutilized crop despite its high content of micronutrients/bioactive phytochemicals and its capacity to thrive in harsh environmental condition. The present study aimed at determining the health benefits of Amaranthus cruentus L. in terms of protection against DNA damage induced by the mycotoxin aflatoxin B1 (AFB1) and oxidative stress using comet assay. The antioxidant potential was further investigated using electron paramagnetic resonance spectroscopy (EPR) and an ARE/Nrf2 reporter gene assay in vitro in a human liver model using the HepG2 cell line. Ethanolic extracts from fresh leaves grown under controlled conditions were used and additionally analyzed for their phytochemical content using liquid chromatography-mass spectrometry (LC-MS). The extracts inhibited both AFB1- and oxidative stress-induced DNA damage in a concentration dependent way with a maximum effect of 57% and 81%, respectively. Oxidative stress triggered using ferrous sulfate was blocked by up to 38% (EPR); the potential to induce antioxidant enzymes using ARE/Nrf2-mediated gene expression was also confirmed. Based on these in vitro findings, further studies on the health-protecting effects of A. cruentus are encouraged to fully explore its health promoting potential and provide the scientific basis for encouraging its cultivation and consumption.
KW - African indigenous vegetables
KW - Aflatoxin B1
KW - Amaranthaceae
KW - Amaranth
KW - Aspergillus
KW - Cancer prevention
Y1 - 2018
U6 - https://doi.org/10.1016/j.fbio.2018.09.006
SN - 2212-4292
SN - 2212-4306
VL - 26
SP - 42
EP - 48
PB - Elsevier
CY - Amsterdam
ER -
TY - JOUR
A1 - Tchewonpi Sagu, Sorel
A1 - Landgräber, Eva
A1 - Henkel, Ina M.
A1 - Huschek, Gerd
A1 - Homann, Thomas
A1 - Bußler, Sara
A1 - Schlüter, Oliver K.
A1 - Rawel, Harshadrai Manilal
T1 - Effect of cereal α-amylase/trypsin inhibitors on developmental characteristics and abundance of digestive enzymes of mealworm larvae (Tenebrio molitor L.)
JF - Insects
N2 - The objective of this work was to investigate the potential effect of cereal α-amylase/trypsin inhibitors (ATIs) on growth parameters and selective digestive enzymes of Tenebrio molitor L. larvae. The approach consisted of feeding the larvae with wheat, sorghum and rice meals containing different levels and composition of α-amylase/trypsin inhibitors. The developmental and biochemical characteristics of the larvae were assessed over feeding periods of 5 h, 5 days and 10 days, and the relative abundance of α-amylase and selected proteases in larvae were determined using liquid chromatography tandem mass spectrometry. Overall, weight gains ranged from 21% to 42% after five days of feeding. The larval death rate significantly increased in all groups after 10 days of feeding (p < 0.05), whereas the pupation rate was about 25% among larvae fed with rice (Oryza sativa L.) and Siyazan/Esperya wheat meals, and only 8% and 14% among those fed with Damougari and S35 sorghum meals. As determined using the Lowry method, the protein contents of the sodium phosphate extracts ranged from 7.80 ± 0.09 to 9.42 ± 0.19 mg/mL and those of the ammonium bicarbonate/urea reached 19.78 ± 0.16 to 37.47 ± 1.38 mg/mL. The total protein contents of the larvae according to the Kjeldahl method ranged from 44.0 and 49.9 g/100 g. The relative abundance of α-amylase, CLIP domain-containing serine protease, modular serine protease zymogen and C1 family cathepsin significantly decreased in the larvae, whereas dipeptidylpeptidase I and chymotrypsin increased within the first hours after feeding (p < 0.05). Trypsin content was found to be constant independently of time or feed material. Finally, based on the results we obtained, it was difficult to substantively draw conclusions on the likely effects of meal ATI composition on larval developmental characteristics, but their effects on the digestive enzyme expression remain relevant.
KW - growth behavior
KW - Tenebrio molitor larvae
KW - feeding
KW - cereal meals
KW - α-amylase/trypsin inhibitors
KW - digestive enzymes quantification
KW - LC-MS/MS
Y1 - 2021
U6 - https://doi.org/10.3390/insects12050454
SN - 2075-4450
VL - 12
IS - 5
PB - MDPI
CY - Basel
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 - Aga-Barfknecht, Heja
A1 - Soultoukis, George A.
A1 - Stadion, Mandy
A1 - Garcia-Carrizo, Francisco
A1 - Jähnert, Markus
A1 - Gottmann, Pascal
A1 - Vogel, Heike
A1 - Schulz, Tim Julius
A1 - Schürmann, Annette
T1 - Distinct adipogenic and fibrogenic differentiation capacities of mesenchymal stromal cells from pancreas and white adipose tissue
JF - International journal of molecular sciences
N2 - Pancreatic steatosis associates with beta-cell failure and may participate in the development of type-2-diabetes. Our previous studies have shown that diabetes-susceptible mice accumulate more adipocytes in the pancreas than diabetes-resistant mice. In addition, we have demonstrated that the co-culture of pancreatic islets and adipocytes affect insulin secretion. The aim of this current study was to elucidate if and to what extent pancreas-resident mesenchymal stromal cells (MSCs) with adipogenic progenitor potential differ from the corresponding stromal-type cells of the inguinal white adipose tissue (iWAT). miRNA (miRNome) and mRNA expression (transcriptome) analyses of MSCs isolated by flow cytometry of both tissues revealed 121 differentially expressed miRNAs and 1227 differentially expressed genes (DEGs). Target prediction analysis estimated 510 DEGs to be regulated by 58 differentially expressed miRNAs. Pathway analyses of DEGs and miRNA target genes showed unique transcriptional and miRNA signatures in pancreas (pMSCs) and iWAT MSCs (iwatMSCs), for instance fibrogenic and adipogenic differentiation, respectively. Accordingly, iwatMSCs revealed a higher adipogenic lineage commitment, whereas pMSCs showed an elevated fibrogenesis. As a low degree of adipogenesis was also observed in pMSCs of diabetes-susceptible mice, we conclude that the development of pancreatic steatosis has to be induced by other factors not related to cell-autonomous transcriptomic changes and miRNA-based signals.
KW - MSCs
KW - fatty pancreas
KW - WAT
KW - lineage commitment
KW - transcriptomics
KW - miRNAs
Y1 - 2022
U6 - https://doi.org/10.3390/ijms23042108
SN - 1422-0067
VL - 23
IS - 4
PB - Molecular Diversity Preservation International
CY - Basel
ER -
TY - JOUR
A1 - Laeger, Thomas
A1 - Castano-Martinez, Teresa
A1 - Werno, Martin W.
A1 - Japtok, Lukasz
A1 - Baumeier, Christian
A1 - Jonas, Wenke
A1 - Kleuser, Burkhard
A1 - Schürmann, Annette
T1 - Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes
JF - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
N2 - Aims/hypothesis Low-protein diets are well known to improve glucose tolerance and increase energy expenditure. Increases in circulating fibroblast growth factor 21 (FGF21) have been implicated as a potential underlying mechanism. Methods We aimed to test whether low-protein diets in the context of a high-carbohydrate or high-fat regimen would also protect against type 2 diabetes in New Zealand Obese (NZO) mice used as a model of polygenetic obesity and type 2 diabetes. Mice were placed on high-fat diets that provided protein at control (16 kJ%; CON) or low (4 kJ%; low-protein/high-carbohydrate [LP/HC] or low-protein/high-fat [LP/HF]) levels. Results Protein restriction prevented the onset of hyperglycaemia and beta cell loss despite increased food intake and fat mass. The effect was seen only under conditions of a lower carbohydrate/fat ratio (LP/HF). When the carbohydrate/fat ratio was high (LP/HC), mice developed type 2 diabetes despite the robustly elevated hepatic FGF21 secretion and increased energy expenditure. Conclusion/interpretation Prevention of type 2 diabetes through protein restriction, without lowering food intake and body fat mass, is compromised by high dietary carbohydrates. Increased FGF21 levels and elevated energy expenditure do not protect against hyperglycaemia and type 2 diabetes per se.
KW - Energy expenditure
KW - FGF21
KW - Hyperglycaemia
KW - Insulin resistance
KW - NZO
KW - Obesity
KW - Protein restriction
Y1 - 2018
U6 - https://doi.org/10.1007/s00125-018-4595-1
SN - 0012-186X
SN - 1432-0428
VL - 61
IS - 6
SP - 1459
EP - 1469
PB - Springer
CY - New York
ER -
TY - JOUR
A1 - Rausch, Ann-Kristin
A1 - Brockmeyer, Robert
A1 - Schwerdtle, Tanja
T1 - Development, validation, and application of a multi-method for the determination of mycotoxins, plant growth regulators, tropane alkaloids, and pesticides in cereals by two-dimensional liquid chromatography tandem mass spectrometry
JF - Analytical & bioanalytical chemistry : a merger of Fresenius' journal of analytical chemistry, Analusis and Quimica analitica
N2 - Mycotoxins and pesticides regularly co-occur in agricultural products worldwide. Thus, humans can be exposed to both toxic contaminants and pesticides simultaneously, and multi-methods assessing the occurrence of various food contaminants and residues in a single method are necessary. A two-dimensional high performance liquid chromatography tandem mass spectrometry method for the analysis of 40 (modified) mycotoxins, two plant growth regulators, two tropane alkaloids, and 334 pesticides in cereals was developed. After an acetonitrile/water/formic acid (79:20:1, v/v/v) multi-analyte extraction procedure, extracts were injected into the two-dimensional setup, and an online clean-up was performed. The method was validated according to Commission Decision (EC) no. 657/2002 and document N° SANTE/12682/2019. Good linearity (R2 > 0.96), recovery data between 70-120%, repeatability and reproducibility values < 20%, and expanded measurement uncertainties < 50% were obtained for a wide range of analytes, including very polar substances like deoxynivalenol-3-glucoside and methamidophos. However, results for fumonisins, zearalenone-14,16-disulfate, acid-labile pesticides, and carbamates were unsatisfying. Limits of quantification meeting maximum (residue) limits were achieved for most analytes. Matrix effects varied highly (−85 to +1574%) and were mainly observed for analytes eluting in the first dimension and early-eluting analytes in the second dimension. The application of the method demonstrated the co-occurrence of different types of cereals with 28 toxins and pesticides. Overall, 86% of the samples showed positive findings with at least one mycotoxin, plant growth regulator, or pesticide.
KW - 2D-LC-MS/MS
KW - Multi-method
KW - Mycotoxins
KW - Modified mycotoxins
KW - Pesticides
KW - Cereals
Y1 - 2021
U6 - https://doi.org/10.1007/s00216-021-03239-1
SN - 1618-2650
SN - 1618-2642
VL - 413
IS - 11
SP - 3041
EP - 3054
PB - Springer
CY - Berlin
ER -
TY - JOUR
A1 - Sagu Tchewonpi, Sorel
A1 - Huschek, Gerd
A1 - Waldbach Braga, Tess
A1 - Rackiewicz, Michal
A1 - Homann, Thomas
A1 - Rawel, Harshadrai Manilal
T1 - Design of Experiment (DoE) for Optimization of HPLC Conditions for the Simultaneous Fractionation of Seven α-Amylase/Trypsin Inhibitors from Wheat (Triticum aestivum L.)
JF - Processes : open access journal
N2 - Wheat alpha-amylase/trypsin inhibitors remain a subject of interest considering the latest findings showing their implication in wheat-related non-celiac sensitivity (NCWS). Understanding their functions in such a disorder is still unclear and for further study, the need for pure ATI molecules is one of the limiting problems. In this work, a simplified approach based on the successive fractionation of ATI extracts by reverse phase and ion exchange chromatography was developed. ATIs were first extracted from wheat flour using a combination of Tris buffer and chloroform/methanol methods. The separation of the extracts on a C18 column generated two main fractions of interest F1 and F2. The response surface methodology with the Doehlert design allowed optimizing the operating parameters of the strong anion exchange chromatography. Finally, the seven major wheat ATIs namely P01083, P17314, P16850, P01085, P16851, P16159, and P83207 were recovered with purity levels (according to the targeted LC-MS/MS analysis) of 98.2 ± 0.7; 98.1 ± 0.8; 97.9 ± 0.5; 95.1 ± 0.8; 98.3 ± 0.4; 96.9 ± 0.5, and 96.2 ± 0.4%, respectively. MALDI-TOF-MS analysis revealed single peaks in each of the pure fractions and the mass analysis yielded deviations of 0.4, 1.9, 0.1, 0.2, 0.2, 0.9, and 0.1% between the theoretical and the determined masses of P01083, P17314, P16850, P01085, P16851, P16159, and P83207, respectively. Overall, the study allowed establishing an efficient purification process of the most important wheat ATIs. This paves the way for further in-depth investigation of the ATIs to gain more knowledge related to their involvement in NCWS disease and to allow the absolute quantification in wheat samples.
KW - wheat
KW - α-amylase/trypsin inhibitors
KW - fractionation
KW - purification
KW - reversed-phase chromatography
KW - ion-exchange chromatography
KW - design of experiment
KW - LC–MS/MS
KW - MALDI-TOF-MS
Y1 - 2022
U6 - https://doi.org/10.3390/pr10020259
SN - 2227-9717
VL - 10
SP - 1
EP - 18
PB - MDPI
CY - Basel, Schweiz
ET - 2
ER -
TY - JOUR
A1 - Rancan, Fiorenza
A1 - Volkmann, Hildburg
A1 - Giulbudagian, Michael
A1 - Schumacher, Fabian
A1 - Stanko, Jessica Isolde
A1 - Kleuser, Burkhard
A1 - Blume-Peytavi, Ulrike
A1 - Calderon, Marcelo
A1 - Vogt, Annika
T1 - Dermal Delivery of the High-Molecular-Weight Drug Tacrolimus by Means of Polyglycerol-Based Nanogels
JF - Pharmaceutics : Molecular Diversity Preservation International
N2 - Polyglycerol-based thermoresponsive nanogels (tNGs) have been shown to have excellent skin hydration properties and to be valuable delivery systems for sustained release of drugs into skin. In this study, we compared the skin penetration of tacrolimus formulated in tNGs with a commercial 0.1% tacrolimus ointment. The penetration of the drug was investigated in ex vivo abdominal and breast skin, while different methods for skin barrier disruption were investigated to improve skin permeability or simulate inflammatory conditions with compromised skin barrier. The amount of penetrated tacrolimus was measured in skin extracts by liquid chromatography tandem-mass spectrometry (LC-MS/MS), whereas the inflammatory markers IL-6 and IL-8 were detected by enzyme-linked immunosorbent assay (ELISA). Higher amounts of tacrolimus penetrated in breast as compared to abdominal skin or in barrier-disrupted as compared to intact skin, confirming that the stratum corneum is the main barrier for tacrolimus skin penetration. The anti-proliferative effect of the penetrated drug was measured in skin tissue/Jurkat cells co-cultures. Interestingly, tNGs exhibited similar anti-proliferative effects as the 0.1% tacrolimus ointment. We conclude that polyglycerol-based nanogels represent an interesting alternative to paraffin-based formulations for the treatment of inflammatory skin conditions.
KW - tacrolimus formulation
KW - nanogels
KW - skin penetration
KW - drug delivery
KW - human excised skin
KW - Jurkat cells
Y1 - 2019
U6 - https://doi.org/10.3390/pharmaceutics11080394
SN - 1999-4923
VL - 11
IS - 8
PB - MDPI
CY - Basel
ER -
TY - JOUR
A1 - Eichelmann, Fabian
A1 - Sellem, Laury
A1 - Wittenbecher, Clemens
A1 - Jäger, Susanne
A1 - Kuxhaus, Olga
A1 - Prada, Marcela
A1 - Cuadrat, Rafael
A1 - Jackson, Kim G.
A1 - Lovegrove, Julie A.
A1 - Schulze, Matthias Bernd
T1 - Deep lipidomics in human plasma: cardiometabolic disease risk and effect of dietary fat modulation
JF - Circulation
N2 - Background: In blood and tissues, dietary and endogenously generated fatty acids (FAs) occur in free form or as part of complex lipid molecules that collectively represent the lipidome of the respective tissue. We assessed associations of plasma lipids derived from high-resolution lipidomics with incident cardiometabolic diseases and subsequently tested if the identified risk-associated lipids were sensitive to dietary fat modification. Methods: The EPIC Potsdam cohort study (European Prospective Investigation into Cancer and Nutrition) comprises 27 548 participants recruited within an age range of 35 to 65 years from the general population around Potsdam, Germany. We generated 2 disease-specific case cohorts on the basis of a fixed random subsample (n=1262) and all respective cohort-wide identified incident primary cardiovascular disease (composite of fatal and nonfatal myocardial infarction and stroke; n=551) and type 2 diabetes (n=775) cases. We estimated the associations of baseline plasma concentrations of 282 class-specific FA abundances (calculated from 940 distinct molecular species across 15 lipid classes) with the outcomes in multivariable-adjusted Cox models. We tested the effect of an isoenergetic dietary fat modification on risk-associated lipids in the DIVAS randomized controlled trial (Dietary Intervention and Vascular Function; n=113). Participants consumed either a diet rich in saturated FAs (control), monounsaturated FAs, or a mixture of monounsaturated and n-6 polyunsaturated FAs for 16 weeks. Results: Sixty-nine lipids associated (false discovery rate<0.05) with at least 1 outcome (both, 8; only cardiovascular disease, 49; only type 2 diabetes, 12). In brief, several monoacylglycerols and FA16:0 and FA18:0 in diacylglycerols were associated with both outcomes; cholesteryl esters, free fatty acids, and sphingolipids were largely cardiovascular disease specific; and several (glycero)phospholipids were type 2 diabetes specific. In addition, 19 risk-associated lipids were affected (false discovery rate<0.05) by the diets rich in unsaturated dietary FAs compared with the saturated fat diet (17 in a direction consistent with a potential beneficial effect on long-term cardiometabolic risk). For example, the monounsaturated FA-rich diet decreased diacylglycerol(FA16:0) by 0.4 (95% CI, 0.5-0.3) SD units and increased triacylglycerol(FA22:1) by 0.5 (95% CI, 0.4-0.7) SD units. Conclusions: We identified several lipids associated with cardiometabolic disease risk. A subset was beneficially altered by a dietary fat intervention that supports the substitution of dietary saturated FAs with unsaturated FAs as a potential tool for primary disease prevention.
KW - cardiovascular diseases
KW - cholesterol
KW - diabetes mellitus
KW - type 2
KW - diet
KW - food
KW - and nutrition
KW - epidemiology
KW - lipids
Y1 - 2022
U6 - https://doi.org/10.1161/CIRCULATIONAHA.121.056805
SN - 0009-7322
SN - 1524-4539
VL - 146
IS - 1
SP - 21
EP - 35
PB - Lippincott Williams & Wilkins
CY - Philadelphia
ER -
TY - JOUR
A1 - Kluth, Oliver
A1 - Stadion, Mandy
A1 - Gottmann, Pascal
A1 - Aga-Barfknecht, Heja
A1 - Jähnert, Markus
A1 - Scherneck, Stephan
A1 - Vogel, Heike
A1 - Krus, Ulrika
A1 - Seelig, Anett
A1 - Ling, Charlotte
A1 - Gerdes, Jantje
A1 - Schürmann, Annette
T1 - Decreased expression of cilia genes in pancreatic islets as a risk factor for type 2 diabetes in mice and humans
JF - Cell reports
N2 - An insufficient adaptive beta-cell compensation is a hallmark of type 2 diabetes (T2D). Primary cilia function as versatile sensory antennae regulating various cellular processes, but their role on compensatory beta-cell replication has not been examined. Here, we identify a significant enrichment of downregulated, cilia-annotated genes in pancreatic islets of diabetes-prone NZO mice as compared with diabetes-resistant B6-ob/ob mice. Among 327 differentially expressed mouse cilia genes, 81 human orthologs are also affected in islets of diabetic donors. Islets of nondiabetic mice and humans show a substantial overlap of upregulated cilia genes that are linked to cell-cycle progression. The shRNA-mediated suppression of KIF3A, essential for ciliogenesis, impairs division of MINE beta cells as well as in dispersed primary mouse and human islet cells, as shown by decreased BrdU incorporation. These findings demonstrate the substantial role of cilia-gene regulation on islet function and T2D risk.
Y1 - 2019
U6 - https://doi.org/10.1016/j.celrep.2019.02.056
SN - 2211-1247
VL - 26
IS - 11
SP - 3027
EP - 3036
PB - Cell Press
CY - Maryland Heights
ER -
TY - JOUR
A1 - Frombach, Janna
A1 - Unbehauen, Michael
A1 - Kurniasih, Indah N.
A1 - Schumacher, Fabian
A1 - Volz, Pierre
A1 - Hadam, Sabrina
A1 - Rancan, Fiorenza
A1 - Blume-Peytavi, Ulrike
A1 - Kleuser, Burkhard
A1 - Haag, Rainer
A1 - Alexiev, Ulrike
A1 - Vogt, Annika
T1 - Core-multishell nanocarriers enhance drug penetration and reach keratinocytes and antigen-presenting cells in intact human skin
JF - Journal of controlled release
N2 - In reconstructed skin and diffusion cell studies, core-multishell nanocarriers (CMS-NC) showed great potential for drug delivery across the skin barrier. Herein, we investigated penetration, release of dexamethasone (DXM), in excised full-thickness human skin with special focus on hair follicles (HF). Four hours and 16 h after topical application of clinically relevant dosages of 10 mu g DXM/cm(2) skin encapsulated in CMS-NC (12 nm diameter, 5.8% loading), presence of DXM in the tissue as assessed by fluorescence microscopy of anti-DXM-stained tissue sections as well as ELISA and HPLC-MS/MS in tissue extracts was enhanced compared to standard LAW-creme but lower compared to DXM aqueous/alcoholic solution. Such enhanced penetration compared to conventional cremes offers high potential for topical therapies, as recurrent applications of corticosteroid solutions face limitations with regard to tolerability and fast drainage. The findings encourage more detailed investigations on where and how the nanocarrier and drug dissociate within the skin and what other factors, e.g. thermodynamic activity, influence the penetration of this formulations. Microscopic studies on the spatial distribution within the skin revealed accumulation in HF and furrows accompanied by limited cellular uptake assessed by flow cytometry (up to 9% of total epidermal cells). FLIM clearly visualized the presence of CMS-NC in the viable epidermis and dermis. When exposed in situ a fraction of up to 25% CD1a(+) cells were found within the epidermal CMS-NC+ population compared to approximately 3% CD1a(+)/CMS-NC+ cells after in vitro exposure in short-term cultures of epidermal cell suspensions. The latter reflects the natural percentage of Langerhans cells (LC) in epidermis suspensions and indicated that CMS-NC were not preferentially internalized by one cell type. The increased CMS-NC+ LC proportion after exposure within the tissue is in accordance with the strategic suprabasal LC-localization. More specifically we postulate that the extensive dendrite meshwork, their position around HF orifices and their capacity to modulate tight junctions facilitated a preferential uptake of CMS-NC by LC within the skin. This newly identified aspect of CMS-NC penetration underlines the potential of CMS-NC for dermatotherapy and encourages further investigations of CMS-NC for the delivery of other molecule classes for which intracellular delivery is even more crucial.
KW - Drug delivery
KW - Skin penetration
KW - Cellular uptake
KW - Nanoparticles
KW - Dendritic cells
KW - High resolution microscopy
Y1 - 2019
U6 - https://doi.org/10.1016/j.jconrel.2019.02.028
SN - 0168-3659
SN - 1873-4995
VL - 299
SP - 138
EP - 148
PB - Elsevier
CY - Amsterdam
ER -
TY - JOUR
A1 - Witt, Barbara
A1 - Stiboller, Michael
A1 - Raschke, Stefanie
A1 - Friese, Sharleen
A1 - Ebert, Franziska
A1 - Schwerdtle, Tanja
T1 - Characterizing effects of excess copper levels in a human astrocytic cell line with focus on oxidative stress markers
JF - Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements, GMS
N2 - Background: Being an essential trace element, copper is involved in diverse physiological processes. However, excess levels might lead to adverse effects. Disrupted copper homeostasis, particularly in the brain, has been associated with human diseases including the neurodegenerative disorders Wilson and Alzheimer?s disease. In this context, astrocytes play an important role in the regulation of the copper homeostasis in the brain and likely in the prevention against neuronal toxicity, consequently pointing them out as a potential target for the neurotoxicity of copper. Major toxic mechanisms are discussed to be directed against mitochondria probably via oxidative stress. However, the toxic potential and mode of action of copper in astrocytes is poorly understood, so far. Methods: In this study, excess copper levels affecting human astrocytic cell model and their involvement in the neurotoxic mode of action of copper, as well as, effects on the homeostasis of other trace elements (Mn, Fe, Ca and Mg) were investigated. Results: Copper induced substantial cytotoxic effects in the human astrocytic cell line following 48 h incubation (EC30: 250 ?M) and affected mitochondrial function, as observed via reduction of mitochondrial membrane potential and increased ROS production, likely originating from mitochondria. Moreover, cellular GSH metabolism was altered as well. Interestingly, not only cellular copper levels were affected, but also the homeostasis of other elements (Ca, Fe and Mn) were disrupted. Conclusion: One potential toxic mode of action of copper seems to be effects on the mitochondria along with induction of oxidative stress in the human astrocytic cell model. Moreover, excess copper levels seem to interact with the homeostasis of other essential elements such as Ca, Fe and Mn. Disrupted element homeostasis might also contribute to the induction of oxidative stress, likely involved in the onset and progression of neurodegenerative disorders. These insights in the toxic mechanisms will help to develop ideas and approaches for therapeutic strategies against copper-mediated diseases.
KW - Copper
KW - Astrocytes
KW - Toxicity
KW - Mitochondria
KW - ROS
KW - Trace elements
Y1 - 2021
U6 - https://doi.org/10.1016/j.jtemb.2021.126711
SN - 1878-3252
VL - 65
PB - Elsevier
CY - München
ER -
TY - JOUR
A1 - Naser, Eyad
A1 - Kadow, Stephanie
A1 - Schumacher, Fabian
A1 - Mohamed, Zainelabdeen H.
A1 - Kappe, Christian
A1 - Hessler, Gabriele
A1 - Pollmeier, Barbara
A1 - Kleuser, Burkhard
A1 - Arenz, Christoph
A1 - Becker, Katrin Anne
A1 - Gulbins, Erich
A1 - Carpinteiro, Alexander
T1 - Characterization of the small molecule ARC39
BT - a direct and specific inhibitor of acid sphingomyelinase in vitro[S]
JF - Journal of Lipid Research
N2 - Inhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently characterized. Here, we found that 1-aminodecylidene bis-phosphonic acid (ARC39) specifically and efficiently (>90%) inhibits both lysosomal and secretory ASM in vitro. Results from investigating sphingomyelin phosphodiesterase 1 (SMPD1/Smpd1) mRNA and ASM protein levels suggested that ARC39 directly inhibits ASM's catalytic activity in cultured cells, a mechanism that differs from that of functional inhibitors of ASM. We further provide evidence that ARC39 dose- and time-dependently inhibits lysosomal ASM in intact cells, and we show that ARC39 also reduces platelet- and ASM-promoted adhesion of tumor cells. The observed toxicity of ARC39 is low at concentrations relevant for ASM inhibition in vitro, and it does not strongly alter the lysosomal compartment or induce phospholipidosis in vitro. When applied intraperitoneally in vivo, even subtoxic high doses administered short-term induced sphingomyelin accumulation only locally in the peritoneal lavage without significant accumulation in plasma, liver, spleen, or brain. These findings require further investigation with other possible chemical modifications. In conclusion, our results indicate that ARC39 potently and selectively inhibits ASM in vitro and highlight the need for developing compounds that can reach tissue concentrations sufficient for ASM inhibition in vivo.
KW - sphingolipids
KW - sphingomyelin
KW - cerami-des
KW - lipid metabolism
KW - enzymology
KW - lysosome
KW - lysosomal hydrolases
KW - acid ceramidase
KW - bisphosphonates
KW - functional inhibitors of acid sphin-gomyelinase
KW - 1-aminodecylidene bis-phosphonic acid
Y1 - 2021
U6 - https://doi.org/10.1194/jlr.RA120000682
SN - 1539-7262
SN - 0022-2275
VL - 61
IS - 6
SP - 896
EP - 910
PB - American Society for Biochemistry and Molecular Biology
CY - Bethesda
ER -
TY - JOUR
A1 - Wardelmann, Kristina
A1 - Rath, Michaela
A1 - Castro, José Pedro
A1 - Blümel, Sabine
A1 - Schell, Mareike
A1 - Hauffe, Robert
A1 - Schumacher, Fabian
A1 - Flore, Tanina
A1 - Ritter, Katrin
A1 - Wernitz, Andreas
A1 - Hosoi, Toru
A1 - Ozawa, Koichiro
A1 - Kleuser, Burkhard
A1 - Weiß, Jürgen
A1 - Schürmann, Annette
A1 - Kleinridders, André
T1 - Central acting Hsp10 regulates mitochondrial function, fatty acid metabolism and insulin sensitivity in the hypothalamus
JF - Antioxidants
N2 - Mitochondria are critical for hypothalamic function and regulators of metabolism. Hypothalamic mitochondrial dysfunction with decreased mitochondrial chaperone expression is present in type 2 diabetes (T2D). Recently, we demonstrated that a dysregulated mitochondrial stress response (MSR) with reduced chaperone expression in the hypothalamus is an early event in obesity development due to insufficient insulin signaling. Although insulin activates this response and improves metabolism, the metabolic impact of one of its members, the mitochondrial chaperone heat shock protein 10 (Hsp10), is unknown. Thus, we hypothesized that a reduction of Hsp10 in hypothalamic neurons will impair mitochondrial function and impact brain insulin action. Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183 and in the arcuate nucleus (ARC) of C57BL/6N male mice. We analyzed mitochondrial function and insulin signaling utilizing qPCR, Western blot, XF96 Analyzer, immunohistochemistry, and microscopy techniques. We show that Hsp10 expression is reduced in T2D mice brains and regulated by leptin in vitro. Hsp10 KD in hypothalamic cells induced mitochondrial dysfunction with altered fatty acid metabolism and increased mitochondria-specific oxidative stress resulting in neuronal insulin resistance. Consequently, the reduction of Hsp10 in the ARC of C57BL/6N mice caused hypothalamic insulin resistance with acute liver insulin resistance.
KW - brain insulin signaling
KW - mitochondria
KW - oxidative stress
KW - fatty acid metabolism
Y1 - 2021
U6 - https://doi.org/10.3390/antiox10050711
SN - 2076-3921
VL - 10
IS - 5
PB - MDPI
CY - Basel
ER -
TY - JOUR
A1 - Klopsch, Rebecca
A1 - Baldermann, Susanne
A1 - Hanschen, Franziska S.
A1 - Voss, Alexander
A1 - Rohn, Sascha
A1 - Schreiner, Monika
A1 - Neugart, Susanne
T1 - Brassica-enriched wheat bread: Unraveling the impact of ontogeny and breadmaking on bioactive secondary plant metabolites of pak choi and kale
JF - Food chemistry
N2 - Consumption of Brassica vegetables is linked to health benefits, as they contain high concentrations of the following secondary plant metabolites (SPMs): glucosinolate breakdown products, carotenoids, chlorophylls, and phenolic compounds. Especially Brassica vegetables are consumed as microgreens (developed cotyledons). It was investigated how different ontogenetic stages (microgreens or leaves) of pak choi (Brassica rapa subsp. chinensis) and kale (Brassica oleracea var. sabellica) differ in their SPM concentration. The impact of breadmaking on SPMs in microgreens (7 days) and leaves (14 days) in pak choi and kale as a supplement in mixed wheat bread was assessed. In leaves, carotenoids, chlorophylls, and phenolic compounds were higher compared to those of microgreens. Breadmaking caused a decrease of SPMs. Chlorophyll degradation was observed, leading to pheophytin and pyropheophytin formation. In kale, sinapoylgentiobiose, a hydroxycinnamic acid derivative, concentration increased. Thus, leaves of Brassica species are suitable as natural ingredients for enhancing bioactive SPM concentrations in bread.
KW - Ontogeny
KW - Brassica
KW - Glucosinolate breakdown product
KW - Flavonoid
KW - Carotenoid
KW - Thermal processing
Y1 - 2019
U6 - https://doi.org/10.1016/j.foodchem.2019.05.113
SN - 0308-8146
SN - 1873-7072
VL - 295
SP - 412
EP - 422
PB - Elsevier
CY - Oxford
ER -
TY - JOUR
A1 - Duydu, Yalcin
A1 - Basaran, Nursen
A1 - Yalcin, Can Özgür
A1 - Ustundag, Aylin
A1 - Aydin, Sevtap
A1 - Anlar, Hatice Gul
A1 - Bacanli, Merve
A1 - Aydos, Kaan
A1 - Atabekoglu, Cem Somer
A1 - Golka, Klaus
A1 - Ickstadt, Katja
A1 - Schwerdtle, Tanja
A1 - Werner, Matthias
A1 - Bolt, Hermann M.
T1 - Boron-exposed male workers in Turkey
BT - no change in sperm Y:X chromosome ratio and in offspring's sex ratio
JF - Archives of toxicology : official journal of EUROTOX
N2 - Boron-associated shifts in sex ratios at birth were suggested earlier and attributed to a decrease in Y- vs. X-bearing sperm cells. As the matter is pivotal in the discussion of reproductive toxicity of boron/borates, re-investigation in a highly borate-exposed population was required. In the present study, 304 male workers in Bandirma and Bigadic (Turkey) with different degrees of occupational and environmental exposure to boron were investigated. Boron was quantified in blood, urine and semen, and the persons were allocated to exposure groups along B blood levels. In the highest ("extreme") exposure group (n = 69), calculated mean daily boron exposures, semen boron and blood boron concentrations were 44.91 +/- 18.32 mg B/day, 1643.23 +/- 965.44 ng B/g semen and 553.83 +/- 149.52 ng B/g blood, respectively. Overall, an association between boron exposure and Y:X sperm ratios in semen was not statistically significant (p > 0.05). Also, the mean Y:X sperm ratios in semen samples of workers allocated to the different exposure groups were statistically not different in pairwise comparisons (p > 0.05). Additionally, a boron-associated shift in sex ratio at birth towards female offspring was not visible. In essence, the present results do not support an association between boron exposure and decreased Y:X sperm ratio in males, even under extreme boron exposure conditions.
KW - Paternal exposure
KW - Boron exposure
KW - Y:X chromosome ratio
KW - Sex ratio at birth
Y1 - 2019
U6 - https://doi.org/10.1007/s00204-019-02391-z
SN - 0340-5761
SN - 1432-0738
VL - 93
IS - 3
SP - 743
EP - 751
PB - Springer
CY - Heidelberg
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 - JOUR
A1 - Wittenbecher, Clemens
A1 - Kuxhaus, Olga
A1 - Boeing, Heiner
A1 - Stefan, Norbert
A1 - Schulze, Matthias Bernd
T1 - Associations of short stature and components of height with incidence of type 2 diabetes
BT - mediating effects of cardiometabolic risk factors
JF - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
N2 - Aims/hypothesis This study aimed to evaluate associations of height as well as components of height (sitting height and leg length) with risk of type 2 diabetes and to explore to what extent associations are explainable by liver fat and cardiometabolic risk markers. Methods A case-cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study comprising 26,437 participants who provided blood samples was designed. We randomly selected a subcohort of 2500 individuals (2029 diabetes-free at baseline and with anamnestic, anthropometrical and metabolic data for analysis). Of the 820 incident diabetes cases identified in the full cohort during 7 years of follow-up, 698 remained for analyses after similar exclusions. Results After adjustment for age, potential lifestyle confounders, education and waist circumference, greater height was related to lower diabetes risk (HR per 10 cm, men 0.59 [95% CI 0.47, 0.75] and women 0.67 [0.51, 0.88], respectively). Leg length was related to lower risk among men and women, but only among men if adjusted for total height. Adjustment for liver fat and triacylglycerols, adiponectin and C-reactive protein substantially attenuated associations between height and diabetes risk, particularly among women. Conclusions/interpretation We observed inverse associations between height and risk of type 2 diabetes, which was largely related to leg length among men. The inverse associations may be partly driven by lower liver fat content and a more favourable cardiometabolic profile.
KW - Adult height
KW - Blood pressure
KW - Diabetes incidence
KW - Leg length
KW - Liver fat
KW - Short stature
KW - Trunk length
Y1 - 2019
U6 - https://doi.org/10.1007/s00125-019-04978-8
SN - 0012-186X
SN - 1432-0428
VL - 62
IS - 12
SP - 2211
EP - 2221
PB - Springer
CY - New York
ER -
TY - JOUR
A1 - Eichelmann, Fabian
A1 - Schulze, Matthias Bernd
A1 - Wittenbecher, Clemens
A1 - Menzel, Juliane
A1 - Weikert, Cornelia
A1 - di Giuseppe, Romina
A1 - Biemann, Ronald
A1 - Isermann, Berend
A1 - Fritsche, Andreas
A1 - Boeing, Heiner
A1 - Aleksandrova, Krasimira
T1 - Association of Chemerin Plasma Concentration With Risk of Colorectal Cancer
JF - JAMA network open
N2 - IMPORTANCE Inflammatory processes have been suggested to have an important role in colorectal cancer (CRC) etiology. Chemerin is a recently discovered inflammatory biomarker thought to exert chemotactic, adipogenic, and angiogenic functions. However, its potential link with CRC has not been sufficiently explored. OBJECTIVE To evaluate the prospective association of circulating plasma chemerin concentrations with incident CRC. DESIGN, SETTING, AND PARTICIPANTS Prospective case-cohort study based on 27 548 initially healthy participants from the European Prospective Investigation Into Cancer and Nutrition (EPIC)-Potsdam cohort who were followed for up to 16 years. Baseline study information and samples were collected between August 23, 1994, and September 25, 1998. Recruitment was according to random registry sampling from the geographical area of Potsdam, Germany, and surrounding municipalities. The last date of study follow-up was May 10, 2010. Statistical analysis was conducted in 2018. MAIN OUTCOMES AND MEASURES Incident CRC, colon cancer, and rectal cancer. Baseline chemerin plasma concentrations were measured by enzyme-linked immunosorbent assay. CONCLUSIONS AND RELEVANCE This study found that the association between chemerin concentration and the risk of incident CRC was linear and independent of established CRC risk factors. Further studies are warranted to evaluate chemerin as a novel immune-inflammatory agent in colorectal carcinogenesis.
Y1 - 2019
U6 - https://doi.org/10.1001/jamanetworkopen.2019.0896
SN - 2574-3805
VL - 2
IS - 3
PB - American Veterinary Medical Association
CY - Chicago
ER -
TY - JOUR
A1 - Schröter, David
A1 - Neugart, Susanne
A1 - Schreiner, Monika
A1 - Grune, Tilman
A1 - Rohn, Sascha
A1 - Ott, Christiane
T1 - Amaranth’s 2-Caffeoylisocitric Acid—An Anti-Inflammatory Caffeic Acid Derivative That Impairs NF-κB Signaling in LPS-Challenged RAW 264.7 Macrophages
JF - Nutrients
N2 - For centuries, Amaranthus sp. were used as food, ornamentals, and medication. Molecular mechanisms, explaining the health beneficial properties of amaranth, are not yet understood, but have been attributed to secondary metabolites, such as phenolic compounds. One of the most abundant phenolic compounds in amaranth leaves is 2-caffeoylisocitric acid (C-IA) and regarding food occurrence, C-IA is exclusively found in various amaranth species. In the present study, the anti-inflammatory activity of C-IA, chlorogenic acid, and caffeic acid in LPS-challenged macrophages (RAW 264.7) has been investigated and cellular contents of the caffeic acid derivatives (CADs) were quantified in the cells and media. The CADs were quantified in the cell lysates in nanomolar concentrations, indicating a cellular uptake. Treatment of LPS-challenged RAW 264.7 cells with 10 µM of CADs counteracted the LPS effects and led to significantly lower mRNA and protein levels of inducible nitric oxide synthase, tumor necrosis factor alpha, and interleukin 6, by directly decreasing the translocation of the nuclear factor κB/Rel-like containing protein 65 into the nucleus. This work provides new insights into the molecular mechanisms that attribute to amaranth’s anti-inflammatory properties and highlights C-IA’s potential as a health-beneficial compound for future research.
KW - inflammation
KW - caffeic acid derivatives
KW - RAW 264
KW - 7 macrophages
KW - NF-kappa B
KW - amaranth
Y1 - 2019
U6 - https://doi.org/10.3390/nu11030571
SN - 2072-6643
VL - 11
IS - 3
PB - MDPI
CY - Basel
ER -
TY - JOUR
A1 - Heunisch, Fabian
A1 - Chaykovska, Lyubov
A1 - von Einem, Gina
A1 - Alter, Markus
A1 - Dschietzig, Thomas
A1 - Kretschmer, Axel
A1 - Kellner, Karl-Heinz
A1 - Hocher, Berthold
T1 - ADMA predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus undergoing coronary angiography
JF - Medicine
N2 - Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of the nitric oxide (NO)-synthase and a biomarker of endothelial dysfunction (ED). ED plays an important role in the pathogenesis of contrast-induced nephropathy (CIN). The aim of our study was to evaluate serum ADMA concentration as a biomarker of an acute renal damage during the follow-up of 90 days after contrast medium (CM) application. Blood samples were obtained from 330 consecutive patients with diabetes mellitus or mild renal impairment immediately before, 24 and 48 hours after the CM application for coronary angiography. The patients were followed for 90 days. The composite endpoints were major adverse renal events (MARE) defined as occurrence of death, initiation of dialysis, or a doubling of serum creatinine concentration. Overall, ADMA concentration in plasma increased after CM application, although, there was no differences between ADMA levels in patients with and without CIN. ADMA concentration 24 hours after the CM application was predictive for dialysis with a specificity of 0.889 and sensitivity of 0.653 at values higher than 0.71 mu mol/L (area under the curve: 0.854, 95% confidential interval: 0.767-0.941, P<0.001). This association remained significant in multivariate Cox regression models adjusted for relevant factors of long-term renal outcome. 24 hours after the CM application, ADMA concentration in plasma was predictive for MARE with a specificity of 0.833 and sensitivity of 0.636 at a value of more than 0.70 mu mol/L (area under the curve: 0.750, 95% confidence interval: 0.602-0.897, P=0.004). Multivariate logistic regression analysis confirmed that ADMA and anemia were significant predictors of MARE. Further analysis revealed that increased ADMA concentration in plasma was highly significant predictor of MARE in patients with CIN. Moreover, patients with CIN and MARE had the highest plasma ADMA levels 24 hours after CM exposure in our study cohort. The impact of ADMA on MARE was independent of such known CIN risk factors as anemia, pre-existing renal failure, pre-existing heart failure, and diabetes. ADMA concentration in plasma is a promising novel biomarker of major contrast-induced nephropathy-associated events 90 days after contrast media exposure.
KW - asymmetric dimethylarginine (ADMA)
KW - biomarkers of renal failure
KW - contrast-induced nephropathy
Y1 - 2017
U6 - https://doi.org/10.1097/MD.0000000000006065
SN - 0025-7974
SN - 1536-5964
VL - 96
IS - 6
PB - Lippincott Williams & Wilkins
CY - Philadelphia
ER -
TY - JOUR
A1 - McVey, Mark J.
A1 - Kim, Michael
A1 - Tabuchi, Arata
A1 - Srbely, Victoria
A1 - Japtok, Lukasz
A1 - Arenz, Christoph
A1 - Rotstein, Ori
A1 - Kleuser, Burkhard
A1 - Semple, John W.
A1 - Kuebler, Wolfgang M.
T1 - Acid sphingomyelinase mediates murine acute lung injury following transfusion of aged platelets
JF - American journal of physiology : Lung cellular and molecular physiology
N2 - Pulmonary complications from stored blood products are the leading cause of mortality related to transfusion. Transfusion-related acute lung injury is mediated by antibodies or bioactive mediators, yet underlying mechanisms are incompletely understood. Sphingolipids such as ceramide regulate lung injury, and their composition changes as a function of time in stored blood. Here, we tested the hypothesis that aged platelets may induce lung injury via a sphingolipid-mediated mechanism. To assess this hypothesis, a two-hit mouse model was devised. Recipient mice were treated with 2 mg/kg intraperitoneal lipopolysaccharide (priming) 2 h before transfusion of 10 ml/kg stored (1-5 days) platelets treated with or without addition of acid sphingomyelinase inhibitor ARC39 or platelets from acid sphingomyelinase-deficient mice, which both reduce ceramide formation. Transfused mice were examined for signs of pulmonary neutrophil accumulation, endothelial barrier dysfunction, and histological evidence of lung injury. Sphingolipid profiles in stored platelets were analyzed by mass spectrophotometry. Transfusion of aged platelets into primed mice induced characteristic features of lung injury, which increased in severity as a function of storage time. Ceramide accumulated in platelets during storage, but this was attenuated by ARC39 or in acid sphingomyelinase-deficient platelets. Compared with wild-type platelets, transfusion of ARC39-treated or acid sphingomyelinase-deficient aged platelets alleviated lung injury. Aged platelets elicit lung injury in primed recipient mice, which can be alleviated by pharmacological inhibition or genetic deletion of acid sphingomyelinase. Interventions targeting sphingolipid formation represent a promising strategy to increase the safety and longevity of stored blood products.
KW - transfusion-related acute lung injury
KW - ceramide
KW - acid sphingomyelinase
KW - platelets
KW - storage
Y1 - 2017
U6 - https://doi.org/10.1152/ajplung.00317.2016
SN - 1040-0605
SN - 1522-1504
VL - 312
IS - 5
SP - 625
EP - 637
PB - American Physiological Society
CY - Bethesda
ER -
TY - JOUR
A1 - Hoehn, Richard S.
A1 - Jernigan, Peter L.
A1 - Japtok, Lukasz
A1 - Chang, Alex L.
A1 - Midura, Emily F.
A1 - Caldwell, Charles C.
A1 - Kleuser, Burkhard
A1 - Lentsch, Alex B.
A1 - Edwards, Michael J.
A1 - Gulbins, Erich
A1 - Pritts, Timothy A.
T1 - Acid sphingomyelinase inhibition in stored erythrocytes reduces transfusion-associated lung inflammation
JF - Annals of surgery : a monthly review of surgical science and practice
N2 - Objective: We aimed to identify the role of the enzyme acid sphingomyelinase in the aging of stored units of packed red blood cells (pRBCs) and subsequent lung inflammation after transfusion.
Summary Background Data: Large volume pRBC transfusions are associated with multiple adverse clinical sequelae, including lung inflammation. Microparticles are formed in stored pRBCs over time and have been shown to contribute to lung inflammation after transfusion.
Methods: Human and murine pRBCs were stored with or without amitriptyline, a functional inhibitor of acid sphingomyelinase, or obtained from acid sphingomyelinase-deficient mice, and lung inflammation was studied in mice receiving transfusions of pRBCs and microparticles isolated from these units.
Results: Acid sphingomyelinase activity in pRBCs was associated with the formation of ceramide and the release of microparticles. Treatment of pRBCs with amitriptyline inhibited acid sphingomyelinase activity, ceramide accumulation, and microparticle production during pRBC storage. Transfusion of aged pRBCs or microparticles isolated from aged blood into mice caused lung inflammation. This was attenuated after transfusion of pRBCs treated with amitriptyline or from acid sphingomyelinase-deficient mice.
Conclusions: Acid sphingomyelinase inhibition in stored pRBCs offers a novel mechanism for improving the quality of stored blood.
KW - acid sphingomyelinase
KW - blood banking
KW - ceramide
KW - lung inflammation
KW - microparticle
Y1 - 2017
U6 - https://doi.org/10.1097/SLA.0000000000001648
SN - 0003-4932
SN - 1528-1140
VL - 265
IS - 1
SP - 218
EP - 226
PB - Lippincott Williams & Wilkins
CY - Philadelphia
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 - 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 - Kopp, Johannes Florian
A1 - Müller, Sandra Marie
A1 - Pohl, Gabriele
A1 - Lossow, Kristina
A1 - Kipp, Anna Patricia
A1 - Schwerdtle, Tanja
T1 - A quick and simple method for the determination of six trace elements in mammalian serum samples using ICP-MS/MS
JF - Journal of trace elements in medicine and biology
N2 - In order to assess the individual trace element status of humans for either medical or scientific purposes, amongst others, blood serum levels are determined. Furthermore, animal models are used to study interactions of trace elements. Most published methods require larger amounts (500-1000 mu L) of serum to achieve a reliable determination of multiple trace elements. However, oftentimes, these amounts of serum cannot be dedicated to a single analysis and the amount available for TE-determination is much lower. Therefore, a published ICP-MS/MS method for trace element determination in serum was miniaturized, optimized and validated for the measurement of Mn, Fe, Cu Zn, I and Se in as little as 50 mu L of human and murine serum and is presented in this work. For validation, recoveries of multiple LOTs and levels from commercially available human reference serum samples were determined, infra- and inter-day variations were assessed and limits of detection and quantification determined. It is shown, that the method is capable of giving accurate and reproducible results for all six elements within the relevant concentration ranges for samples from humans living in central Europe as well as from laboratory mice. As a highlight, the achieved limits of detection and quantification for Mn were found to be at 0.02 mu g/L serum and 0.05 mu g/L serum, respectively, while using an alkaline diluent for the parallel determination of iodine.
Y1 - 2019
U6 - https://doi.org/10.1016/j.jtemb.2019.04.015
SN - 0946-672X
VL - 54
SP - 221
EP - 225
PB - Elsevier
CY - München
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 - 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 - JOUR
A1 - Wiesner-Reinhold, Melanie
A1 - Barknowitz, Gitte
A1 - Florian, Simone
A1 - Mewis, Inga
A1 - Schumacher, Fabian
A1 - Schreiner, Monika
A1 - Glatt, Hansruedi
T1 - 1-Methoxy-3-indolylmethyl DNA adducts in six tissues, and blood protein adducts, in mice under pak choi diet: time course and persistence
JF - Archives of toxicology : official journal of EUROTOX
N2 - We previously showed that purified 1-methoxy-3-indolylmethyl (1-MIM) glucosinolate, a secondary plant metabolite in Brassica species, is mutagenic in various in vitro systems and forms DNA and protein adducts in mouse models. In the present study, we administered 1-MIM glucosinolate in a natural matrix to mice, by feeding a diet containing pak choi powder and extract. Groups of animals were killed after 1, 2, 4 and 8 days of pak choi diet, directly or, in the case of the 8-day treatment, after 0, 8 and 16 days of recovery with pak choi-free diet. DNA adducts [N-2-(1-MIM)-dG, N-6-(1-MIM)-dA] in six tissues, as well as protein adducts [tau N-(1-MIM)-His] in serum albumin (SA) and hemoglobin (Hb) were determined using UPLC-MS/MS with isotopically labeled internal standards. None of the samples from the 12 control animals under standard diet contained any 1-MIM adducts. All groups receiving pak choi diet showed DNA adducts in all six tissues (exception: lung of mice treated for a single day) as well as SA and Hb adducts. During the feeding period, all adduct levels continuously increased until day 8 (in the jejunum until day 4). During the 14-day recovery period, N-2-(1-MIM)-dG in liver, kidney, lung, jejunum, cecum and colon decreased to 52, 41, 59, 11, 7 and 2%, respectively, of the peak level. The time course of N-6-(1-MIM)-dA was similar. Immunohistochemical analyses indicated that cell turnover is a major mechanism of DNA adduct elimination in the intestine. In the same recovery period, protein adducts decreased more rapidly in SA than in Hb, to 0.7 and 37%, respectively, of the peak level, consistent with the differential turnover of these proteins. In conclusion, the pak choi diet lead to the formation of high levels of adducts in mice. Cell and protein turnover was a major mechanism of adduct elimination, at least in gut and blood.
KW - 1-Methoxy-3-indolylmethyl glucosinolate
KW - Neoglucobrassicin
KW - DNA adducts
KW - Blood protein adducts
KW - Pak choi
Y1 - 2019
U6 - https://doi.org/10.1007/s00204-019-02452-3
SN - 0340-5761
SN - 1432-0738
VL - 93
IS - 6
SP - 1515
EP - 1527
PB - Springer
CY - Heidelberg
ER -