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 - Gisch, Ulrike Alexandra
A1 - Robert, Margaux
A1 - Berlin, Noemi
A1 - Nebout, Antoine
A1 - Etile, Fabrice
A1 - Teyssier, Sabrina
A1 - Andreeva, Valentina A.
A1 - Hercberg, Serge
A1 - Touvier, Mathilde
A1 - Peneau, Sandrine
T1 - Mastery is associated with weight status, food intake, snacking, and eating disorder symptoms in the NutriNet-Sante cohort study
JF - Frontiers in Nutrition
N2 - Mastery is a psychological resource that is defined as the extent to which individuals perceive having control over important circumstances of their lives. Although mastery has been associated with various physical and psychological health outcomes, studies assessing its relationship with weight status and dietary behavior are lacking. The aim of this cross-sectional study was to assess the relationship between mastery and weight status, food intake, snacking, and eating disorder (ED) symptoms in the NutriNet-Sante cohort study. Mastery was measured with the Pearlin Mastery Scale (PMS) in 32,588 adults (77.45% female), the mean age was 50.04 (14.53) years. Height and weight were self-reported. Overall diet quality and food group consumption were evaluated with >= 3 self-reported 24-h dietary records (range: 3-27). Snacking was assessed with an ad-hoc question. ED symptoms were assessed with the Sick-Control-One-Fat-Food Questionnaire (SCOFF). Linear and logistic regression analyses were conducted to assess the relationship between mastery and weight status, food intake, snacking, and ED symptoms, controlling for sociodemographic and lifestyle characteristics. Females with a higher level of mastery were less likely to be underweight (OR: 0.88; 95%CI: 0.84, 0.93), overweight [OR: 0.94 (0.91, 0.97)], or obese [class I: OR: 0.86 (0.82, 0.90); class II: OR: 0.76 (0.71, 0.82); class III: OR: 0.77 (0.69, 0.86)]. Males with a higher level of mastery were less likely to be obese [class III: OR: 0.75 (0.57, 0.99)]. Mastery was associated with better diet quality overall, a higher consumption of fruit and vegetables, seafood, wholegrain foods, legumes, non-salted oleaginous fruits, and alcoholic beverages and with a lower consumption of meat and poultry, dairy products, sugary and fatty products, milk-based desserts, and sweetened beverages. Mastery was also associated with lower snacking frequency [OR: 0.89 (0.86, 0.91)] and less ED symptoms [OR: 0.73 (0.71, 0.75)]. As mastery was associated with favorable dietary behavior and weight status, targeting mastery might be a promising approach in promoting healthy behaviors.
KW - mastery
KW - locus of control
KW - weight status
KW - diet quality
KW - food group consumption
KW - snacking
KW - eating disorder symptoms
KW - large population
Y1 - 2022
U6 - https://doi.org/10.3389/fnut.2022.871669
SN - 2296-861X
VL - 9
PB - Frontiers Media
CY - Lausanne
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 -