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 - 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 - 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 - 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 - 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 -