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 -
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 - 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 - 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 - 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 - Borremans, An
A1 - Bußler, Sara
A1 - Sagu Tchewonpi, Sorel
A1 - Rawel, Harshadrai Manilal
A1 - Schlüter, Oliver K.
A1 - Leen, Van Campenhout
T1 - Effect of blanching plus fermentation on selected functional properties of mealworm (Tenebrio molitor) powders
JF - Foods : open access journal
N2 - The aim of this study was to determine the effect of blanching followed by fermentation of mealworms (Tenebrio molitor) with commercial meat starter cultures on the functional properties of powders produced from the larvae. Full fat and defatted powder samples were prepared from non-fermented and fermented mealworm pastes. Then the crude protein, crude fat, and dry matter contents, pH, bulk density, colour, water and oil binding capacity, foaming capacity and stability, emulsion capacity and stability, protein solubility, quantity of free amino groups, and protein composition of the powders were evaluated. Regardless of the starter culture used, the blanching plus fermentation process reduced the crude and soluble protein contents of the full fat powders and in general impaired their water and oil binding, foaming, and emulsifying properties. Defatting of the powders improved most functional properties studied. The o-phthaldialdehyde assay revealed that the amount of free amino groups was higher in the fermented powders while sodium dodecyl sulfate polyacrylamide gel electrophoresis demonstrated that the soluble proteins of the fermented powders were composed of molecules of lower molecular mass compared to non-fermented powders. As molecular sizes of the soluble proteins decreased, it was clear that the protein structure was also modified by the fermentation process, which in turn led to changes in functional properties. In general, it was concluded that fermentation of mealworms with blanching as a pre-treatment does not contribute to the functional properties studied in this work. Nevertheless, the results confirmed that the properties of non-fermented powders are comparable to other food protein sources.
KW - mealworm
KW - fermentation
KW - functional properties
KW - insect proteins
KW - SDS-PAGE
Y1 - 2020
U6 - https://doi.org/10.3390/foods9070917
SN - 2304-8158
VL - 9
IS - 7
PB - MDPI
CY - Basel
ER -
TY - JOUR
A1 - Dwi Putra, Sulistyo Emantoko
A1 - Reichetzeder, Christoph
A1 - Hasan, Ahmed Abdallah Abdalrahman Mohamed
A1 - Slowinski, Torsten
A1 - Chu, Chang
A1 - Krämer, Bernhard K.
A1 - Kleuser, Burkhard
A1 - Hocher, Berthold
T1 - Being born large for gestational age is associated with increased global placental DNA methylation
JF - Scientific Reports
N2 - Being born small (SGA) or large for gestational age (LGA) is associated with adverse birth outcomes and metabolic diseases in later life of the offspring. It is known that aberrations in growth during gestation are related to altered placental function. Placental function is regulated by epigenetic mechanisms such as DNA methylation. Several studies in recent years have demonstrated associations between altered patterns of DNA methylation and adverse birth outcomes. However, larger studies that reliably investigated global DNA methylation are lacking. The aim of this study was to characterize global placental DNA methylation in relationship to size for gestational age. Global DNA methylation was assessed in 1023 placental samples by LC-MS/MS. LGA offspring displayed significantly higher global placental DNA methylation compared to appropriate for gestational age (AGA; p<0.001). ANCOVA analyses adjusted for known factors impacting on DNA methylation demonstrated an independent association between placental global DNA methylation and LGA births (p<0.001). Tertile stratification according to global placental DNA methylation levels revealed a significantly higher frequency of LGA births in the third tertile. Furthermore, a multiple logistic regression analysis corrected for known factors influencing birth weight highlighted an independent positive association between global placental DNA methylation and the frequency of LGA births (p=0.001).
KW - fetal origins hypothesis
KW - birth weight
KW - repetitive elements
KW - glucocorticoid receptor
KW - nutrient transport
KW - growth restriction
KW - later health
KW - pregnancy
KW - genes
KW - patterns
Y1 - 2020
U6 - https://doi.org/10.1038/s41598-020-57725-0
SN - 2045-2322
VL - 10
IS - 1
SP - 1
EP - 10
PB - Springer Nature
CY - London
ER -
TY - JOUR
A1 - Lang, Judith
A1 - Bohn, Patrick
A1 - Bhat, Hilal
A1 - Jastrow, Holger
A1 - Walkenfort, Bernd
A1 - Cansiz, Feyza
A1 - Fink, Julian
A1 - Bauer, Michael
A1 - Schumacher, Fabian
A1 - Kleuser, Burkhard
A1 - Lang, Karl S.
T1 - Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease
JF - Nature Communications
N2 - Macrophages have important protective functions during infection with herpes simplex virus type 1 (HSV-1). However, molecular mechanisms that restrict viral propagation and protect from severe disease are unclear. Here we show that macrophages take up HSV-1 via endocytosis and transport the virions into multivesicular bodies (MVBs). In MVBs, acid ceramidase (aCDase) converts ceramide into sphingosine and increases the formation of sphingosine-rich intraluminal vesicles (ILVs). Once HSV-1 particles reach MVBs, sphingosine-rich ILVs bind to HSV-1 particles, which restricts fusion with the limiting endosomal membrane and prevents cellular infection. Lack of aCDase in macrophage cultures or in Asah1(-/-) mice results in replication of HSV-1 and Asah1(-/-) mice die soon after systemic or intravaginal inoculation. The treatment of macrophages with sphingosine enhancing compounds blocks HSV-1 propagation, suggesting a therapeutic potential of this pathway. In conclusion, aCDase loads ILVs with sphingosine, which prevents HSV-1 capsids from penetrating into the cytosol.
KW - immunology
KW - infection
KW - membrane fusion
KW - phagocytosis
KW - sphingolipids
Y1 - 2020
U6 - https://doi.org/10.1038/s41467-020-15072-8
SN - 2041-1723
VL - 11
IS - 1
SP - 1
EP - 15
PB - Nature Publishing Group UK
CY - London
ER -
TY - JOUR
A1 - Boekstegers, Felix
A1 - Marcelain, Katherine
A1 - Barahona Ponce, Carol
A1 - Baez Benavides, Pablo F.
A1 - Müller, Bettina
A1 - de Toro, Gonzalo
A1 - Retamales, Javier
A1 - Barajas, Olga
A1 - Ahumada, Monica
A1 - Aleksandrova, Krasimira
A1 - Bermejo, Justo Lorenzo
T1 - ABCB1/4 gallbladder cancer risk variants identified in India also show strong effects in Chileans
JF - Cancer Epidemiology
N2 - Background: The first large-scale genome-wide association study of gallbladder cancer (GBC) recently identified and validated three susceptibility variants in the ABCB1 and ABCB4 genes for individuals of Indian descent. We investigated whether these variants were also associated with GBC risk in Chileans, who show the highest incidence of GBC worldwide, and in Europeans with a low GBC incidence.
Methods: This population-based study analysed genotype data from retrospective Chilean case-control (255 cases, 2042 controls) and prospective European cohort (108 cases, 181 controls) samples consistently with the original publication.
Results: Our results confirmed the reported associations for Chileans with similar risk effects. Particularly strong associations (per-allele odds ratios close to 2) were observed for Chileans with high Native American (=Mapuche) ancestry. No associations were noticed for Europeans, but the statistical power was low.
Conclusion: Taking full advantage of genetic and ethnic differences in GBC risk may improve the efficiency of current prevention programs.
KW - cancer epidemiology
KW - gallbladder cancer
KW - native American ancestry
KW - population-specific risk marker
Y1 - 2020
VL - 65
PB - Elsevier
CY - Amsterdam
ER -
TY - JOUR
A1 - Winkelbeiner, Nicola Lisa
A1 - Wandt, Viktoria Klara Veronika
A1 - Ebert, Franziska
A1 - Lossow, Kristina
A1 - Bankoglu, Ezgi E.
A1 - Martin, Maximilian
A1 - Mangerich, Aswin
A1 - Stopper, Helga
A1 - Bornhorst, Julia
A1 - Kipp, Anna Patricia
A1 - Schwerdtle, Tanja
T1 - A Multi-Endpoint Approach to Base Excision Repair Incision Activity Augmented by PARylation and DNA Damage Levels in Mice
BT - Impact of Sex and Age
JF - International Journal of Molecular Sciences
N2 - Investigation of processes that contribute to the maintenance of genomic stability is one crucial factor in the attempt to understand mechanisms that facilitate ageing. The DNA damage response (DDR) and DNA repair mechanisms are crucial to safeguard the integrity of DNA and to prevent accumulation of persistent DNA damage. Among them, base excision repair (BER) plays a decisive role. BER is the major repair pathway for small oxidative base modifications and apurinic/apyrimidinic (AP) sites. We established a highly sensitive non-radioactive assay to measure BER incision activity in murine liver samples. Incision activity can be assessed towards the three DNA lesions 8-oxo-2’-deoxyguanosine (8-oxodG), 5-hydroxy-2’-deoxyuracil (5-OHdU), and an AP site analogue. We applied the established assay to murine livers of adult and old mice of both sexes. Furthermore, poly(ADP-ribosyl)ation (PARylation) was assessed, which is an important determinant in DDR and BER. Additionally, DNA damage levels were measured to examine the overall damage levels. No impact of ageing on the investigated endpoints in liver tissue were found. However, animal sex seems to be a significant impact factor, as evident by sex-dependent alterations in all endpoints investigated. Moreover, our results revealed interrelationships between the investigated endpoints indicative for the synergetic mode of action of the cellular DNA integrity maintaining machinery.
KW - maintenance of genomic integrity
KW - ageing
KW - sex
KW - DNA damage
KW - base excision repair (incision activity)
KW - DNA damage response
KW - poly(ADP-ribosyl)ation
KW - liver
Y1 - 2020
U6 - https://doi.org/10.3390/ijms21186600
SN - 1422-0067
VL - 21
IS - 18
PB - Molecular Diversity Preservation International
CY - Basel
ER -
TY - JOUR
A1 - Christakoudi, Sofa
A1 - Tsilidis, Konstantinos K.
A1 - Muller, David C.
A1 - Freisling, Heinz
A1 - Weiderpass, Elisabete
A1 - Overvad, Kim
A1 - Söderberg, Stefan
A1 - Häggström, Christel
A1 - Pischon, Tobias
A1 - Dahm, Christina C.
A1 - Zhang, Jie
A1 - Tjønneland, Anne
A1 - Schulze, Matthias Bernd
T1 - A Body Shape Index (ABSI) achieves better mortality risk stratification than alternative indices of abdominal obesity: results from a large European cohort
JF - Scientific Reports
N2 - Abdominal and general adiposity are independently associated with mortality, but there is no consensus on how best to assess abdominal adiposity. We compared the ability of alternative waist indices to complement body mass index (BMI) when assessing all-cause mortality. We used data from 352,985 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) and Cox proportional hazards models adjusted for other risk factors. During a mean follow-up of 16.1 years, 38,178 participants died. Combining in one model BMI and a strongly correlated waist index altered the association patterns with mortality, to a predominantly negative association for BMI and a stronger positive association for the waist index, while combining BMI with the uncorrelated A Body Shape Index (ABSI) preserved the association patterns. Sex-specific cohort-wide quartiles of waist indices correlated with BMI could not separate high-risk from low-risk individuals within underweight (BMI<18.5 kg/m(2)) or obese (BMI30 kg/m(2)) categories, while the highest quartile of ABSI separated 18-39% of the individuals within each BMI category, which had 22-55% higher risk of death. In conclusion, only a waist index independent of BMI by design, such as ABSI, complements BMI and enables efficient risk stratification, which could facilitate personalisation of screening, treatment and monitoring.
KW - all-cause mortality
KW - anthropometric measures
KW - mass index
KW - overweight
KW - cancer
KW - prediction
KW - adiposity
KW - size
Y1 - 2020
VL - 10
IS - 1
PB - Springer Nature
CY - Berlin
ER -