@article{StepanovskaZivkovicEnzmannetal.2020, author = {Stepanovska, Bisera and Zivkovic, Aleksandra and Enzmann, Gaby and Tietz, Silvia and Homann, Thomas and Kleuser, Burkhard and Engelhardt, Britta and Stark, Holger and Huwiler, Andrea}, title = {Morpholino analogues of fingolimod as novel and selective S1P1 ligands with in vivo efficacy in a mouse model of experimental antigen-induced encephalomyelitis}, series = {International journal of molecular sciences}, volume = {21}, journal = {International journal of molecular sciences}, number = {18}, publisher = {MDPI}, address = {Basel}, issn = {1422-0067}, doi = {10.3390/ijms21186463}, pages = {17}, year = {2020}, abstract = {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.}, language = {en} } @article{RothwellMurphyAleksandrovaetal.2020, author = {Rothwell, Joseph A. and Murphy, Neil and Aleksandrova, Krasimira and Schulze, Matthias Bernd and Bešević, Jelena and Kliemann, Nathalie and Jenab, Mazda and Ferrari, Pietro and Achaintre, David and Gicquiau, Audrey and Vozar, B{\´e}atrice and Scalbert, Augustin and Huybrechts, Inge and Freisling, Heinz and Prehn, Cornelia and Adamski, Jerzy and Cross, Amanda J. and Pala, Valeria Maria and Boutron-Ruault, Marie-Christine and Dahm, Christina C. and Overvad, Kim and Gram, Inger Torhild and Sandanger, Torkjel M. and Skeie, Guri and Jakszyn, Paula and Tsilidis, Kostas K. and Hughes, David J. and van Guelpen, Bethany and Bod{\´e}n, Stina and S{\´a}nchez, Maria-Jos{\´e} and Schmidt, Julie A. and Katzke, Verena and K{\"u}hn, Tilman and Colorado-Yohar, Sandra and Tumino, Rosario and Bueno-de-Mesquita, Bas and Vineis, Paolo and Masala, Giovanna and Panico, Salvatore and Eriksen, Anne Kirstine and Tj{\o}nneland, Anne and Aune, Dagfinn and Weiderpass, Elisabete and Severi, Gianluca and Chaj{\`e}s, V{\´e}ronique and Gunter, Marc J.}, title = {Metabolic signatures of healthy lifestyle patterns and colorectal cancer risk in a European cohort}, series = {Clinical gastroenterology and hepatology}, volume = {20}, journal = {Clinical gastroenterology and hepatology}, publisher = {Elsevier}, address = {New York, NY}, issn = {1542-3565}, doi = {10.1016/j.cgh.2020.11.045}, pages = {E1061 -- E1082}, year = {2020}, abstract = {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.}, language = {en} } @article{LiStomaLottaetal.2020, author = {Li, Chen and Stoma, Svetlana and Lotta, Luca A. and Warner, Sophie and Albrecht, Eva and Allione, Alessandra and Arp, Pascal P. and Broer, Linda and Buxton, Jessica L. and Boeing, Heiner and Langenberg, Claudia and Codd, Veryan}, title = {Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length}, series = {American Journal of Human Genetics}, volume = {106}, journal = {American Journal of Human Genetics}, number = {3}, publisher = {Elsevier}, address = {Amsterdam}, pages = {16}, year = {2020}, abstract = {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.}, language = {en} } @article{OlayideLargeStridhetal.2020, author = {Olayide, Priscilla and Large, Annabel and Stridh, Linnea and Rabbi, Ismail and Baldermann, Susanne and Stavolone, Livia and Alexandersson, Erik}, title = {Gene expression and metabolite profiling of thirteen Nigerian cassava landraces to elucidate starch and carotenoid composition}, series = {Agronomy}, volume = {10}, journal = {Agronomy}, number = {3}, publisher = {MDPI}, address = {Basel}, issn = {2073-4395}, doi = {10.3390/agronomy10030424}, pages = {1 -- 16}, year = {2020}, abstract = {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.}, language = {en} } @article{McNultyGoupilAlbaradoetal.2020, author = {McNulty, Margaret A. and Goupil, Brad A. and Albarado, Diana C. and Casta{\~n}o-Martinez, Teresa and Ambrosi, Thomas H. and Puh, Spela and Schulz, Tim Julius and Sch{\"u}rmann, Annette and Morrison, Christopher D. and Laeger, Thomas}, title = {FGF21, not GCN2, influences bone morphology due to dietary protein restrictions}, series = {Bone Reports}, volume = {12}, journal = {Bone Reports}, publisher = {Elsevier}, address = {Amsterdam}, issn = {2352-1872}, doi = {10.1016/j.bonr.2019.100241}, pages = {1 -- 10}, year = {2020}, abstract = {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.}, language = {en} } @article{BorremansBusslerSaguTchewonpietal.2020, author = {Borremans, An and Bußler, Sara and Sagu Tchewonpi, Sorel and Rawel, Harshadrai Manilal and Schl{\"u}ter, Oliver K. and Leen, Van Campenhout}, title = {Effect of blanching plus fermentation on selected functional properties of mealworm (Tenebrio molitor) powders}, series = {Foods : open access journal}, volume = {9}, journal = {Foods : open access journal}, number = {7}, publisher = {MDPI}, address = {Basel}, issn = {2304-8158}, doi = {10.3390/foods9070917}, pages = {17}, year = {2020}, abstract = {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.}, language = {en} } @article{DwiPutraReichetzederHasanetal.2020, author = {Dwi Putra, Sulistyo Emantoko and Reichetzeder, Christoph and Hasan, Ahmed Abdallah Abdalrahman Mohamed and Slowinski, Torsten and Chu, Chang and Kr{\"a}mer, Bernhard K. and Kleuser, Burkhard and Hocher, Berthold}, title = {Being born large for gestational age is associated with increased global placental DNA methylation}, series = {Scientific Reports}, volume = {10}, journal = {Scientific Reports}, number = {1}, publisher = {Springer Nature}, address = {London}, issn = {2045-2322}, doi = {10.1038/s41598-020-57725-0}, pages = {1 -- 10}, year = {2020}, abstract = {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).}, language = {en} } @article{LangBohnBhatetal.2020, author = {Lang, Judith and Bohn, Patrick and Bhat, Hilal and Jastrow, Holger and Walkenfort, Bernd and Cansiz, Feyza and Fink, Julian and Bauer, Michael and Schumacher, Fabian and Kleuser, Burkhard and Lang, Karl S.}, title = {Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease}, series = {Nature Communications}, volume = {11}, journal = {Nature Communications}, number = {1}, publisher = {Nature Publishing Group UK}, address = {London}, issn = {2041-1723}, doi = {10.1038/s41467-020-15072-8}, pages = {1 -- 15}, year = {2020}, abstract = {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.}, language = {en} } @article{BoekstegersMarcelainBarahonaPonceetal.2020, author = {Boekstegers, Felix and Marcelain, Katherine and Barahona Ponce, Carol and Baez Benavides, Pablo F. and M{\"u}ller, Bettina and de Toro, Gonzalo and Retamales, Javier and Barajas, Olga and Ahumada, Monica and Aleksandrova, Krasimira and Bermejo, Justo Lorenzo}, title = {ABCB1/4 gallbladder cancer risk variants identified in India also show strong effects in Chileans}, series = {Cancer Epidemiology}, volume = {65}, journal = {Cancer Epidemiology}, publisher = {Elsevier}, address = {Amsterdam}, pages = {5}, year = {2020}, abstract = {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.}, language = {en} } @article{WinkelbeinerWandtEbertetal.2020, author = {Winkelbeiner, Nicola Lisa and Wandt, Viktoria Klara Veronika and Ebert, Franziska and Lossow, Kristina and Bankoglu, Ezgi E. and Martin, Maximilian and Mangerich, Aswin and Stopper, Helga and Bornhorst, Julia and Kipp, Anna Patricia and Schwerdtle, Tanja}, title = {A Multi-Endpoint Approach to Base Excision Repair Incision Activity Augmented by PARylation and DNA Damage Levels in Mice}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {18}, publisher = {Molecular Diversity Preservation International}, address = {Basel}, issn = {1422-0067}, doi = {10.3390/ijms21186600}, pages = {19}, year = {2020}, abstract = {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.}, language = {en} }