This is the institutional Repository of the Helmholtz Centre for Infection Research in Braunschweig/Germany (HZI), the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarbrücken/Germany, the TWINCORE Zentrum für Exprerimentelle und Klinische Infektionsforschung, Hannover/Germany,Helmholtz-Institut für RNA-basierte Infektionsforschung (HIRI), Braunschweig Integrated Centre for Systems biology (BRICS), Centre for Structural Systems Biology (CSSB) and the Study Centre Hannover, Hannover/Germany.

 

  • Unexpected roles for ADH1 and SORD in catalyzing the final step of erythritol biosynthesis.

    Schlicker, Lisa; Szebenyi, Doletha M E; Ortiz, Semira R; Heinz, Alexander; Hiller, Karsten; Field, Martha S; HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany. (American Society for Biochemistry and Molecular Biology, 2019-11-01)
    The low-calorie sweetener erythritol is endogenously produced from glucose through the pentose phosphate pathway in humans. Erythritol is of medical interest because elevated plasma levels of this polyol are predictive for visceral adiposity gain and development of type 2 diabetes. However, the mechanisms behind these associations remain unknown because the erythritol biosynthesis pathway, particularly the enzyme catalyzing the final step of erythritol synthesis (reduction of erythrose to erythritol), is not characterized. In this study, we purified two enzymes from rabbit liver capable of catalyzing the conversion of erythrose to erythritol: alcohol dehydrogenase 1 (ADH1) and sorbitol dehydrogenase (SORD). Both recombinant human ADH1 and SORD reduce erythrose to erythritol, using NADPH as a co-factor, and cell culture studies indicate that this activity is primarily NADPH-dependent. We found that ADH1 variants vary markedly in both their affinity for erythrose and their catalytic capacity (turnover number). Interestingly, the recombinant protein produced from the ADH1B2 variant, common in Asian populations, is not active when NADPH is used as a co-factor in vitro We also confirmed SORD contributes to intracellular erythritol production in human A549 lung cancer cells, where ADH1 is minimally expressed. In summary, human ADH1 and SORD catalyze the conversion of erythrose to erythritol, pointing to novel roles for two dehydrogenase proteins in human glucose metabolism that may contribute to individual responses to diet. Proteomics data are available via ProteomeXchange with identifier PXD015178.
  • The mRNA-binding Protein TTP/ZFP36 in Hepatocarcinogenesis and Hepatocellular Carcinoma.

    Kröhler, Tarek; Kessler, Sonja M; Hosseini, Kevan; List, Markus; Barghash, Ahmad; Patial, Sonika; Laggai, Stephan; Gemperlein, Katja; Haybaeck, Johannes; Müller, Rolf; et al. (MDPI, 2019-11-08)
    Hepatic lipid deposition and inflammation represent risk factors for hepatocellular carcinoma (HCC). The mRNA-binding protein tristetraprolin (TTP, gene name ZFP36) has been suggested as a tumor suppressor in several malignancies, but it increases insulin resistance. The aim of this study was to elucidate the role of TTP in hepatocarcinogenesis and HCC progression. Employing liver-specific TTP-knockout (lsTtp-KO) mice in the diethylnitrosamine (DEN) hepatocarcinogenesis model, we observed a significantly reduced tumor burden compared to wild-type animals. Upon short-term DEN treatment, modelling early inflammatory processes in hepatocarcinogenesis, lsTtp-KO mice exhibited a reduced monocyte/macrophage ratio as compared to wild-type mice. While short-term DEN strongly induced an abundance of saturated and poly-unsaturated hepatic fatty acids, lsTtp-KO mice did not show these changes. These findings suggested anti-carcinogenic actions of TTP deletion due to effects on inflammation and metabolism. Interestingly, though, investigating effects of TTP on different hallmarks of cancer suggested tumor-suppressing actions: TTP inhibited proliferation, attenuated migration, and slightly increased chemosensitivity. In line with a tumor-suppressing activity, we observed a reduced expression of several oncogenes in TTP-overexpressing cells. Accordingly, ZFP36 expression was downregulated in tumor tissues in three large human data sets. Taken together, this study suggests that hepatocytic TTP promotes hepatocarcinogenesis, while it shows tumor-suppressive actions during hepatic tumor progression.
  • The synergistic effect of chlorotoxin-mApoE in boosting drug-loaded liposomes across the BBB.

    Formicola, Beatrice; Dal Magro, Roberta; Montefusco-Pereira, Carlos V; Lehr, Claus-Michael; Koch, Marcus; Russo, Laura; Grasso, Gianvito; Deriu, Marco A; Danani, Andrea; Bourdoulous, Sandrine; et al. (BMC, 2019-11-11)
    We designed liposomes dually functionalized with ApoE-derived peptide (mApoE) and chlorotoxin (ClTx) to improve their blood-brain barrier (BBB) crossing. Our results demonstrated the synergistic activity of ClTx-mApoE in boosting doxorubicin-loaded liposomes across the BBB, keeping the anti-tumour activity of the drug loaded: mApoE acts promoting cellular uptake, while ClTx promotes exocytosis of liposomes.
  • Injection of Antibodies against Immunodominant Epitopes Tunes Germinal Centers to Generate Broadly Neutralizing Antibodies.

    Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Elsevier, 2019-10-29)
    Broadly neutralizing antibodies are crucial for the control of many life-threatening viral infections like HIV, influenza, or hepatitis. Their induction is a prime goal in vaccine research. Using computer simulations, we identify strategies to promote the generation of broadly neutralizing antibodies in natural germinal center (GC) reactions. The simulations predict a feedback loop based on antibodies and memory B cells from previous GC reactions that promotes GCs to focus on new epitopes. Memory-derived or injected antibodies specific for immunodominant epitopes control epitope availability, suppress the participation of memory B cells in the GC reaction, and allow for the evolution of other B cells to affinity mature for hidden or rare epitopes. This defines a natural selection mechanism for GC B cells to concentrate on new epitopes rather than refine affinity to already-covered epitopes. This principle can be used for the design and testing of future therapies and vaccination protocols.
  • Cytotoxic, anti-biofilm and antimicrobial polyketides from the plant associated fungus Chaetosphaeronema achilleae.

    Narmani, Abolfazl; Teponno, Rémy Bertrand; Helaly, Soleiman E; Arzanlou, Mahdi; Stadler, Marc; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Elsevier, 2019-10-23)
    From extracts of the plant associated fungus Chaetosphaeronema achilleae collected in Iran, a previously unreported isoindolinone named chaetosisoindolinone (1) and a previously undescribed indanone named chaetosindanone (2) were isolated in addition to five known metabolites, 2-(2-acetyl-3,5-dihydroxyphenyl) acetic acid (3), vulculic acid (4), 2-(2-acetyl-3-hydroxy-5-methoxyphenyl)acetic acid (5), curvulin (6), and curvulol (7). Their structures were elucidated on the basis of extensive spectroscopic analysis and high-resolution mass spectrometry. The isolated compounds were tested for their antimicrobial, anti-biofilm, and nematicidal activities. Compound 2 exhibited cytotoxicity against the human breast adenocarcinoma MCF-7 cells with an IC50 value of 1.5 μg/mL. Furthermore, compounds 4 and 7 almost completely inhibited biofilm formation in Staphylococcus aureus at 256 μg/mL. Weak antimicrobial activities were also observed for some of the isolated compounds against Mucor hiemalis, Rhodoturula glutinis, Chromobacterium violaceum, and Staphylococcus aureus.

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