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1.
Anne-Margarethe Enge Florian Kaltner Christoph Gottschalk Albert Braeuning Stefanie Hessel-Pras 《International journal of molecular sciences》2021,22(8)
1,2-unsaturated pyrrolizidine alkaloids (PAs) are secondary plant metabolites occurring as food contaminants that can cause severe liver damage upon metabolic activation in hepatocytes. However, it is yet unknown how these contaminants enter the cells. The role of hepatic transporters is only at the beginning of being recognized as a key determinant of PA toxicity. Therefore, this study concentrated on assessing the general mode of action of PA transport in the human hepatoma cell line HepaRG using seven structurally different PAs. Furthermore, several hepatic uptake and efflux transporters were targeted with pharmacological inhibitors to identify their role in the uptake of the PAs retrorsine and senecionine and in the disposition of their N-oxides (PANO). For this purpose, PA and PANO content was measured in the supernatant using LC-MS/MS. Also, PA-mediated cytotoxicity was analyzed after transport inhibition. It was found that PAs are taken up into HepaRG cells in a predominantly active and structure-dependent manner. This pattern correlates with other experimental endpoints such as cytotoxicity. Pharmacological inhibition of the influx transporters Na+/taurocholate co-transporting polypeptide (SLC10A1) and organic cation transporter 1 (SLC22A1) led to a reduced uptake of retrorsine and senecionine into HepaRG cells, emphasizing the relevance of these transporters for PA toxicokinetics. 相似文献
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Dr. Timo Broese Dr. Peter Ehlers Dr. Peter Langer Dr. Jan von Langermann 《Chembiochem : a European journal of chemical biology》2021,22(23):3314-3318
Fluoro-substituted and heteroaromatic compounds are valuable intermediates for a variety of applications in pharma- and agrochemistry and synthetic chemistry. This study investigates the chemoenzymatic preparation of chiral alcohols bearing a heteroaromatic ring with an increasing degree of fluorination in α-position. Starting from readily available picoline derivatives prochiral α-halogenated acyl moieties were introduced with excellent selectivity and 64–95 % yield. The formed carbonyl group was subsequently reduced to the corresponding alcohols using the alcohol dehydrogenase from Lactobacillus kefir, yielding an enantiomeric excess of 95–>99 % and up to 98 % yield. 相似文献
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Friederike Freiin von Hvel Ekaterini Kefalakes Claudia Grothe 《International journal of molecular sciences》2021,22(1)
Fibroblast growth factor 2 (FGF-2), ubiquitously expressed in humans and mice, is functionally involved in cell growth, migration and maturation in vitro and in vivo. Based on the same mRNA, an 18-kilo Dalton (kDa) FGF-2 isoform named FGF-2 low molecular weight (FGF-2LMW) isoform is translated in humans and rodents. Additionally, two larger isoforms weighing 21 and 22 kDa also exist, summarized as the FGF-2 high molecular weight (FGF-2HMW) isoform. Meanwhile, the human FGF-2HMW comprises a 22, 23, 24 and 34 kDa protein. Independent studies verified a specific intracellular localization, mode of action and tissue-specific spatiotemporal expression of the FGF-2 isoforms, increasing the complexity of their physiological and pathophysiological roles. In order to analyze their spectrum of effects, FGF-2LMW knock out (ko) and FGF-2HMWko mice have been generated, as well as mice specifically overexpressing either FGF-2LMW or FGF-2HMW. So far, the development and functionality of the cardiovascular system, bone formation and regeneration as well as their impact on the central nervous system including disease models of neurodegeneration, have been examined. This review provides a summary of the studies characterizing the in vivo effects modulated by the FGF-2 isoforms and, thus, offers a comprehensive overview of its actions in the aforementioned organ systems. 相似文献
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Dr. Raysa Khan Tareque Dr. Storm Hassell-Hart Dr. Tobias Krojer Dr. Anthony Bradley Dr. Srikannathasan Velupillai Dr. Romain Talon Dr. Michael Fairhead Dr. Iain J. Day Kamlesh Bala Dr. Robert Felix Dr. Paul D. Kemmitt Prof. Paul Brennan Prof. Frank von Delft Dr. Laura Díaz Sáez Prof. Kilian Huber Prof. John Spencer 《ChemMedChem》2020,15(24):2513-2520
Combined photochemical arylation, “nuisance effect” (SNAr) reaction sequences have been employed in the design of small arrays for immediate deployment in medium-throughput X-ray protein–ligand structure determination. Reactions were deliberately allowed to run “out of control” in terms of selectivity; for example the ortho-arylation of 2-phenylpyridine gave five products resulting from mono- and bisarylations combined with SNAr processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified. 相似文献
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Stefanie Vanbecelaere Katrien Van den Berghe Frederik Cornillie Delphine Sasanguie Bert Reynvoet Fien Depaepe 《Journal of Computer Assisted Learning》2020,36(4):502-513
For the training of academic skills, digital educational games with integrated adaptivity are promising. Adaptive games are considered superior to non-adaptive games, because they constantly assess children's performance, and accordingly adapt the difficulty of the tasks corresponding to the children's individual level. However, empirical evidence with regard to the effectivity of adaptive compared to non-adaptive games is limited. A study was conducted with 191 children from the third year of Kinder garten who were enrolled in one of three conditions, that is, playing an adaptive version of the reading game (RG), a non-adaptive version of the RG or training with pen-and-paper exercises. In all three conditions, children trained emergent reading (phonological awareness and letter knowledge) once a week for 30 min over a period of 5 weeks. Children's performance on cognitive (phonological awareness, letter knowledge, reading fluency) and non-cognitive (motivation, self-concept) factors was assessed. Results revealed a significant improvement in phonological awareness and letter knowledge in all conditions. However, no differences between the conditions were observed with respect to children's improvement on phonological awareness and letter knowledge or on their post-test scores for reading fluency. With regard to motivation and self-concept, again, no differences in these non-cognitive factors were observed across conditions. 相似文献
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Bengü Ergüden 《Yeast (Chichester, England)》2019,36(2):99-105
The correct separation of chromosomes during mitosis is necessary to prevent genetic instability and aneuploidy, which are responsible for cancer and other diseases, and it depends on proper centrosome duplication. In a recent study, we found that Smy2 can suppress the essential role of Mps2 in the insertion of yeast centrosome into the nuclear membrane by interacting with Eap1, Scp160, and Asc1 and designated this network as SESA (S my2, E ap1, S cp160, A sc1). Detailed analysis showed that the SESA network is part of a mechanism which regulates translation of POM34 mRNA. Thus, SESA is a system that suppresses spindle pole body duplication defects by repressing the translation of POM34 mRNA. In this study, we performed a genome-wide screening in order to identify new members of the SESA network and confirmed Dhh1 as a putative member. Dhh1 is a cytoplasmic DEAD-box helicase known to regulate translation. Therefore, we hypothesized that Dhh1 is responsible for the highly selective inhibition of POM34 mRNA by SESA. 相似文献