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- 저자 : Van Nieuwerburgh, Filip (검색결과 2 건)
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Jeong, Tae-Yong,Asselman, Jana,De Schamphelaere, Karel A.C.,Van Nieuwerburgh, Filip,Deforce, Dieter,Kim, Sang Don Elsevier 2018 Environmental pollution Vol.241 No.-
<P><B>Abstract</B></P> <P>Propranolol (PRO), a human β-AR (β-adrenergic receptor) antagonist, is considered to result in specific effects in a non-target species, <I>D. magna,</I> based on our previous studies. The present study investigated the effects of β-AR agents, including an antagonist and agonist using pharmacologically relevant endpoints as well as a more holistic gene expression approach to reveal the impacts and potential mode of actions (MOAs) in the model non-target species. Results show that the responses in cardiac endpoints and gene expression in <I>D. magna</I> are partially similar but distinguishable from the observations in different organisms. No effect was observed on heart size growth in PRO and isoprenaline (ISO) exposure. The contraction capacity of the heart was decreased in ISO exposure, and the heart rate was decreased in PRO exposure. Time-series exposures showed different magnitudes of effect on heart rate and gene expression dependent on the type of chemical exposure. Significant enrichment of gene families involved in protein metabolism and biotransformation was observed within the differentially expressed genes, and we also observed differential expression in juvenile hormone-inducible proteins in ISO and PRO exposure, which is suspected of having endocrine disruption potential. Taken together, deviation between the effects of PRO and ISO in <I>D. magna</I> and other organisms suggests dissimilarity in MOAs or attributes of target bio-molecules between species. Additionally, PRO and ISO may act as endocrine disruptors based on the gene expression observation. Results in the present study confirm that it is challenging to predict ecological impact of active pharmaceutical ingredients (APIs) based on the available data acquired through human-focused studies. Furthermore, the present study provided unique data and a case study on the impact of APIs in a non-target organism.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Long- and short-term effects of β-adrenergic antagonist and agonist on <I>D. magna</I> were studied. </LI> <LI> Six-day exposure to isoprenaline and propranolol reduced heart contraction capacity and heart rate, respectively. </LI> <LI> Gene expression analysis propose potential modes of actions, including endocrine disruption. </LI> <LI> Study results suggest differential effects on heart function and whole body gene expression in <I>Daphnia magna</I>. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
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Discovery of the leinamycin family of natural products by mining actinobacterial genomes
Pan, Guohui,Xu, Zhengren,Guo, Zhikai,Hindra,Ma, Ming,Yang, Dong,Zhou, Hao,Gansemans, Yannick,Zhu, Xiangcheng,Huang, Yong,Zhao, Li-Xing,Jiang, Yi,Cheng, Jinhua,Van Nieuwerburgh, Filip,Suh, Joo-Won,Duan National Academy of Sciences 2017 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.114 No.52
<P>Nature's ability to generate diverse natural products from simple building blocks has inspired combinatorial biosynthesis. The knowledge-based approach to combinatorial biosynthesis has allowed the production of designer analogs by rational metabolic pathway engineering. While successful, structural alterations are limited, with designer analogs often produced in compromised titers. The discovery-based approach to combinatorial biosynthesis complements the knowledge-based approach by exploring the vast combinatorial biosynthesis repertoire found in Nature. Here we showcase the discovery-based approach to combinatorial biosynthesis by targeting the domain of unknown function and cysteine lyase domain (DUF-SH) didomain, specific for sulfur incorporation from the leinamycin (LNM) biosynthetic machinery, to discover the LNM family of natural products. By mining bacterial genomes from public databases and the actinomycetes strain collection at The Scripps Research Institute, we discovered 49 potential producers that could be grouped into 18 distinct clades based on phylogenetic analysis of the DUF-SH didomains. Further analysis of the representative genomes from each of the clades identified 28 lnm-type gene clusters. Structural diversities encoded by the LNM-type biosynthetic machineries were predicted based on bioinformatics and confirmed by in vitro characterization of selected adenylation proteins and isolation and structural elucidation of the guangnanmycins and weishanmycins. These findings demonstrate the power of the discovery-based approach to combinatorial biosynthesis for natural product discovery and structural diversity and highlight Nature's rich biosynthetic repertoire. Comparative analysis of the LNM-type biosynthetic machineries provides outstanding opportunities to dissect Nature's biosynthetic strategies and apply these findings to combinatorial biosynthesis for natural product discovery and structural diversity.</P>
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