The nucleoprotein (NP) of Ebola virus (EBOV) and Marburg virus (MARV) is an essential component of the viral ribonucleoprotein complex and significantly impacts replication and transcription of the viral RNA genome. Although NP is regarded as a promising antiviral druggable target, no chemical ligands have been reported to interact with EBOV NP or MARV NP. We identified two compounds from a traditional Chinese medicine Gancao (licorice root) that can bind both NPs by combining affinity mass spectrometry and metabolomics approaches. These two ligands, 18β-glycyrrhetinic acid and licochalcone A, were verified by defined compound mixture screens and further characterized with individual ligand binding assays. Accompanying biophysical analyses demonstrate that binding of 18β-glycyrrhetinic acid to EBOV NP significantly reduces protein thermal stability, induces formation of large NP oligomers, and disrupts the critical association of viral ssRNA with NP complexes whereas the compound showed no such activity on MARV NP. Our study has revealed the substantial potential of new analytical techniques in ligand discovery from natural herb resources. In addition, identification of a chemical ligand that influences the oligomeric state and RNA-binding function of EBOV NP sheds new light on antiviral drug development.
Carbon monoxide (CO) as an emerging treatment holds great promise for inducing the apoptosis of cancer cells. Here coordination assembled strategy is first reported for synthesis of Cu(II)‐flavone coordination polymer (NCu‐FleCP) CO nanoprodrug that is stable in normal physiological conditions, and yet readily reduces to small size prodrug complex and releases CO on demand under glutathione (GSH) and near infrared (NIR) light. Specifically, after uptaking by cancer cells, local GSH attacked coordination bond within NCu‐FleCP, resulting in the release of Cu(I) and free Fle. The CC bond of Fle is cleavage under NIR light to release CO for gas therapy, and Cu(I) reacts with local H2O2 through Fenton like reaction to generate hydroxyl radicals (•OH) for chemodynamic therapy. Detailed in vitro and in vivo experiments demonstrate that the CO prodrug system in generating a sufficient quantity of CO and •OH offers remarkable destructive effects against cancer cells without causing toxicity to surrounding normal tissues. The study provides a solid foundation to develop smart coordination polymer CO prodrugs with on‐demand CO release, enhanced permeability and retention effect, and biodegradability for multimodal synergistic therapy.
Wood has attracted increasing scientific interest in the field of green electronics, biological devices, bioenergy, and energy storage because of its abundance, low cost, biocompatibility, and natural vessel structure. However, its potential application in the important area of environmental monitoring has not yet been effectively explored. In this work, gold nanoparticles (NPs) encapsulated in porous wood (denoted as Au@wood) for high-performance colorimetric detection of Hg in aqueous solution have been constructed. The detection mechanism is based on Hg-triggered methylene blue (MB) reduction-assisted signal amplification. In such a detection system, Au NPs can be used as a specific identification element for the binding of Hg due to the formation of gold amalgam to initiate catalytic activity of gold. The low-cost natural wood is introduced to prevent the aggregation of Au NPs and increase the contact area between MB and Au NPs in three-dimensional space. MB, as a tracer molecule, enables the output signals to be directly observed by the naked eye. Such a detection system exhibited an ultralow detection limit of 32 pM for Hg, which is greatly lower than the threshold levels (10 nM) for drinking water and other colorimetric methods. The proposed detection system also exhibits high selectivity against other metal ions and works well for environmental water and blood samples. The resultant Au@wood sensor is low cost, easy handling, and convenient, making it an attractive material for point-of-use monitoring of Hg in environmental and biological samples.
Progression to androgen independent (AI) is the main cause of death in prostate cancer, and the mechanism is still unclear. By reviewing the expression profiles of 26 prostate cancer samples in a holistic view, we found a group of genes differentially expressed in AI compared with androgen-dependent groups (P-value<0.01, t-test). Focusing on apoptosis, proliferation, hormone and angiogenesis, we found a group of genes such as thioredoxin domain containing 5 , tumor necrosis factor receptor superfamily, member 10a , ribosomal protein S19 and Janus kinase 2 upregulated in AI prostate cancer, could play important roles in the transition from AD to AI and could be biomarkers of prognosis.
The Elongator complex promotes formation of 5-methoxycarbonylmethyl (mcm5) and 5-carbamoylmethyl (ncm5) side-chains on uridines at the wobble position of cytosolic eukaryotic tRNAs. In all eukaryotic organisms tested to date, the inactivation of Elongator not only leads to the lack of mcm5/ncm5 groups in tRNAs, but also a wide variety of additional phenotypes. Although the phenotypes are most likely caused by a translational defect induced by reduced functionality of the hypomodified tRNAs, the mechanism(s) underlying individual phenotypes are poorly understood. In this study, we show that the genetic background modulates the phenotypes induced by the lack of mcm5/ncm5 groups in Saccharomyces cerevisiae. We show that the stress-induced growth defects of Elongator mutants are stronger in the W303 than in the closely related S288C genetic background and that the phenotypic differences are caused by the known polymorphism at the locus for the mRNA binding protein Ssd1. Moreover, the mutant ssd1 allele found in W303 cells is required for the reported histone H3 acetylation and telomeric gene silencing defects of Elongator mutants. The difference at the SSD1 locus also partially explains why the simultaneous lack of mcm5 and 2-thio groups at wobble uridines is lethal in the W303 but not in the S288C background. Collectively, our results demonstrate that the SSD1 locus modulates phenotypes induced by the lack of Elongator-dependent tRNA modifications.
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