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[Display omitted] • A new lifetime profile platform was developed for rapid, high-throughput screening of drug libraries. • Repurposing of sodium stibogluconate as an inhibitor of the important DNA repair enzyme UDG. • Provides a proof-of-concept for using the time-resolved screening approach to discover repurposing opportunities. Repurposing drugs can significantly reduce the time and costs associated with drug discovery and development. However, many drug compounds possess intrinsic fluorescence, resulting in aberrations such as auto-fluorescence, scattering and quenching, in fluorescent high-throughput screening assays. To overcome these drawbacks, time-resolved technologies have received increasing attention. In this study, we have developed a rapid and efficient screening platform based on time-resolved emission spectroscopy in order to screen for inhibitors of the DNA repair enzyme, uracil-DNA glycosylase (UDG). From a database of 1456 FDA/EMA-approved drugs, sodium stibogluconate was discovered as a potent UDG inhibitor. This compound showed synergistic cytotoxicity against 5-fluorouracil-resistant cancer cells. This work provides a promising future for time-resolved technologies for high-throughput screening (HTS), allowing for the swift identification of bioactive compounds from previously overlooked scaffolds due to their inherent fluorescence properties. [ABSTRACT FROM AUTHOR]

Graphical abstract A facile colorimetric assay was developed for the accurate detection of H 2 O 2 and glucose with the CeO 2 /Y hybrid nanocomposite as a highly efficient peroxidase-mimicking nanozyme, which shows the synergistic effects of outstanding activity of highly dispersed CeO 2 nanoparticles and high surface area and pore volume of zeolite Y as support. Abstract Owing to the high costs and instability of natural enzymes, the development of enzyme mimics based on inorganic nanomaterials has attracted a wide concern in recent years. In this work, a stable nanocomposite composed of highly dispersed CeO 2 nanoparticles decorated on zeolite Y as support (CeO 2 /Y) was synthesized by a facile wet impregnation method, and the CeO 2 /Y nanocomposite was firstly proposed as an efficient peroxidase-mimicking nanozyme for accurate detection of H 2 O 2 and glucose. The best catalyst was the nanocomposite with CeO 2 to zeolite Y mass ratio of 0.20 (denoted as 20CeO 2 /Y), showing a better affinity and higher catalytic constant to the substrate of H 2 O 2 and 3,3′,5,5′-tetramethylbenzidine (TMB) than horseradish peroxidase (HRP) enzymes by the steady-state kinetic analysis. The enzyme-mimicking catalyst could be used over a wider range of pH and temperature for a long-time reuse in TMB oxidation. A facile colorimetric assay was set up for the accurate detection of H 2 O 2 and glucose, with the detection limits of 0.323 μM and 35.4 μM, respectively. The CeO 2 /Y-based peroxidase mimic was used to precisely detect the glucose concentration in real blood serum samples, exhibiting a great potential to be constructed as a reliable biosensor for glucose detection in some complex systems. The superior peroxidase-mimicking performance of CeO 2 /Y nanocomposite is attributed to the synergistic effects of outstanding activity of highly dispersed CeO 2 nanoparticles (5–10 nm) and adsorption properties of zeolite Y with large surface area (517 m2·g−1) and pore volume (0.329 cm3·g−1). [ABSTRACT FROM AUTHOR]

Abstract: Non-ribosomal peptides (NRPs) are a diverse family of secondary metabolites with a broad range of biological activities. We started to develop an eukaryotic microbial platform based on the yeast Saccharomyces cerevisiae for heterologous production of NRPs using δ-(l-α-aminoadipyl)–l-cysteinyl–d-valine (ACV) as a model NRP. The Penicillium chrysogenum gene pcbAB encoding ACV synthetase was expressed in S. cerevisiae from a high-copy plasmid together with phosphopantetheinyl transferase (PPTase) encoding genes from Aspergillus nidulans, P. chrysogenum and Bacillus subtilis, and in all the three cases production of ACV was observed. To improve ACV synthesis, several factors were investigated. Codon optimization of the 5′ end of pcbAB did not significantly increase ACV production. However, a 30-fold enhancement was achieved by lowering the cultivation temperature from 30 to 20°C. When ACVS and PPTase encoding genes were integrated into the yeast genome, a 6-fold decrease in ACV production was observed indicating that gene copy number was one of the rate-limiting factors for ACV production in yeast. [Copyright &y& Elsevier]

Abstract: Background: The sepsis-induced acute liver injury majorly depends on the dysfunction of mitochondria and the loss of cellular energy. Aquaporin 8 (AQP8) can modulate water transport and osmotic swelling of mitochondria in the inner mitochondrial membrane of the liver. In this study, we explore the effects of tetramethylpyrazine (TMP) on protecting the structure of hepatocyte mitochondria and modulating the expression of AQP8. Materials and methods: Forty-eight rats were randomly allocated to four groups: control group receiving sham procedure, septic group receiving cecal ligation and puncture (CLP), therapeutic group receiving 60 mg/kg of ligustrazine (TMP) intravenously from caudal vein immediately after CLP, and preventive group receiving 60 mg/kg/d of ligustrazine intravenously from caudal vein for 7 d before CLP. The mitochondrial ultrastructure of rat liver was observed. The protein expression of AQP8 was assayed by Western blot. Analysis of AQP8 messenger RNA (mRNA) expression level was performed by the reverse transcription–polymerase chain reaction. The mean fluorescence intensity (MFI) of rhodamine 123 (Rh 123) was measured by flow cytometry. The serum tumor necrosis factor alpha (TNF-α) level was determined by the enzyme-linked immunosorbent assay. Results: The mitochondrial ultrastructure was markedly damaged in the septic group, whereas it was lightly damaged in the therapeutic and preventive groups. Compared with the control group, the AQP8 protein expression and MFI were significantly reduced, and the steady-state AQP8 mRNA and serum TNF-α levels were increased in the septic, therapeutic, and preventive groups. Compared with the septic group, the AQP8 protein expression and MFI were increased, and the steady-state AQP8 mRNA and serum TNF-α levels were decreased significantly in the therapeutic and preventive groups. There was no significant difference in morphologic characteristics, AQP8 protein level, AQP8 mRNA level, MFI, and serum TNF-α level between the therapeutic and the preventive groups. Linear positive correlation was observed between the AQP8 protein level and the MFI of Rh 123. Linear negative correlation was observed between the AQP8 protein level or the MFI of Rh 123 and serum TNF-α level. Conclusions: TMP has protective effect on hepatocellular mitochondria from damage in sepsis by ameliorating the expression of AQP8 protein in liver mitochondria. The protective effect of TMP on the liver mitochondria might not have a difference between using TMP before or after the occurrence of sepsis. [Copyright &y& Elsevier]

Graphitic carbon nitride (g-C 3 N 4) has attracted enormous interest because of its prominent photocatalytic performance. Due to the planar π conjugation structure which should provide good binding energy for adsorption of metal atoms including lithium (Li) and sodium (Na), g-C 3 N 4 also possesses great application potential in ion batteries. Here, first-principles calculations are performed to investigate its application in lithium ion batteries (LIBs), focusing on the electric field effect on the Li storage. Our results revealed that Li adsorbed C 3 N 4 (Li–C 3 N 4) exhibits good modulation of its Li binding energy by applying external vertical electric field. The Bader charge analysis and charge density difference calculations provide a deep insight into the tunable Li adsorption to C 3 N 4 sheets. Our theoretical results suggest that C 3 N 4 is a suitable anode material for LIBs. • The physical mechanism concerning the good Li storage is unraveled.. • Strong ionic bonding between Li and C3N4 layer is demonstrated by charge density difference and Bader charge analysis. • Both the average charge and binding energies of Li exhibit good modulation by external electric field. • Non-monotonous variation of the binding energy of Li with electric field is revealed. [ABSTRACT FROM AUTHOR]