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Comprehensive Summary TAG‐assisted peptide synthesis technology enables optimal conservation of Fmoc amino acid raw materials and chemical solvents while eliminating the need for intricate chromatographic purification processes. This work presents a 4,4'‐diphenylphosphonoxy diphenylcarbinol tag‐mediated liquid‐phase synthesis approach for preparing side‐to‐tail cyclopeptides macolacin which has strong activity against gram‐negative bacteria, and its 15 analogues containing four N‐methylation modified cyclopeptides, as well as an investigation of their structure‐activity relationship (SAR). The synthesis of macolacin analogues primarily focuses on the modifications of the N‐methylation group of Ile‐7 and the tail fatty acyl chain of macolacin. The incorporation of N‐methylation for Ile‐7, along with the dihalogenated or monohalogenated benzoic acids for tail modification, exhibited remarkable antibacterial efficacy and minimal hepatocellular toxicity in vitro. The present study identified an N‐methylation‐modified antimicrobial cyclopeptide Ma14 that exhibits rapid bactericidal efficacy against A. baumanii, etc., while showing reduced hepatocellular toxicity. Molecular docking simulations were conducted to investigate the binding of cyclopeptides to the outer membrane protein BamA of A. baumannii. The findings demonstrated the stable binding interactions of the cyclopeptides with the BamA protein and then presented a novel approach to explain the bacteriostatic mechanism of macolacin‐based cyclopeptide antibiotics. [ABSTRACT FROM AUTHOR]

Photo-sensitive probes based on coumarin deserve extensive attention because of their high biocompatibility, quantum yield, and stability. The synthesis of coumarin and its derivatives is mainly based on four classical methods: Perkin synthesis, Knoevenagel synthesis, Wittig synthesis, and Pechmann synthesis. As everyone knows, fluorescent probes consist of a recognition group, a bridging group, and a luminescent group. Mechanism of fluorescent probes can be roughly summarized into four models: Chelation-induced enhanced fluorescence (CHEF), intramolecular charge transfer (ICT), photoinduced electron transfer (PET), and aggregation-induced luminescence (AIE), which can instruct the design of coumarin-based photo-sensitive probes. Since the fluorescence-based probe was first reported, probes based on coumarin have found widespread application in analytical chemistry, proving to be a selective, efficient, and convenient tool in ion monitoring, molecular monitoring, cell imaging, drug delivery, and many other fields. In this critical review, the synthetic routes of these compounds and the design for fluorescent probes were reported. Furthermore, the recent researches on the employment of coumarin in analytical chemistry were also introduced. Finally, the future research trends and application foreground of coumarin derivatives were forecasted herein. [ABSTRACT FROM AUTHOR]

Fungal azaphilones have attracted widespread attention due to their significant potential as sources of food pigments and pharmaceuticals. Genome mining and gene cluster activation represent powerful tools and strategies for discovering novel natural products and bioactive molecules. Here, a putative azaphilone biosynthetic gene cluster lut from the endophytic fungus Talaromyces sp. was identified through genome mining. By overexpressing the pathway-specific transcription factor LutB, five new sclerotiorin-type azaphilones ( 1 , 6 , 8 , and 10 - 11 ) together with seven known analogues ( 2 - 5 , 7 , 9 , 12 ) were successfully produced. Compounds 8 and 9 exhibited antibacterial activity against Bacillus subtilis with MIC values of 64 and 16 μg/mL, respectively. Compound 11 showed cytotoxic activity against HCT116 and GES-1 with IC 50 values of 10.9 and 4.9 μM, respectively, while 1 , 4 , 5 , and 7 - 10 showed no obvious cytotoxic activity. Gene inactivation experiments confirmed the role of the lut cluster in the production of compounds 1 - 12 . Subsequent feeding experiments unveiled the novel functional diversity of the dual megasynthase system. Furthermore, a LutC-LutD binary oxidoreductase system was discovered, and in combination with DFT calculations, the basic biosynthetic pathway of the sclerotiorin-type azaphilones was characterized. This study provided a good example for the discovery of new azaphilones and further uncovered the biosynthesis of these compounds.

Background and Aims: The common characteristics of alcohol-associated liver injury (ALI) include abnormal liver function, infiltration of inflammatory cells, and generation of oxidative stress. The gastrin-releasing peptide receptor (GRPR) is activated by its neuropeptide ligand, gastrin-releasing peptide (GRP). GRP/GRPR appears to induce the production of cytokines in immune cells and promotes neutrophil migration. However, the effects of GRP/GRPR in ALI are unknown., Approach and Results: We found high GRPR expression in the liver of patients with alcohol-associated steatohepatitis and increased pro-GRP levels in peripheral blood mononuclear cells of these patients compared with that of the control. Increased expression of GRP may be associated with histone H3 lysine 27 acetylation induced by alcohol, which promotes the expression of GRP and then GRPR binding. Grpr-/- and Grprflox/floxLysMCre mice alleviated ethanol-induced liver injury with relieved steatosis, lower serum alanine aminotransferase, aspartate aminotransferase, triglycerides, malondialdehyde, and superoxide dismutase levels, reduced neutrophil influx, and decreased expression and release of inflammatory cytokines and chemokines. Conversely, the overexpression of GRPR showed opposite effects. The pro-inflammatory and oxidative stress roles of GRPR might be dependent on IRF1-mediated Caspase-1 inflammasome and NOX2-dependent reactive oxygen species pathway, respectively. In addition, we verified the therapeutic and preventive effects of RH-1402, a novel GRPR antagonist, for ALI., Conclusions: A knockout or antagonist of GRPR during excess alcohol intake could have anti-inflammatory and antioxidative roles, as well as provide a platform for histone modification-based therapy for ALI., (Copyright © 2023 American Association for the Study of Liver Diseases.)

We designed and fabricated a novel high throughput brain-on-chip with three dimensional structure with the aim to simulate the in vivo three-dimensional growth environment for brain tissues. The chip consists of a porous filter and 3D brain cell particles, and is loaded into a conventional 96-well plate for use. The filter and the particle molds were fabricated by using computer modeling, 3D printing of positive mold and agarose-PDMS double reversal mold. The 3D cell particles were made by pouring and solidifying a suspension of mouse embryonic brain cells with sodium alginate into a cell particle mold, and then cutting the resulting hydrogel into pieces. The loaded brain-on-chip was used to determine the neurotoxicity of pesticides. The cell particles were exposed to 0, 10, 30, 50, 100 and 200 µmol/L of chlorpyrifos or imidacloprid, separated conveniently from the medium by removing the porous filter after cultivation. Subsequently, cell proliferation, acetylcholinesterase activity and lactate dehydrogenase release were determined for toxicity evaluation. The embryonic brain cells were able to grow and proliferate normally in the hydrogel particles loaded into the filter in a 96-well plate. Pesticide neurotoxicity test showed that both chlorpyrifos and imidacloprid presented dose-dependent inhibition on cell growth and proliferation. Moreover, the pesticides showed inhibition on acetylcholinesterase activity and increase release of lactate dehydrogenase. However, the effect of imidacloprid was significantly weaker than that of chlorpyrifos. In conclusion, a novel brain-on-chip was developed in this study, which can be used to efficiently assess the drug neurotoxicity, pharmacodynamics, and disease mechanism by combining with a microtiterplate reader.

Objective: To observe the change of the gene expression of N-methyl-D-aspartate receptors (NMDAR) subunits in rat hippocampus after scalding., Methods: The backs of the rats were shaved and immersed in warm water for 10 sec. to make control group (C), and the backs shaved and immersed in hot water (90 degrees C) for 10 sec to make 30% full skin scalding model as the scalding group (S). The mRNA expression of the subunits of rat hippocampus NMDAR-NMDAR1, NMDAR2A, NMDAR2B, NMDAR2D was determined with RT-PCR technique in C group and at 0.5, 1, 2 and 4 postburn hours (PBHs) in S group., Results: (1) There exhibited no obvious change of the mRNA expression of all the subunits of NMDAR at 0.5 and 1 PBH in S group when compared with that in C group. But the mRNA expression of NMDAR1 increased for 24.3% and 20.9% and that of NMDAR2A increased for 27.8% and 27.6% at 2 and 4 PBHs respectively when compared with that in C group (P < 0.05). In addition, the mRNA expression of NMDAR2B and NMDAR2D revealed no change after scalding., Conclusion: The receptor channel constructed by NMDAR1/NMDAR2A demonstrated increased mRNA expression at 2 PBH, which might lead to the further opening of NMDAR after scalding which might participate in the maladjustment of HPA axis during scalding stress and the following pathophysiological changes.