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Objective To investigate the mechanism of Astragalus membranaceus (AM) in the treatment of vascular dementia (VD) by network pharmacology and molecular docking. Methods The active components of AM were collected from TCMSP database, and the targets of active components were predicted in TargetNet database according to the SMILES. The VD targets were collected by GeneCards database, and the common targets of active components and VD was calculated to obtain the potential targets of AM in the treatment of VD. The active components-target network was constructed by Cytoscape 3.9.1 software. The potential targets of AM in the treatment of VD were imported into STRING database to construct protein-protein interaction (PPI) network, which was analyzed to obtain core targets. The core targets were imported into DAVID database to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The molecular docking was performed to assess the affinity of main active components of AM and the corresponding VD core targets via AutoDock software. Results A total of 20 active components of AM were collected, including jaranol, isorhamnetin, isoflavanone, kaempferol and quercetin, and a total of 102 predicted targets were obtained. A total of 3 556 VD targets were screened, 71 common targets of AM and VD were calculated, and 36 core targets were obtained by PPI analysis, including SLC6A4, ESR1, PTGS2, ABCB1 and AR. A total of 187 GO items and 32 KEGG pathways were enriched, mainly focusing on neurological function, hormone signal and angiogenesis. Molecular docking showed good affinity between the main active components of AM and VD core targets. Conclusion AM treats VD mainly by regulating neurological function, hormone signal and angiogenesis.

The 2024 aluminum alloy is one of the high-quality lightweight materials. Friction stir welding (FSW) has shown advantages in reducing welding defects and improving welding quality in 2024 aluminum alloys. Currently, the research regarding FSW joint corrosion performance is mainly about the joint without plastic deformation. However, FSW joints often need to be formed into complex shapes by plastic deformation. The influence of plastic deformation on the corrosion performance of FSW joints is the focus of scientific research. To address this problem, the effect of high-temperature deformation on the mechanical properties and corrosion behavior of 2024 aluminum alloy joints was researched. The exfoliation corrosion test, scanning electron microscopy, energy-dispersive spectroscopy, and transmission electron microscopy were employed to analyze the corrosion mechanism and microstructure. The results show that high-temperature deformation of the weld nugget zone greatly affects the mechanical properties and corrosion behavior of the FSW joint. Compared with the 0% deformation specimen, the hardness and tensile strength of the 20% deformation FSW joint increased by 32% and 21%, respectively. The FSW joint with 20% deformation shows the best mechanical properties and corrosion resistance. The number of precipitated S' phases of the FSW joint increases when the deformation increases to 20%, and the shape of the S' phase is a regular round particle shape. The dislocation density of the FSW joint increases continuously during deformation, which provides a favorable nucleation location for the S' phase. [ABSTRACT FROM AUTHOR]

Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In order to expand the application of alkenyl oxindoles for targeted protein degradation, we designed and synthesized a series of heterobifunctional compounds by conjugating different alkenyl oxindoles with bromodomain-containing protein 4 (BRD4) inhibitor JQ1. Through structure-activity relationship study, we successfully developed JQ1-alkenyl oxindole conjugates that potently degrade BRD4. Unexpectedly, we found that these molecules degrade BRD4 through the ubiquitin-proteasome system, rather than the autophagy-lysosomal pathway. Using pooled CRISPR interference (CRISPRi) screening, we revealed that JQ1-alkenyl oxindole conjugates recruit the E3 ubiquitin ligase complex CRL4DCAF11 for substrate degradation. Furthermore, we validated the most potent heterobifunctional molecule HL435 as a promising drug-like lead compound to exert antitumor activity both in vitro and in a mouse xenograft tumor model. Our research provides new employable proteolysis targeting chimera (PROTAC) moieties for targeted protein degradation, providing new possibilities for drug discovery. Targeted protein degradation strategies are promising avenues for drug development, but it is important to broaden the toolbox of E3 ligases that can be engaged. This study shows that alkenyl oxindole compounds act as novel E3 ligase ligands and recruit the CRL4-DCAF11 E3 ubiquitin ligase complex for substrate degradation. [ABSTRACT FROM AUTHOR]

A tremendous quantity of brackish water with a high proportion of divalent cations is in great need of water softening. Layer-stacked graphene oxide membranes show potential in membrane processing due to their molecular sieving properties, but show poor selective retention of cations due to unstable interlayer spacing and electrostatic interaction. In this study, a partially reduced graphene oxide (prGO) and chitosan (CS) nanohybrid membrane (prGO-CS) was fabricated to achieve the selective retention of divalent cations by adjusting the configuration and controlling the surface charge. The prGO-CS membrane, which included a CS skin and embedded prGO sheets, showed a performance boost of 98.0% rejection of Mg2+ and 95.5% rejection of Ca2+ when compared with a CS membrane. The membrane showed good water softening performance for brackish water under low operation pressure with a high Na+/Mg2+ selectivity of 33.8. The excellent performance was attributed to the dense structure and positive charge of prGO-CS.