Discovery of novel and potent dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment via structure-based pharmacophore modelling, virtual screening, and molecular docking, molecular dynamics simulation studies, and biological evaluation

Article

Author: Hua, Huilian ; Chen, Shutong ; Zhang, Yan ; Niu, Miao-Miao ; Qiao, Xiao ; Wu, Xiangyu

Colorectal cancer (CRC) is one of the most common cancers worldwide. Nowadays, owing to the complex mechanism of tumorigenesis, simultaneous inhibition of multiple targets is an important anticancer strategy. Recent studies have demonstrated receptor tyrosine kinase AXL (AXL) and histone deacetylase 2 (HDAC2) are closely associated with colorectal cancer. Herein, we identified five hit compounds concurrently targeting AXL and HDAC2 using virtual screening. Inhibitory experiments revealed these hit compounds potently inhibited AXL and HDAC2 in the nanomolar range. Among them, Hit-3 showed the strongest inhibitory effects which were better than that of the positive control groups. Additionally, MD assays showed that Hit-3 could bind stably to the AXL and HDAC2 active pockets. Further MTT assays demonstrated that Hit-3 showed potent anti-proliferative activity. Most importantly, Hit-3 exhibited significant in vivo antitumor efficacy in xenograft models. Collectively, this study is the first discovery of dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment.

01 Sep 2024·Cytometry Part B: Clinical Cytometry

Possible alternative strategies to implement basophil activation testing in multicentric studies

Article

Author: Dupont, Thomas ; Cabanski, Maciej ; Verles, Aurélie ; Carsin, Ania ; Vitaliti, Alessandra ; Busnel, Jean‐Marc ; Bourgoin, Pénélope ; Agabriel, Chantal

AbstractThe Basophil Activation Test (BAT) enables flow cytometry characterization of basophil reactivity against specific allergenic molecules. The focus now revolves around democratizing this tool, but, as blood sample stability could be challenging, after having developed a simplified approach, herein, we aimed to characterize two strategies for implementing BAT in multicentric studies: store and ship blood before or after sample processing. Fresh heparin‐ and EDTA‐anticoagulated whole blood samples followed both BAT workflows: “collect, store, process & analyze” or “collect, process, store & analyze”. Storage temperatures of 18–25 °C or 2–8 °C and preservation times from 0 to 7 days were considered. Interleukin‐3 was also evaluated. With the “collect, store, process & analyze” workflow, heparin‐anticoagulated blood and 18–25 °C storage were better than other conditions. While remaining possible, basophil activation exhibited a possible reactivity decay after 24 h. Under the conditions tested, interleukin‐3 had no role in enhancing basophil reactivity after storage. Conversely, the “collect, process, store & analyze” workflow demonstrated that either heparin‐ or EDTA‐anticoagulated blood can be processed and kept up to 7 days at 18–25 °C or 2–8 °C before being analyzed. Various strategies can be implemented to integrate BAT in multicentric studies. The “collect, store, process & analyze” workflow remains a simplified logistical approach, but depending on time required to ship from the clinical centers to the reference laboratories, it might not be applicable, or should be used with caution. The “collect, process, store & analyze” workflow may constitute a workflow improvement to provide significant flexibility without impact on basophil reactivity.

01 Jun 2024·Food Chemistry: X

Effect of sulfuric acid hydrolysis on the structure and Pickering emulsifying capacity of acorn starch

Article

Author: Shi, Yuzhong ; Geng, Sheng ; Yuan, Chao ; Guo, Changsheng ; Liu, Benguo

The acid-hydrolyzed acorn starch samples (HAS-1, HAS-2, HAS-3, and HAS-4) were prepared from natural acorn starch (NAS) at sulfuric acid concentrations of 1, 2, 3, and 4 mol/L for 2 d. The particle characteristics and structures of HAS were investigated, and Pickering high internal phase emulsions (HIPEs) based on HAS were constructed and characterized. The results showed that with an increase in sulfuric acid concentration, the size, yield, amylose content, molecular weight, and amylopectin chain length of HAS gradually decreased. HAS retained an A-type crystal structure, and its relative crystallinity and short-range order degree gradually increased with increasing sulfuric acid concentration. Acid hydrolysis treatment improved the wettability of NAS, and its effect was positively correlated with the sulfuric acid concentration. HAS-3 and HAS-4 could stabilize the Pickering HIPEs with an oil phase volume fraction of 80% at c ≥ 1.5%. The mechanical properties of the HIPEs were positively correlated with c.

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