Optimization of the synthesis of BET BD2 selective inhibitor XY153.

XY153 is a promising BET BD2 inhibitor with an IC50 value of 0.79 nM against BRD4 BD2. It shows 354-fold selectivity over BRD4-BD1 and 6-fold selectivity over other BET BD2 domains. However, the reported synthesis route of XY153 and its derivatives are extremely poor-yielding. After the synthesis of three key fragments, XY153 can only be obtained with a yield of 1.3 % in the original four-step reaction. In this study, we reported a three-step alternative route in the synthesis process of XY153. The reaction conditions for this route were thoroughly investigated and optimized, resulting in a significantly improved yield of 61.5 %. This efficient synthesis route establishes a robust chemical foundation for the rapid synthesis of XY153 derivatives as BET BD2 inhibitors in the near future.

Drug-repurposing by virtual and experimental screening of PFKFB3 inhibitors for pancreatic cancer therapy.

Pancreatic cancer (PC) is the most frequently occurring cancer, with few effective treatments and a 5-year survival rate of only about 11%. It is characterized by stiff interstitium and pressure on blood vessels, leading to an increased glycolytic metabolism. PFKFB3 plays an important role in glycolysis, and its products (fructose-2,6-bisphosphate), which are allosteric PFK1 activators, limit the glycolytic rate. In this study, 14 PFKFB3 inhibitors were obtained by virtually screening the FDA-approved compound library. Subsequently, the in-vitro investigations confirmed that Lomitapide and Cabozantinib S-malate exhibit the excellent potential to inhibit PFKFB3. The combined administration of Lomitapide and Gemcitabine at a certain molar ratio indicated an enhanced anti-tumor effect in Orthotopic Pancreatic Cancer (OPC) models. This investigation provides a new treatment strategy for PC therapy.

Disulfide Bond-Based SN38 Prodrug Nanoassemblies with High Drug Loading and Reduction-Triggered Drug Release for Pancreatic Cancer Therapy.

Purpose: Chemotherapy is a significant and effective therapeutic strategy that is frequently utilized in the treatment of cancer. Small molecular prodrug-based nanoassemblies (SMPDNAs) combine the benefits of both prodrugs and nanomedicine into a single nanoassembly with high drug loading, increased stability, and improved biocompatibility. Methods: In this study, a disulfide bond inserted 7-ethyl-10-hydroxycamptothecin (SN38) prodrug was rationally designed and then used to prepare nanoassemblies (SNSS NAs) that were selectively activated by rich glutathione (GSH) in the tumor site. The characterization of SNSS NAs and the in vitro and in vivo evaluation of their antitumor effect on a pancreatic cancer model were performed. Results: In vitro findings demonstrated that SNSS NAs exhibited GSH-induced SN38 release and cytotoxicity. SNSS NAs have demonstrated a passive targeting effect on tumor tissues, a superior antitumor effect compared to irinotecan (CPT-11), and satisfactory biocompatibility with double dosage treatment. Conclusion: The SNSS NAs developed in this study provide a new method for the preparation of SN38-based nano-delivery systems with improved antitumor effect and biosafety.

Damage Identification Method for Medium- and Small-Span Bridges Based on Macro-Strain Data under Vehicle-Bridge Coupling.

The damage identification method based on macro-strain modality has shown good results for large-span flexible bridges. However, medium- and small-span bridges have a high stiffness, and the axle system is embodied. The strong time-varying vibration characteristics, coupled with the non-stationary characteristics of vehicle loads, make it difficult to accurately determine the stable strain modes of such bridges. To solve this problem, a damage localization index in the form of an amplitude vector matrix of the mutual energy density spectrum based on macro-strain was constructed using wavelet transform de-noising and reconstruction technology and cross-correlation function. The macro-static strain and macro-dynamic strain data obtained from a vehicle-bridge coupling experiment were reconstructed through wavelet transform, and the factors influencing the damage indices were analyzed. The results showed that the proposed indicators could help realize an accurate damage localization for medium- and small-span bridge systems with different damage degrees under the action of vehicle-bridge coupling.

Design of Flow Velocity and Direction Monitoring Sensor Based on Fiber Bragg Grating.

The real-time monitoring of the flow environment parameters, such as flow velocity and direction, helps to accurately analyze the effect of water scour and provide technical support for the maintenance of pier and abutment foundations in water. Based on the principle of the Fiber Brag Grating sensor, a sensor for monitoring the flow velocity and direction in real-time is designed in this paper. Meanwhile, the theoretical calculation formulas of flow velocity and direction are derived. The structural performance of the sensor is simulated and analyzed by finite element analysis. The performance requirements of different parts of the sensor are clarified. After a sample of the sensor is manufactured, calibration experiments are conducted to verify the function and test the accuracy of the sensor, and the experimental error is analyzed. The experimental results indicate that the sensor designed in this paper achieves a high accuracy for the flow with a flow velocity of 0.05-5 m/s and the flow velocity monitoring error is kept within 7%, while the flow direction monitoring error is kept within 2°. The sensor can meet the actual monitoring requirements of the structures in water and provide reliable data sources for water scour analysis.

Angelica Essential Oil Loaded Electrospun Gelatin Nanofibers for Active Food Packaging Application.

The development of food packaging possessing bioactivities which could extend the shelf life of food has gained increased interest in recent years. In this study, gelatin nanofibers with encapsulated angelica essential oil (AEO) were fabricated via electrospinning. The morphology of gelatin/AEO nanofibers was examined by scanning electron microscopy (SEM) and the addition of AEO resulted in the increase of fiber diameter. The proton nuclear magnetic resonance (1H-NMR) spectra were measured to confirm the presence of AEO in nanofibers. The hydrophobic property of gelatin nanofibers was also found to be improved with the addition of AEO. The nanofibers incorporated with AEO showed significant antioxidant activity and inhibitory effect against both Gram-negative and Gram-positive bacteria in a concentration dependent manner. Furthermore, the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay demonstrated that the developed gelatin/AEO nanofibers revealed no cytotoxicity effect. Thus, gelatin nanofibers incorporated with AEO can be used as potential food packaging.

Honey loaded alginate/PVA nanofibrous membrane as potential bioactive wound dressing.

Honey is an ancient natural wound-healing agent and has been reintroduced to modern clinical wound care as it has various bioactivities. In this study, honey was incorporated into an alginate/PVA-based electrospun nanofibrous membrane to develop an efficient wound dressing material. The morphology and chemical composition of the nanofibrous membrane were observed by scanning electron microscopy and characterized via Fourier transform infrared spectroscopy, respectively, demonstrating that honey was successfully introduced to the nanofibers. The nanofibrous membranes with increasing honey content showed enhanced antioxidant activity, suggesting the ability to control the overproduction of reactive oxygen species. Disc diffusion assay and dynamic contact assay proved the antibacterial activity of the honey loaded nanofibers towards Gram-positive bacterium (Staphylococcus aureus) and Gram-negative bacterium (Escherichia coli). The cytotoxicity assay illustrated the non-cytotoxicity and biocompatibility of the nanofibrous membranes. Therefore, the developed honey/alginate/PVA nanofibrous membranes are promising for wound dressings.