Research progress of active probes targeting specific aminoacids / 药学学报

Activity-based protein (proteomic) profiling (ABPP) has emerged as a key component of the broad field of chemical techniques capable of directly analyzing enzyme activity in living systems. With the deepening of research on electrophilic warheads and nucleophilic amino acids, and the continuous proposal and improvement of effective development strategies, the application of amino acid-targeting active probes in various biological systems has facilitated the identification, development of new targets in various disease contexts and discovery of inhibitors. The purpose of this review is to summarize the latest progress in the design and application of active probes targeting specific amino acids, in order to provide support for the further development of amino acid-targeted covalent inhibitordrugs.

Design, synthesis and antidiabetic activity studies of purine derivatives / 药学学报

Based our previous work, twelve purine derivatives were designed and synthesized as dual modulators of GPR119 and DPP-4by conjugating the GPR119 activating and DPP-4 inhibiting fragments with the position 6 and 9 of purine core via an approach of merged pharmacophores. Compound 11, bearing 2-fluoro-4-methylsulphonyl anilide and cyanopyrrolidine moieties, exhibited the most potent GPR119 agonistic activities (EC50 = 0.33 μmol·L-1, IA = 71.1%) and DPP-4 inhibitory (58.4% inhibition at 10 μmol·L-1, 21.2% inhibition at 1 μmol·L-1) activities in the in vitro antidiabetic study. Subsequently, we performed studies on structure activity relationships and molecular docking to guide the further drug design.

Morphological and functional parameters of left atrial appendage play a greater role in atrial fibrillation relapse after radiofrequency ablation.

This study was to quantitatively investigate the role of morphological and functional parameters of the left atrium (LA) and left atrial appendage (LAA) with 256-slice spiral computed tomography (CT) in the recurrence of atrial fibrillation (AF) after radiofrequency ablation (RFA). Eighty-three patients with AF who underwent RFA for the first time were divided into the recurrence (n = 27) and non-recurrence (n = 56) groups. All patients underwent a 256-slice spiral CT examination before the operation. The clinical data and quantitative measurement of the morphology and functional parameters of the LA and LAA were analyzed, including the maximal and minimal volume, ejection fraction and volume, and volume strain of LAA and LA (LAAVmax, LAAVmin, LAAEF, LAAEV, and LAA-VS, LAVmax, LAVmin, LAEF, LAEV and LA-VS, respectively). The CHA2DS2-VASc score and the proportion of patients with heart failure were significantly (P < 0.05) higher in the recurrence than non-recurrence group. The LAAVmax, LAAVmin, LAVmax, LAVmin, LAAV and LAV were all significantly greater in the recurrence than non-recurrence group (P < 0.05), and the perimeter, major and minor axes of LAA orifice and LAA depth were also significantly greater in the recurrence than non-recurrence group. The LAAEF, LAEF and LAA-VS were significantly (P < 0.05) lower in the recurrence than non-recurrence group (P < 0.05). Heart failure, CHA2DS2-VASC score, LAEF, LAV, LAAEF and LAA-VS were univariately significant (P < 0.05) risk factors for AF recurrence after ablation. Multivariate analysis revealed LAAEF (HR: 0.790, 95% CI: 0.657-0.950, P = 0.012) and LAAV (HR: 1.160, 95% CI: 1.095-1.229, P <0.001) to be two significant independent predictors of recurrence. ROC curve analysis showed that LAAEF <44.68% had the highest predictive value for recurrence after radiofrequency ablation, with the sensitivity of 90% and specificity of 67.4%, whereas LAA volume >9.25 ml had the highest predictive value for AF recurrence after RFA, with the sensitivity of 85.2% and specificity of 67.9%. In conclusion, the volume of left atrium, volume and morphology of left atrial appendage have all significantly increased while the ejection fraction and volume strain of left atrium and left atrial appendage have both significantly decreased in recurrence than in non-recurrence after radiofrequency ablation. The ejection fraction and volume of left atrial appendage are significant independent predictors of atrial fibrillation recurrence after radiofrequency ablation.

Concentration-dependent effects of nitric oxide on tumors and chemosensitivity / 药学学报

The resistance and dose limitation of tumors is a serious obstacle to cytotoxic drug therapy in the field of medical oncology. Nitric oxide (NO) is a powerful adjuvant for tumor hypersensitivity for traditional chemotherapy and radiation therapy. The concentration of NO plays an important role in affecting its anti-tumor effect. This review summarizes the mechanism of concentration-dependent effects of NO on tumor cells and the mechanism of chemotherapy sensitization. It provides evidence for rational use of NO to exert anti-tumor effects, and overcoming multidrug resistance and anti-tumor drug development.

Recent advances in G protein coupled receptor 119 agonists / 药学学报

G protein-coupled receptor 119 (GPR119) has been a promising target for the treatment of type 2 diabetes. It can not only directly promote insulin secretion, but also indirectly increase insulin secretion by stimulating the release of glucose-dependent GIP/CLP-1 without causing hypoglycemia. The remarkable advantages of small molecule GPR119 agonists make it one of the research hotspots for the development of type 2 diabetes drugs. This article reviews the anti-diabetic small molecules based on the GPR119 target in the past five years.

Preparation and <italic>in vitro</italic> evaluation of phospholipid-coated silver-graphene quantum dot multifunctional nanoparticles / 药学学报

@#In this paper, multifunctional silver-graphene quantum dot nanoparticles coated with phospholipids (ADG-DDPC) were prepared and their properties were evaluated <italic>in vitro</italic>. Cationic phospholipids 1,2-diolefinoxy-3-trimethy-laminopropane (DOTAP) was absorbed first onto the surface of the core of silver nanoparticle (AgNPs) through the mutual attraction between the positive and negative charge. Based on the principle of phase transformation and hydrophobic interaction, dstearyl-phosphatidylglycolamine-polyethylene-glycol-cyclic-cRGD peptide (DSPE-PEG₂₀₀₀-cRGD) self-assembled onto the outlayer of DOTAP of AgNPs. A stable multifunctional nano-preparation was formed and its ultraviolet absorption, particle size distribution, morphology,<italic>in vitro</italic> release behavior, ability to kill cancer cells and cell uptake were studied. The maximum UV absorption of the synthesized nanometer preparation was about 400 nm. Malvern particle size meter and transmission electron microscope showed that the particle size of the nano- preparation was about 30-40 nm and its particle size distribution was uniform. The <italic>in vitro</italic> release of nano-preparation was positively correlated with the concentration of H₂O₂. The IC₅₀ value of AgNPs for tumor cells was (347.78 ± 0.06) ng·mL^-1, and the IC₅₀ value of ADG-DDPC for tumor cells was (209.68 ± 0.09) ng·mL^-1, indicating that ADG-DDPC possessed a stronger cytotoxicity than that of AgNPs. Cell uptake experiment showed that ADG-DDPC could be absorbed by tumor cells and exhibited fluoresce inside those cells. In conclusion, ADG-DDPC was successfully prepared, and <italic>in vitro</italic>characterization study pointed to that the nano-preparation exhibits a higher antitumor activity than AgNPs.