Design and Synthesis of Acridine-Triazole and Acridine-Thiadiazole Derivatives and Their Inhibitory Effect against Cancer Cells.

We report herein the design and synthesis of a series of novel acridine-triazole and acridine-thiadiazole derivatives. The newly synthesized compounds and the key intermediates were all evaluated for their antitumor activities against human foreskin fibroblasts (HFF), human gastric cancer cells-803 (MGC-803), hepatocellular carcinoma bel-7404 (BEL-7404), large cell lung cancer cells (NCI-H460), and bladder cancer cells (T24). Most of the compounds exhibited high levels of antitumor activity against MGC-803 and T24 but low toxicity against human normal liver cells (LO2), and their effect was even better than the commercial anticancer drugs, 5-fluorouracil (5-FU) and cis-platinum. Further, pharmacological mechanisms such as topo I, cell cycle, cell apoptosis, and neovascularization were all evaluated. Only a few compounds exhibited potent topo I inhibitory activity at 100 µM. In addition, the most active compounds with an IC50 value of 5.52-8.93 µM were chosen, and they could induce cell apoptosis in the G2 stage of MGC-803 or mainly arrest T24 cells in the S stage. To our delight, most of the compounds exhibited lower zebrafish cytotoxicity but could strongly inhibit the formation of zebrafish sub-intestinal veins, indicating a potential for clinical application.

Curcumin-loaded multifunctional chitosan gold nanoparticles: An enhanced PDT/PTT dual-modal phototherapeutic and pH-responsive antimicrobial agent.

Overuse of antibiotics has led to the emergence of multidrug resistant (MDR) bacteria.. Photothermal (PTT) and photodynamic therapy (PDT) have may be effective alternatives for antibiotics in the treatment of bacterial infections. In this study, based on chitosan (CS)-coated gold nanoparticles, a pH stimulus-responsive drug delivery system was developed, which can anchor to the cell membrane for photodynamic therapy and photothermal therapy, and enhance the therapeutic potential of curcumin (Cur). Release experiments showed that AuNPs/CS-Cur nanocomposites released curcumin in a pH-dependent manner, which may facilitate the drug to be delivered to the acidic bacterial infection environment. CS as the outer layer covered on gold nanoparticles could improve the dispersibility of Cur in aqueous solution, gold nanoparticles prevent rapid photobleaching of curcumin, thus ensuring the yield of singlet oxygen under irradiation, and enhance the electrostatic binding with bacteria cell membrane. Under light conditions, AuNPs/CS-Cur can produce a large amount of reactive oxygen species and heat to kill S. aureus and E. coli. Compared with free Cur-mediated PDT, the complex significantly improved the synergistic PTT/PDT photoinactivation ability against S. aureus and E. coli. In addition, AuNPs/CS-Cur had good biocompatibility. Therefore, AuNPs/CS-Cur possessed the characteristics of electrostatic targeting, photodynamic and photothermal antibacterial therapy, which would become an efficient and safe antibacterial nano-platform and provide new ideas for the treatment of bacterial infection.

Discovery of once-weekly, peptide-based selective GLP-1 and cholecystokinin 2 receptors co-agonizts.

A group of long-acting, peptide-based, and selective GLP-1R/CCK-2R dual agonizts were identified by rational design. Guided by sequence analysis, structural elements of the CCK-2R agonist moiety were engineered into the GLP-1R agonist Xenopus GLP-1, resulting in hybrid peptides with potent GLP-1R/CCK-2R dual activity. Further modifications with fatty acids resulted in novel metabolically stable peptides, among which 3d and 3 h showed potent GLP-1R and CCK-2R activation potencies and comparable stability to semaglutide. In food intake tests, 3d and 3 h also showed a potent reduction in food intake, superior to that of semaglutide. Moreover, the acute hypoglycemic and insulinotropic activities of 3d and 3 h were better than that of semaglutide and ZP3022. Importantly, the limited pica response following 3d and 3 h administration in SD rats preliminarily indicated that the food intake reduction effects of 3d and 3 h are independent of nausea/vomiting. In a 35-day study in db/db mice, every two days administration of 3d and 3 h increased islet areas and numbers, insulin contents, ß-cell area, ß-cell proliferation, as well as improved glucose tolerance, and decreased HbA1c, to a greater extent than ZP3022 and semaglutide. In a 21-day study in DIO mice, once-weekly administration of 3d and 3 h significantly induced body weight loss, improved glucose tolerance, and normalized lipid metabolism, to a greater extent than semaglutide. The current study showed the antidiabetic and antiobesity potentials of GLP-1R/CCK-2R dual agonizts that warrant further investigation.

Preparation and characterization of hemoglobin-silver composites as biocompatible antiseptics.

Microbial contamination has been a major challenge in a wide variety of fields such as biomedical and biomaterial applications. The development of biomaterials that possess excellent antibacterial ability and biocompatibility is of great importance to enhance the service life of biomaterials. In this study, the main protein component of red blood cells, hemoglobin (Hb), was employed to prepare Ag-Hb nanocomposites as novel biocompatible antiseptics. The formation of Ag-Hb nanocomposites on the titanium substrate are confirmed by field-emission scanning electron microscopy, Fourier transformed infrared spectroscopic, contact angles, and inductively coupled plasma atomic emission spectrometry analysis. The Ag-Hb titanium shows potent antibacterial ability against planktonic bacteria in the suspension and ability to prevent bacterial adhesion. Moreover, the Ag-Hb titanium shows excellent biocompatibility, which supports healthy osteoblast cellular activity and osteoblast differentiation. The results indicate that the Ag-Hb nanocomposites can be potentially useful for the fabrication of biomaterials for long-term applications.