Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M2 Receptor.

Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high M2R affinities (pKi (radioligand competition binding): 9.10-9.59). Binding studies at M1 and M3-M5 receptors indicated a M2R preference. Flow cytometric and high-content imaging saturation and competition binding (M1R, M2R, and M4R) confirmed occupation of the orthosteric site. Confocal microscopy revealed that fluorescence was located mainly at the cell membrane (CHO-hM2R cells). Results from dissociation and saturation binding experiments (M2R) in the presence of allosteric M2R modulators (dissociation: W84, LY2119620, and alcuronium; saturation binding: W84) were consistent with a competitive mode of action between the fluorescent probes and the allosteric ligands. Taken together, these lines of evidence indicate that these ligands are useful fluorescent molecular tools to label the M2R in imaging and binding studies and suggest that they have a dualsteric mode of action.

Effect of high-frequency electric field on the tissue sticking of minimally invasive electrosurgical devices.

Generally minimally invasive surgery is performed using an endoscope and other instruments including electrosurgical units (ESUs), and the adhesion of tissue to electrodes is a major concern. The mechanism governing this tissue sticking, especially the influence of high-frequency electric field, is still unclear. In this study, the effect of high-frequency electric field on the tissue sticking upon electrodes was investigated. The electrosurgical cutting test was performed on ex vivo fresh porcine liver under blend mode using a monopolar ESU. A heat-adherence test without electric field was used as a control. For the control group, the electrode was heated and maintained at a certain temperature and directly in contact with porcine liver. Both sticking tissues obtained from these two tests are partially carbonized porcine liver tissue, but their microstructure and bonding with electrode are obviously different. The sticking tissue formed just under heat is composed of biggish nanoparticles of different sizes which are loosely aggregated and has a weak bonding with the electrode, while the sticking tissue from the electrosurgical cutting test consists of tightly packed fine nanoparticles of equable size as a result of thermo-electric coupling and has a strong bonding with the electrode. Obviously, high-frequency electric field plays an extremely important role in the formation of the sticking tissue. It is the thermo-electric coupling that underlies the function of minimally invasive electrosurgical devices, and the effect of high-frequency electric field cannot be ignored in the tissue sticking study and anti-sticking strategies.

[Novel derivatives of diosgenin: design, synthesis and anti-tumor activity].

Diosgenin can inhibit the growth of A375 and K562 cell lines and induce their apoptosis with an effect on pro-apoptotic members of Bcl-2 family. To study the SAR of diosgenin derivatives, and to improve the anti-tumor activity of diosgenin, a series of novel diosgenin derivatives were designed and synthesized. Their anti-tumor activities in vitro were evaluated. The results revealed that most of the new derivatives had potent effects against K562, A375 and A549 (three tumor cell lines) in vitro, and had no or less effect against H293 and L02 (two normal cell lines). Particularly, some compounds (e.g. 1, 6-8) showed excellent activities on K562 with IC50 values ranging from 1.96 to 4.35 micromol x L(-1).