Inhibition of intracellular dipeptidyl peptidases 8 and 9 enhances parthenolide's anti-leukemic activity.

Parthenolide is selectively toxic to leukemia cells; however, it also activates cell protective responses that may limit its clinical application. Therefore, we sought to identify agents that synergistically enhance parthenolide's cytotoxicity. Using a high-throughput combination drug screen, we identified the anti-hyperglycemic, vildagliptin, which synergized with parthenolide to induce death of the leukemia stem cell line, TEX (combination index (CI)=0.36 and 0.16, at effective concentration (EC) 50 and 80, respectively; where CI <1 denotes statistical synergy). The combination of parthenolide and vildagliptin reduced the viability and clonogenic growth of cells from acute myeloid leukemia patients and had limited effects on the viability of normal human peripheral blood stem cells. The basis for synergy was independent of vildagliptin's primary action as an inhibitor of dipeptidyl peptidase (DPP) IV. Rather, using chemical and genetic approaches we demonstrated that the synergy was due to inhibition of the related enzymes DPP8 and DPP9. In summary, these results highlight DPP8 and DPP9 inhibition as a novel chemosensitizing strategy in leukemia cells. Moreover, these results suggest that the combination of vildagliptin and parthenolide could be useful for the treatment of leukemia.

A novel mesoporous biomaterial for treating dentin hypersensitivity.

An ideal material has yet to be discovered that can completely treat dentin hypersensitivity; however, calcium phosphate precipitation has exhibited potential value for the treatment of dentin hypersensitivity by the occlusion of dentinal tubules. We hypothesized that a novel mesoporous silica biomaterial (nano CaO@mesoporous silica, NCMS) containing nano-sized calcium oxide particles mixed with 30% phosphoric acid can efficiently occlude dentinal tubules and significantly reduce dentin permeability, even with the presence of pulpal pressure. This highly supersaturated Ca(2+)-and HPO(4)(2-)ion-containing NCMS paste was brushed onto dentin surfaces, and the ions diffused deeply into the dentinal tubules and formed a CaHPO(4).2H(2)O precipitation with a depth of 100 microm. The results of the dentin permeability tests showed that the novel mesoporous material exhibited a significant reduction in dentin permeability (p < 0.05), even under simulated pulpal pressure, as compared with our previously developed material, DP-bioglass, and a commercial desensitizing material, Seal & Protect.

Phase, compositional, and morphological changes of human dentin after Nd:YAG laser treatment.

Although techniques for repairing root fracture have been proposed, the prognosis is generally poor. If the fusion of a root fracture by laser is possible, it will offer an alternative to extraction. Our group has attempted to use lasers to fuse a low melting-point bioactive glass to fractured dentin. This report is focused on the phase, compositional, and morphological changes observed by means of X-ray diffractometer, Fourier transforming infrared spectroscopy, and scanning electron microscopy-energy dispersive X-ray spectroscopy in human dentin after exposure to Nd:YAG laser. The irradiation energies were from 150 mJ/ pulse-10 pps-4 s to 150 mJ/pulse-30 pps-4 s. After exposure to Nd:YAG laser, dentin showed four peaks on the X-ray diffractometer that corresponding to a-tricalcium phosphate (TCP) and beta-TCP at 20 = 30.78 degrees/34.21 degrees and 32.47 degrees/33.05 degrees, respectively. The peaks of a-TCP and beta-TCP gradually increased in intensity with the elevation of irradiation energy. In Fourier transforming infrared analysis, two absorption bands at 2200 cm(-1) and 2015 cm(-1) could be traced on dentin treated by Nd:YAG laser with the irradiation energies beyond 150 mJ/pulse-10 pps-4 s. The energy dispersive X-ray results showed that the calcium/phosphorus ratios of the irradiated area proportionally increased with the elevation of irradiation energy. The laser energies of 150 mJ/ pulse-30 pps-4 s and 150 mJ/pulse-20 pps-4 s could result in the a-TCP formation and collagen breakdown. However, the formation of glass-like melted substances without a-TCP at the irradiated site was induced by the energy output of 150 mJ/ pulse-10 pps-4 s. Scanning electron micrographs also revealed that the laser energy of 150 mJ/ pulse-10 pps-4 s was sufficient to prompt melting and recrystallization of dentin crystals without cracking. Therefore, we suggest that the irradiation energy of Nd:YAG laser used to fuse a low melting-point bioactive glass to dentin is 150 mJ/ pulse-10 pps-4 s.

GABAB receptor-mediated effects in synaptosomes of lethargic (lh/lh) mice.

Previously, we have shown a significant increase in number of GABAB receptor binding sites in neocortex and thalamus of lethargic (lh/lh) mice, a mutant strain exhibiting absence seizures. This study was performed to test our hypothesis that presynaptic GABAB receptors would inhibit [3H]GABA release to a greater degree in lh/lh mice compared with their nonepileptic littermates (designated +/+). Synaptosomes isolated from neocortex and thalamus of age-matched male lh/lh and +/+ mice were similar in uptake of [3H]GABA. In the neocortical preparation, baclofen dose-dependently inhibited [3H]GABA release evoked by 12 mM KCl, an effect mediated by GABAB receptors. The maximal inhibition (Imax) value was significantly greater (80%) in lh/lh than +/+ mice, whereas the IC50 (3 microM) was unchanged. In the thalamic preparation, the effect of baclofen (50 microM) was 58% less robust in lh/lh mice. Other effects mediated by GABAB receptors (inhibitions in Ca2+ uptake and cyclic AMP formation) were also significantly reduced in thalamic synaptosomes from lh/lh mice. These data suggest a greater presynaptic GABAB receptor-mediated effect in neocortex and a reduced effect in thalamic nuclei of lh/lh mice. It is possible that selective effects of presynaptic GABAB receptors or GABA release in neocortex and thalamic nuclei of lh/lh mice may contribute to mechanisms underlying absence seizures.

Sintered porous DP-bioactive glass and hydroxyapatite as bone substitute.

There is extensive experimental and surgical experience with the use of bone tissue to fill defects in the skeleton, to bridge non-union sites, and to pack defects in bone created from cyst curettage. DP-bioactive glass with a chemical composition of Na2O 8.4%, SiO2 39.6%, P2O5 12% and CaO 40% has been reported as an alternative bone substitute of high mechanical strength, good biocompatibility. and which has a tight bond with living tissue. The bonding layer between DP-bioactive glass and bone tissue was considered to be formed by dissolution of calcium and phosphate ions from the DP-bioactive glass into the surrounding body fluids. The biological hydroxyapatite was suspected to deposit directly onto the bonding layer. In order to confirm the interaction between the DP-bioactive glass and bone tissue, the developed bioactive glass was implanted into rabbit femur condyle for 2-32 weeks. The histological evaluation of DP-bioactive glass as a bone substitute was also investigated in the study. Porous hydroxyapatite bioceramic was used in the control group and the results were compared with those of DP-bioactive glass. The interface between the DP-bioactive glass and bone tissue examined with SEM-EPMA showed that the bioactive glass formed a reaction layer on the surface within 2 weeks after operation and formed a direct bond with natural bone. The elements contained in the bioactive glass apparently interdiffuse with the living bone and biological hydroxyapatite deposited onto the diffusion area, which was proved by EPMA and TEM. After implantation for over 8 weeks, the DP-bioactive glass was gradually biodegraded and absorbed by the living bone. Histological examination using the optical microscope showed that osteocytes grow into the inside of the DP-bioactive glass and the bioactive glass would be expected to be a part of bone.