Sucutiniranes A and B, new cassane-type diterpenes from Bowdichia nitida

Two new cassane-type diterpenes, sucutiniranes A (1) and B (2), have been isolated from the seeds of Bowdichia nitida together with 6alpha-acetoxyvouacapane (3) and 6alpha,7beta-diacetoxyvouacapane (4), and the structures of 1 and 2 were elucidated by using 2D NMR data and chemical correlations. Sucutinirane A (1) and 3 showed a moderate cytotoxicity against human colon carcinoma COLO201 cells, and 6alpha,7beta-diacetoxyvouacapane (4) showed in vitro antiplasmodial activity against parasite Plasmodium falciparum 3D7.     

Surface-induced phase separation of a sphingomyelin/cholesterol/ganglioside GM1-planar bilayer on mica surfaces and microdomain molecular conformation that accelerates Aβ oligomerization

Ganglioside GM1 mediates the amyloid beta (Aβ) aggregation that is the hallmark of Alzheimer's disease (AD). To investigate how ganglioside-containing lipid bilayers interact with Aβ, we examined the interaction between Aβ40 and supported planar lipid bilayers (SPBs) on mica and SiO₂ substrates by using atomic force microscopy, fluorescence microscopy, and molecular dynamics computer simulations. These SPBs contained several compositions of sphingomyelin, cholesterol, and GM1 and were treated at physiological salt concentrations. Surprisingly high-speed Aβ aggregation of fibril formations occurred at all GM1 concentrations examined on the mica surface, but on the SiO₂ surface, only globular agglomerates formed and they formed slowly. At a GM1 concentration of 20 mol%, unique triangular regions formed on the mica surface and the rapidly formed Aβ aggregations were observed only outside these regions. We have found that some unique surface-induced phase separations are induced by the GM1 clustering effects and the strong interactions between the GM1 head group and the water layer adsorbed in the ditrigonal cavities on the mica surface. The speed of Aβ40 aggregation and the shape of the agglomerates depend on the molecular conformation of GM1, which varies depending on the substrate materials. We identified the conformation that significantly accelerates Aβ40 aggregation, and we think that the detailed knowledge about the GM1 molecular conformation obtained in this work will be useful to those investigating Aβ-GM1 interactions.     

Identification of Highly Selective and Potent Histone Deacetylase 3 Inhibitors Using Click Chemistry-Based Combinatorial Fragment Assembly

To find histone deacetylase 3 (HDAC3)-selective inhibitors, a series of 504 candidates was assembled using “click chemistry”, by reacting nine alkynes bearing a zinc-binding group with 56 azide building blocks in the presence of Cu(I) catalyst. Screening of the 504-member triazole library against HDAC3 and other HDAC isozymes led to the identification of potent and selective HDAC3 inhibitors T247 and T326. These compounds showed potent HDAC3 inhibition with submicromolar IC₅₀s, whereas they did not strongly inhibit other isozymes. Compounds T247 and T326 also induced a dose-dependent selective increase of NF-κB acetylation in human colon cancer HCT116 cells, indicating selective inhibition of HDAC3 in the cells. In addition, these HDAC3-selective inhibitors induced growth inhibition of cancer cells, and activated HIV gene expression in latent HIV-infected cells. These findings indicate that HDAC3-selective inhibitors are promising candidates for anticancer drugs and antiviral agents. This work also suggests the usefulness of the click chemistry approach to find isozyme-selective HDAC inhibitors.     

Drift and fluctuating motion of artificial platelets during the lateral transport and adhesion process near the wall

Recombinant glycoprotein Ibα latex beads (rGPIbα-LB) are a potential solution to overcoming platelet transfusion problems with artificial platelets. To understand the transport process of artificial platelets and to estimate the particle motion when adhering to the wall surface, we evaluated the lateral motion of rGPIbα-LB in terms of drift and random motion, because the lateral motion is an important factor for transport and adhesion. We observed the lateral motion of rGPIbα-LB flowing with red blood cells toward the immobilized von Willebrand factor (vWf) surface in a model arteriole at wall shear rates of 200–1000 s^?1 and 0–40% Hct. At 40% Hct, wall shear rate dependence was observed for the drift motion, i.e. the lateral velocity of rGPIbα-LB toward the wall. In the near-wall region, the drift motion of contacting particles differed substantially from that of non-contacting particles. Additionally, the trajectories of contacting particles on the vWf surface had specific motion that was not observed on the BSA surface. These results suggest that the adhesion force between rGPIbα and vWf is highly associated with the motion of particles near the wall. These features are desirable for artificial platelets, particularly for the adhesion process.     

Effects of intravenous cariporide on release of norepinephrine and myoglobin during myocardial ischemia/reperfusion in rabbits

Aims

To examine the effects of cariporide, a Na⁺/H⁺ exchanger-1 inhibitor, on cardiac norepinephrine (NE) and myoglobin release during myocardial ischemia/reperfusion by applying a microdialysis technique to the rabbit heart.

Main methods

In anesthetized rabbits, two dialysis probes were implanted into the left ventricular myocardium and were perfused with Ringer's solution. Cariporide (0.3 mg/kg) was injected intravenously, followed by occlusion of the left circumflex coronary artery. During 30-min coronary occlusion followed by 30-min reperfusion, four consecutive 15-min dialysate samples (two during ischemia and two during reperfusion) were collected in vehicle and cariporide-treated groups. Dialysate myoglobin and NE concentrations were measured by immunochemistry and high-performance liquid chromatography, respectively.

Key findings

Dialysate myoglobin and NE concentrations increased significantly during myocardial ischemia/reperfusion in both vehicle and cariporide-treated groups (P < 0.01 vs. baseline). In cariporide-treated group, dialysate myoglobin concentrations were significantly lower than those in vehicle group throughout ischemia/reperfusion (P < 0.01 at 0–15 min of ischemia, P < 0.05 at 15–30 min of ischemia, P < 0.01 at 0–15 min of reperfusion, and P < 0.01 at 15–30 min of reperfusion). However, dialysate NE concentrations in cariporide-treated group were lower than those in vehicle group only during ischemia (P < 0.01 at 0–15 min of ischemia, and P < 0.05 at 15–30 min of ischemia).

Significance

When administered before ischemia, cariporide reduces myoglobin release during ischemia/reperfusion and decreases NE release during ischemia.