Sun-Ok Kim

Fully integrated 54nm STT-RAM with the smallest bit cell dimension for high density memory application

A compact STT(Spin-Transfer Torque)-RAM with a 14F2 cell was integrated using modified DRAM processes at the 54nm technology node. The basic switching performance (R-H and R-V) of the MTJs and current drivability of the access transistors were characterized at the single bit cell level. Through the direct access capability and normal chip operation in our STT-RAM test blocks, the switching behavior of bit cell arrays was also analyzed statistically. From this data and from the scaling trend of STT-RAM, we estimate that the unit cell dimension below 30nm can be smaller than 8F2.

KR-31378 ameliorates atherosclerosis by blocking monocyte recruitment in hypercholestrolemic mice

The recruitment of monocytes into the artery wall is a crucial early step in atherogenesis. A novel compound, KR‐31378, has been shown to be a neuroprotective agent for ischemia‐reperfusion damage in rat brain via its potent antioxidant and antiapoptotic actions. Here, we report the effects of this compound on atherogenesis and possible mechanisms of action. In Ldlr knockout mice fed with a high‐fat, high‐cholesterol diet, treatment with KR‐31378 significantly inhibited fatty streak formation and macrophage accumulation. To address the possibility that KR‐31378 may influence the initial stages of atherogenesis, we examined its effect on the adhesion and migration of monocytes to endothelial cells stimulated with tumor necrosis factor‐α. KR‐31378 decreased the adhesion in a dose‐dependent manner. The observed decreases in cell adhesion and migration correlated with KR‐31378‐mediated down‐regulation of vascular cell adhesion molecule‐1 (VCAM‐1) and interleukin (IL)‐8. Nuclear factor‐κB (NF‐κB) is known to regulate the expression of adhesive and chemotactic molecules including VCAM‐1 and IL‐8. Indeed, transient transfection experiments, electrophoretic mobility shift assay, and IκB degradation assay showed that KR‐31378 decreased NF‐κB activation. These results indicate that KR‐31378 potently reduces fatty streak formation by inhibiting NF‐κB‐dependent cellular adhesion and chemotactic molecule expression, which are crucial to monocyte infiltration into the arterial wall during the early stages of atherogenesis.

Cardioselective anti-ischemic ATP-sensitive potassium channel (KATP) openers: Benzopyranyl indoline and indole analogues

This paper describes the design, syntheses, and biological evaluations of novel ATP-sensitive potassium channel (K(ATP)) openers, benzopyranyl indoline and indole derivatives. Among those, two enantiomers of indoline-2-carboxylic ethyl esters (14, 18) showed the best cardioprotective activities both in vitro and in vivo, while their vasorelaxation potencies were very low (concentration for 50% inhibition of vasorelaxation >30 microM). The cardioprotective effect of 14 was completely reversed by 5-hydroxydecanoate, a selective mitochondrial K(ATP) blocker, indicating its provable protective mechanism through the mitochondrial K(ATP) opening. In addition, we performed conformational analyses using 2D-NMR, X-ray crystallography and molecular modeling to study the structure-activity relationships in this series of compounds.

KR-31372 inhibits KDR/Flk-1 tyrosine phosphorylation via K+ATP channel opening in its antiangiogenic effect

The aim of this study was to identify the signaling pathway of the antiangiogenesis by (2R,3R,4S)-N-cyano-N-(6-nitro-3,4-dihydro-hydroxy-2-methyl-2-dimethoxymethyl 2H-1-benzopyran-4yl)-N-benzylguanidine (KR-31372). KR-31372 inhibited the in vitro basal tube formation using Matrigel-coated plate and in vivo neovascularizations in mice induced by Matrigel containing vascular endothelial growth factor (VEGF(165), 5 ng/ml). VEGF(165) markedly increased cell proliferation using 5-bromo-2-deoxyuridine incorporation and chemotactic migration using transwell chamber in human umbilical vein endothelial cells, those of which were significantly suppressed by pretreatment with KR-31372 and levcromakalim concentration dependently. The suppression of all these variables were strongly antagonized by glibenclamide, ATP-sensitive K(+) channel blocker. KR-31372 (10(-6)-10(-4) M) and levcromakalim (10(-5) M) concentration-dependently suppressed the VEGF(165)-induced increases in KDR/Flk-1 tyrosine phosphorylation as well as the extracellular signal-related kinase 1/2 (ERK1/2), p38 MAK and p125(FAK) tyrosine phosphorylation. These variables were significantly antagonized by glibenclamide. In conclusion, KR-31372 significantly inhibited the KDR/Flk-1 tyrosine phosphorylation-linked ERK1/2, p38 MAPK and p125(FAK) tyrosine phosphorylation via mediation of K(+)(ATP) channel opening, thereby resulting in antiangiogenesis.

KR 31372, a benzopyran derivative, inhibits oxidized LDL-stimulated proliferation and migration of vascular smooth muscle cells.

Abstract— KR 31372 is a benzopyran derivative. Both [3H]thymidine incorporation and migrations (chemotactic and wound‐edge) of cultured smooth muscle cells (SMCs) were greatly stimulated by oxidized low‐density lipoprotein (LDL). These effects were significantly suppressed by KR 31372 (10−7‐ 10−6M) and PDGF‐BB antibody (10−8‐ 10−6M). Preincubation with KR 31372 led to a decrease in the synthesis of PDGF‐BB‐like immunoreactivity (PDGF‐BB‐LI) that had been stimulated by oxidized LDL. Otherwise, KR 31372 and probucol strongly inhibited the production of thiobarbituric acid reactive substances (TBARS) caused by the incubation of LDL with Cu2+ion, and significantly reduced the intracellular oxidative stress when stimulated with H2O2. Taken together, it is suggested that KR 31372 may inhibit the oxidized LDL‐stimulated syntheses of DNA and PDGF‐BB, and migration of the SMCs, in part, via the antioxidant activity.

KR-31543 reduces the production of proinflammatory molecules in human endothelial cells and monocytes and attenuates atherosclerosis in mouse model

KR-31543, (2S, 3R, 4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl) amino]-3,4-dihydro-2-dimethyoxymethyl-3-hydroxy-2-methyl-2H-1-benz opyran is a new neuroprotective agent for ischemia-reperfusion damage. It has also been reported that KR-31543 has protective effects on lipid peroxidation and H2O2-induced reactive oxygen species production. In this study, we investigated the anti-inflammatory and anti-atherogenic properties of KR-31543. We observed that KR-31543 treatment reduced the production of MCP-1, IL-8, and VCAM-1 in HUVECs, and of MCP-1 and IL-6 in THP-1 human monocytes. We also examined the effect of KR-31543 on monocytes migration in vitro. KR-31543 treatment effectively reduced the migration of THP-1 human monocytes to the HUVEC monolayer in a dose-dependent manner. We next examined the effects of this compound on atherogenesis in LDL receptor deficient (Ldlr-/-) mice. After 10 weeks of western diet, the formation of atherosclerotic lesion in aorta was reduced in the KR-31543-treated group compared to the control group. The accumulation of macrophages in lesion was also reduced in KR-31543 treated group. However, the plasma levels of total cholesterol, HDL, LDL, and triglyceride were not affected by KR-31543 treatment. Taken together, these results show that KR-31543 has anti-inflammatory properties on human monocytes and endothelial cells, and inhibits fatty streak lesion formation in mouse model of atherosclerosis, suggesting the potential of KR-31543 for the treatment for atherosclerosis.