The E693Delta mutation has been suggested as a cause of dementia because of enhanced formation of synaptotoxic Abeta oligomers. Our findings may provide genetic validation in humans for the emerging hypothesis that the synaptic and cognitive impairment in AD is primarily caused by soluble Abeta oligomers.

Abstract-In cultured vascular smooth muscle cells (VSMCs), Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) are expressed constitutively and play a role in angiotensin II (Ang II)-induced intracellular signaling and proliferation. However, little is known regarding the relevance of these proteins to the process of vascular remodeling. The role of JAK and STAT proteins in vascular remodeling and their functional coupling with Ang II were examined in balloon-injured rat carotid artery. Immunoreactive Jak2, Tyk2, Stat1, and Stat3 were not detected in the intact artery. Immunohistostaining showed transient expressions of these JAKs and STATs in medial and neointimal VSMCs at days 2 and 5, respectively, with a peak at day 7 in both layers. The expressions declined to insignificant levels by day 14. Ang II type 1 receptors (AT 1 s) were coexpressed in the medial and neointimal VSMCs expressing Jak2 and Stat3. The Jak2 and Stat3 inductions in the injured artery were accompanied by constitutive Jak2 and Stat3 phosphorylations, which were enhanced by ex vivo Ang II stimulation via AT 1 . Additionally, a Jak2 inhibitor, AG490, blocked the Ang II-induced Stat3 phosphorylation. Furthermore, local treatment with AG490 inhibited constitutive Stat3 phosphorylation and neointimal VSMC replication and subsequently reduced neointima formation in the injured artery. In conclusion, JAK and STAT proteins were inducible in medial and neointimal VSMCs after vascular injury and were functionally coupled to AT 1 .

The oral cavity in healthy subjects has a well-balanced microbiota that consists of more than 700 species. However, a disturbance of this balance, with an increase of harmful microbes and a decrease of beneficial microbes, causes oral disorders such as periodontal disease or dental caries. Nowadays, probiotics are expected to confer oral health benefits by modulating the oral microbiota. This study screened new probiotic candidates with potential oral health benefits and no harmful effects on the oral cavity. We screened 14 lactobacillus strains and 36 streptococcus strains out of 896 oral isolates derived from healthy subjects. These bacteria did not produce volatile sulfur compounds or water-insoluble glucan, had higher antibacterial activity against periodontal bacteria, and had higher adherence activity to oral epithelial cells or salivary-coated hydroxyapatite in vitro. We then evaluated the risk of primary cariogenicity and infective endocarditis of the selected oral isolates. As a result, Lactobacillus crispatus YIT 12319, Lactobacillus fermentum YIT 12320, Lactobacillus gasseri YIT 12321, and Streptococcus mitis YIT 12322 were selected because they showed no cariogenic potential in an artificial mouth system and a lower risk of experimental infective endocarditis in a rat model. These candidates are expected as new probiotics with potential oral health benefits and no adverse effects on general health.

Abstract-The roles of adventitial vasa vasorum have been highlighted in vascular wall homeostasis. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor in physiological and pathophysiological conditions. However, little is known regarding the changes in adventitial vasa vasorum and the mechanism of the formation in hypertensive arteries. Accordingly, endothelial cell proliferation, adventitial vasa vasorum count, and expression of VEGF signaling axis proteins were examined in the ascending aorta of hypertensive Wistar rats that underwent suprarenal aortic constriction.Hypertension not only induced medial and adventitial thickening but also significantly increased adventitial vasa vasorum count by day 28. Preceding the medial thickening, BrdU ϩ -proliferative endothelial cells were observed in the adventitia but not in the media and intima after day 3; they peaked at day 7 and remained modestly increased at day 28. The BrdU ϩ endothelial cells showed induction of Ets-1, a transcription factor mediating angiogenic response of VEGF. Furthermore, concomitant expression of VEGF and a hypoxia-inducible transcription factor (HIF-1␣) was observed in the outer layers of medial smooth muscle cells at day 3 and extended to the middle layers of medial smooth muscle cells at day 7, returning to lower levels by day 28. In conclusion, adventitial vasa vasorum formation was induced by hypertension through the HIF-1␣/VEGF/Ets-1 pathway during hypertensive remodeling. There is convincing evidence that disruption of blood flow to the AVV results in medial necrosis 3 and intimal hyperplasia. 4,5 Moreover, it has been demonstrated that in balloon-injured arteries, the arterial wall oxygen supply is impaired after injury but is later compensated for by new AVV formation. 6 Accordingly, the role of AVV has been highlighted in vascular wall homeostasis. Most conduit and muscular arteries have vasa vasorum in the adventitia but not in the media; oxygen and nutrients are supplied by diffusion from the AVV to the outer media and from the main vessel lumen to the inner media. 7 Oxygen requirements of the vessel wall itself are relatively modest. 8 However, medial thickening may create the hypoxic zone in the media by increasing the distance required for oxygen diffusion from the lumen. 9,10 Because hypertension produces medial thickening, it is conceivable that the AVV plays a role in the maintenance of homeostasis during vascular remodeling in hypertensive arteries. However, there has been little study of the AVV in hypertensive arteries.Vascular endothelial growth factor (VEGF) has potent mitogenic and promigratory actions specific for endothelial cells (ECs), intimately linked with new vessel development in physiological and various diseased situations. 11,12 These stimulatory effects on ECs are initiated by the binding of VEGF to its high-affinity tyrosine kinase receptor Flk-1 13 and subsequently result in activation of a transcription factor, Ets-1, leading to conversion of ECs to the angiogenic phenotype. 14,15 A ...

This study examined the effect of 8-[2-(2-pentylcyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA), a newly synthesized linoleic acid derivative with cyclopropane rings instead of cis -double bonds, on protein kinase C (PKC) activity. In the in situ PKC assay with reverse-phase highperformance liquid chromatography, DCP-LA significantly activated PKC in PC-12 cells in a concentration-dependent (10 nM-100 mM) manner, with the maximal effect at 100 nM, and the DCP-LA effect was blocked by GF109203X, a PKC inhibitor, or a selective inhibitor peptide of the novel PKC isozyme PKC-e. Furthermore, DCP-LA activated PKC in HEK-293 cells that was inhibited by the small, interfering RNA against PKC-e. In the cell-free PKC assay, of the nine isozymes examined here, DCP-LA most strongly activated PKC-e, with .7-fold potency over other PKC isozymes, in the absence of dioleoyl-phosphatidylserine and 1,2-dioleoyl-snglycerol; instead, the DCP-LA action was inhibited by dioleoyl-phosphatidylserine. DCP-LA also activated PKC-g, a conventional PKC, but to a much lesser extent compared with that for PKC-e, by a mechanism distinct from PKC-e activation. Thus, DCP-LA serves as a selective activator of PKC-e, possibly by binding to the phosphatidylserine binding site on PKC-e. These results may provide fresh insight into lipid signaling in PKC activation.-Kanno, T., H. Yamamoto, T. Yaguchi, R. Hi, T. Mukasa, H. Fujikawa, T. Nagata, S. Yamamoto, A. Tanaka, and T. Nishizaki. The linoleic acid derivative DCP-LA selectively activates PKC-e, possibly binding to the phosphatidylserine binding site. J. Lipid Res. 2006Res. . 47: 1146Res. -1156 Supplementary key words 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid . protein kinase C-e . protein kinase C-g Protein kinase C (PKC) is linked to lipid signaling pathways and participates in a wide range of signal transduction pathways. PKC isozymes are classified as conventional PKCs, such as PKC-a, -bI, -bII, and -g; novel PKCs, such as PKC-d, -e, -h, -u, and -m; and atypical PKCs, such as PKC-l/L for mouse/human, -z, and -r. PKCs are activated via several pathways mediated by phospholipase C, phospholipase A 2 , phospholipase D, and phosphatidylcholine-specific phospholipase C (1-3). Phospholipase C hydrolyzes phosphatidylinositol 4,5-bisphosphate into diacylglycerol and inositol 1,4,5-trisphosphate, the latter activating inositol 1,4,5-trisphosphate receptors to release Ca 21 from intracellular calcium stores, and conventional PKCs are activated by diacylglycerol and intracellular Ca 21 increase (1, 2). Phosphatidylcholine-specific phospholipase C produces diacylglycerol by hydrolysis of phosphatidylcholine, thereby activating PKC (3). Cis-unsaturated free fatty acids, such as arachidonic, oleic, linoleic, linolenic, and docosahexaenoic acid, that are produced by phospholipase A 2 -catalyzed hydrolysis of phosphatidylcholine activate novel PKCs in a Ca 21 -independent manner (1, 2). The free fatty acids, alternatively, may synergistically activate conventional PKCs or ...