Atsushi Honda

Telmisartan induces proliferation of human endothelial progenitor cells via PPARγ-dependent PI3K/Akt pathway

OBJECTIVE Although recent clinical trials have suggested that angiotensin II type 1 receptor blockers (ARBs) reduced cardiovascular events, the precise mechanisms involved are still unknown. Telmisartan, an ARB, has recently been identified as a ligand of peroxisome proliferator-activated receptor-gamma (PPARgamma). On the other hand, since endothelial progenitor cells (EPCs) are thought to play a critical role in ischemic diseases, we investigated effects of telmisartan on proliferation of EPCs. METHODS AND RESULTS Human peripheral blood mononuclear cells were isolated from healthy volunteers, and cultured on fibronectin-coated dishes in the presence or absence of telmisartan. Four days after starting culture, adherent cells were collected, and equal numbers of cells were reseeded into methylcellulose medium with or without telmisartan. In the presence of telmisartan, numbers of colonies increased in a dose-dependent manner. DiI-AcLDL uptake and lectin and CD31, CD34 staining revealed that these colonies were EPCs. Increase in colony number by treatment with telmisartan was absolutely inhibited when cultured with a specific inhibitor of PPARgamma. In addition, we observed that specific inhibitors of phosphoinositide-3 kinase (PI3K) abolished telmisartan-stimulated increase of monocytic EPC-like cells and telmisartan induced phosphorylation of Akt. Furthermore, mRNA expression of p21 was downregulated in a dose dependent manner, suggesting that growth inductive effects of telmisartan might be regulated by the PI3K/Akt and p21 signaling pathway. CONCLUSIONS These findings suggest that telmisartan might contribute to endothelial integrity and vasculogenesis in ischemic regions by increasing numbers of EPCs.

Chlorovulones, new halogenated marine prostanoids with an antitumor activity from the stolonifer clavularia viridis Quoy and Gaimard

Abstract New halogenated marine prostanoids, chlorovulone I, II and III were isolated from the stolonifer Clavularia viridis Quoy and Gaimard. The structure elucidation and the antitumor activity of chlorovulones were described.

Antileukemic effect of coral-prostanoids clavulones from the stolonifer Clavularia viridis on human myeloid leukemia (HL-60) cells

To elucidate the biological activities of coral-prostanoids, clavulones, discovered from the Japanese stolonifer Clavularia viridis, we examined the effect of clavulone on the cell growth of human cancer (human promyelocytic leukemia (HL-60) cells and HeLa cells) and normal (Chang liver cells and lung fibroblasts) cells in vitro. Clavulone showed strong antiproliferative and cytotoxic activities in the human cells and it had some selectivity to leukemic (HL-60) cells over other HeLa cells or normal cells on the basis of the IC50 values and cytotoxic effect of the cells. The IC50 value of clavulone in the HL-60 cells was about 0.4 microM (0.2 micrograms/ml). Over 1.0 microM (0.5 micrograms/ml), clavulone showed a significant cytotoxic activity on the HL-60 cells. The data on DNA synthesis and flow cytometric analysis revealed that clavulone arrests the cells in the G1-phase and inhibits the cell growth of HL-60 cells by inhibiting S-phase DNA synthesis. These results suggest that clavulone has a potent antileukemic effect on HL-60 cells.

Hyaluronic acid in rabbit pericardial fluid and its production by pericardium

High‐M r(> 2 × 106) hyaluronic acid (about 82 ) was found for the first time in rabbit pericardial fluid. Biosynthetic experiments with minced pericardium from rabbit showed that the high‐M rhyaluronic acid in the pericardial fluid was actively synthesized by the pericardium from [3H]glucosamine.

Alterations in glycosaminoglycans of the aorta of vitamin E-deficient rats

To elucidate whether or not a vitamin E-deficient diet affects the rat aorta extracellular matrix, we examined the alterations in glycosaminoglycans (GAGs), as one of the components of the extracellular matrix of the aorta. The total amount of uronic acid, as an index of GAG, decreased significantly in the aorta of vitamin E-deficient rats. The components of GAG were identified as hyaluronic acid (HA), heparan sulfate (HS), dermatan sulfate (DS) and chondroitin sulfate (CS) by electrophoresis together with enzymic digestion. The amount of sulfated GAGs, especially the amount of DS and CS, decreased in the aorta of vitamin E-deficient rats. The biosynthetic activity of GAG was determined by using [3H]glucosamine and [35S]sulfate. The total biosynthetic activity of GAG and the incorporation of [3H]glucosamine into HA, HS, DS and CS decreased markedly in the aorta of vitamin E-deficient rats. The decrease in the production of sulfated GAGs, especially DS, which is involved in the potent antithrombogenic activity, could be related to the lower anticoagulant activity in the aorta of vitamin E-deficient rats.

Comparative study on glycosaminoglycansulfotransferases in rat costal cartilage and chick embryo cartilage

1. The comparative features of glycosaminoglycan-sulfotransferase system in rat costal cartilage and chick-embryo cartilage were examined. Some different properties of glycosaminoglycan-sulfotransferases in the cartilage of both the animals have been observed. 2. This study shows that rat costal cartilage contains more 4-sulfotransferase than 6-sulfotransferase and that that reverse situation pertains to chick-embryo cartilage, although both the rat and chick-embryo cartilage contain two sulfotransferase species. 3. Our preliminary experiments by use of rat sulfotransferases and chick endogenous acceptor or of chick sulfotransferases and rat sulfotransferases and chick endogenous acceptor or of chick sulfotransferases and rat endogenous acceptor suggest that sulfotransferases in a given tissue play a central role in determining which sites of the N-acetylgalactosamine moiety of chondroitin sulfates occurring in the tissue are sulfated.

Mechanism of Age-Dependent Decrease in Sulfation of Chondroitin Sulfate

A number of investigators have been concerned with the relationship between extracellular substances and aging (1,2). It is generally recognized that the amount of hexosamine-containing substances in tissue decreases with age, while the insoluble collagen content in the tissue increases with age (3). Recently, it has been reported that the decrease in elasticity of cartilage with age is related to the content and structure of the proteoglycan in the matrix (4).