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ABSTRACT: Adenosine, a modulator of neuronal function in the mammalian central nervous system, exerts a neuroprotective effect via the adenosine A(1) receptor; however, its effect on neural stem cells (NSCs) remains unclear. Because adenosine is released in response to pathological conditions and NSCs play a key role in neuroregeneration, we tested the hypothesis that adenosine is capable of stimulating NSC proliferation. We demonstrated that NSCs dominantly express adenosine A(1) and A(2B) receptors. Adenosine and the adenosine A(1) receptor agonist cyclopentyladenosine (CPA) increased proliferation of NSCs, and this CPA-induced cell proliferation was attenuated by the A(1) antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPA). CPA also induced phosphorylation of extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase/ERK kinase (MEK), and Akt, and their phosphorylation was inhibited by DPCPA. In addition, CPA-induced cell proliferation was inhibited by MEK and Akt inhibitors. These results suggest that activation of adenosine A(1) receptor-stimulated proliferation of NSCs occurs via MEK/ERK and Akt signaling pathways.
Journal of Neuroscience Research 08/2008; 86(13):2820-8. · 2.74 Impact Factor
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Hideki Masaki,
Tetsuya Ishikawa,
Shunichi Takahashi,
Masafumi Okumura,
Noriko Sakai,
Megumi Haga,
Katsuya Kominami, Hideyuki Migita,
Fiona McDonald,
Fumiki Shimada,
Kazuhiro Sakurada
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ABSTRACT: Induction of pluripotent stem cells from human fibroblasts has been achieved by the ectopic expression of two different sets of four genes. However, the mechanism of the pluripotent stem cell induction has not been elucidated. Here we identified a marked heterogeneity in colonies generated by the four-gene (Oct3/4, Sox2, c-Myc, and Klf4) transduction method in human neonatal skin-derived cells. The four-gene transduction gave a higher probability of induction for archetypal pluripotent stem cell marker genes (Nanog, TDGF, and Dnmt3b) than for marker genes that are less specific for pluripotent stem cells (CYP26A1 and TERT) in primary induction culture. This tendency may reflect the molecular mechanism underlying the induction of human skin-derived cells into pluripotent stem cells. Among the colonies induced by the four-gene transduction, small cells with a high nucleus-to-cytoplasm ratio could be established by repeated cloning. Subsequently established cell lines were similar to human embryonic stem cells as well as human induced pluripotent stem (iPS) cells derived from adult tissue in morphology, gene expression, long-term self-renewal ability, and teratoma formation. Genome-wide single-nucleotide polymorphism array analysis of the human iPS cell line indicates that the induction process did not induce DNA mutation.
Stem cell research 12/2007; 1(2):105-15. · 3.39 Impact Factor
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ABSTRACT: 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), a natural ligand of the peroxisome proliferator-activated receptor-gamma (PPARgamma), has been shown to inhibit proinflammatory gene expression, but the signaling mechanisms involved remain unclear. Because retinoic acid receptor-related orphan receptor-alpha (RORalpha) has been reported to suppress tumor necrosis factor-alpha (TNF-alpha)-induced expression of proinflammatory genes, we hypothesized that 15d-PGJ2 may induce RORalpha expression resulting in inhibition of proinflammatory gene expression.
We demonstrate that 15d-PGJ2 induced RORalpha1 and RORalpha4 expression and inhibited TNF-alpha-induced vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression in human umbilical vein endothelial cells (HUVECs). In contrast, the synthetic PPARgamma ligand pioglitazone weakly induced RORalpha4 expression but did not affect RORalpha1 expression or TNF-alpha-induced gene expression. Biphenol A diglycidyl ether, a PPARgamma antagonist, did not block the effect of 15d-PGJ2 on RORalpha expression. Adenovirus-mediated overexpression of RORalpha1 inhibited TNF-alpha-induced VCAM-1 and ICAM-1 expression, and overexpression of a mutant form of RORalpha1 (RORalpha1Delta), which inhibited transcriptional activity of RORalpha1 and RORalpha4, attenuated its inhibition. Furthermore, we found that RORalpha1Delta attenuated the inhibitory actions of 15d-PGJ2 on TNF-alpha-induced VCAM-1 and ICAM-1 expression.
These results suggest that 15d-PGJ2 inhibits TNF-alpha-induced expression of proinflammatory genes mediated in part via induction of RORalpha in HUVECs. This mechanism provides a novel insight into PPARgamma-independent actions of 15d-PGJ2.
Arteriosclerosis Thrombosis and Vascular Biology 05/2005; 25(4):710-6. · 6.37 Impact Factor
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ABSTRACT: Rev-erbalpha and retinoic acid receptor-related orphan receptor-alpha (RORalpha) are orphan nuclear receptors but their effects on transcription are opposed. Here, we show that Rev-erbalpha was expressed predominantly in vascular smooth muscle cells (VSMCs) rather than endothelial cells. Overexpression of Rev-erbalpha upregulated the expression of interleukin-6 and cyclooxygenase-2, and increased transactivation by NF-kappaB and translocation of p65 to the nucleus in A7r5 VSMCs. Furthermore, the expression of Rev-erbalpha was upregulated by RORalpha1 but that upregulation was attenuated by Rev-erbalpha itself in A7r5 VSMCs. These results suggest a regulatory link between Rev-erbalpha and the NF-kappaB pathway.
FEBS Letters 04/2004; 561(1-3):69-74. · 3.54 Impact Factor
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ABSTRACT: Retinoic acid receptor-related orphan receptor-alpha (RORalpha) is a nuclear orphan receptor. Adenovirus-mediated overexpression of RORalpha1 and RORalpha4 suppressed tumor necrosis factor-alpha (TNF-alpha)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) in human umbilical vein endothelial cells. Overexpression of RORalpha1 and RORalpha4 also suppressed TNF-alpha-stimulated translocation of p50 and p65 to the nucleus. In contrast, dominant-negative deletion mutants of RORalpha1 and RORalpha4 failed to suppress the induction of VCAM-1 and ICAM-1 and translocations of p50 and p65. These results suggest that RORalpha1 and RORalpha4 regulate the inflammatory responses via inhibition of the nuclear factor-kappaB signaling pathway in endothelial cells.
FEBS Letters 02/2004; 557(1-3):269-74. · 3.54 Impact Factor
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YASUHIKO YAMAMOTO,
SHO-ICHI YAMAGISHI,
HIDETO YONEKURA,
TOSHIO DOI,
HIROKO TSUJI,
ICHIRO KATO,
SHIN TAKASAWA,
HIROSHI OKAMOTO,
JOYNAL ABEDIN,
NOBUSHIGE TANAKA,
SHIGERU SAKURAI, HIDEYUKI MIGITA,
HIROYUKI UNOKI,
HUA WANG,
TAKAHIRO ZENDA,
PING-SHENG WU,
YASUNORI SEGAWA,
TOMOMI HIGASHIDE,
KAZUO KAWASAKI,
HIROSHI YAMAMOTO
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ABSTRACT: This study concerns whether advanced glycation endproducts (AGE) are related to microvascular derangement in diabetes, exemplified by pericyte loss and angiogenesis in retinopathy and by mesangial expansion in nephropathy. AGE caused a decrease in viable pericytes cultivated from bovine retina. On the other hand, AGE stimulated the growth and tube formation of human microvascular endothelial cells (EC), this being mediated by autocrine vascular endothelial growth factor. In AGE-exposed rat mesangial cells, type IV collagen synthesis was induced. Those AGE actions were dependent on a cell surface receptor for AGE (RAGE), because they were abolished by RAGE antisense or ribozyme. The AGE-RAGE system may thus participate in the development of diabetic microangiopathy. This proposition was supported by experiments with animal models; several indices characteristic of retinopathy were correlated with circulating AGE levels in OLETF rats. The predisposition to nephropathy was augmented in RAGE transgenic mice when they became diabetic.
Annals of the New York Academy of Sciences 04/2000; 902(1):163 - 172. · 3.15 Impact Factor
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Hideto Yonekura,
Shigeru Sakurai,
Xiaoxu Liu, Hideyuki Migita,
Hua Wang,
Sho-ichi Yamagishi,
Motohiro Nomura,
Md. Joynal Abedin,
Hiroyuki Unoki,
Yasuhiko Yamamoto,
Hiroshi Yamamoto
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ABSTRACT: We have shown previously that vascular endothelial growth factor (VEGF) synthesized by the cellular constituents of small
vessels per se, viz.endothelial cells and pericytes, participates in the hypoxia-driven proliferation of both cell types (Nomura, M., Yamagishi,
S., Harada, S., Hayashi, Y., Yamashima, T., Yamashita, J., Yamamoto, H. (1995)J. Biol. Chem. 270, 28316–28324; Yamagishi, S., Yonekura, H., Yamamoto, Y., Fujimori, H., Sakurai, S., Tanaka, N., and Yamamoto, H. (1999)
Lab. Invest. 79, 501–509). In this study, we examined the expression of the recently isolated VEGF gene family members (placenta growth
factor (PlGF), VEGF-B, and VEGF-C) in human dermal microvascular endothelial cells and bovine retinal pericytes cultured under
various oxygen tensions. Quantitative reverse transcription-polymerase chain reaction analyses demonstrated that the two cell
types possess not only VEGF (VEGF-A) mRNA, but also VEGF-B, VEGF-C, and PlGF mRNAs. Among them, only VEGF-A mRNA was induced
under hypoxia. Competitive reverse transcription-polymerase chain reaction showed that, under normoxic conditions, the rank
order of mRNA content in endothelial cells was PlGF > VEGF-B > VEGF-C > VEGF-A and that mRNA coding for PlGF was expressed
at >100-fold higher levels than VEGF-A mRNA. In pericytes, the rank order was VEGF-C > VEGF-A > VEGF-B > PlGF, and ∼7-fold
higher levels of VEGF-C mRNA compared with VEGF-A mRNA were noted in this cell type. Furthermore, antisense inhibition of
PlGF protein production lowered the endothelial cell synthesis of DNA under hypoxic conditions. The results suggest that these
VEGF family members may also take active parts in angiogenesis.
Journal of Biological Chemistry 12/1999; 274(49):35172-35178. · 4.77 Impact Factor
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Nucleic Acids Research. 01/1999; 27:2591-2600.
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ABSTRACT: Two FDPase isozymes have been purified by DEAE-Sephadex column chromatography and gel filtration, and then characterized from endosperms of germinating castor beans (Ricinus communis). One of the enzymes is localized in the cytosol and the other is confined to plastids. There are physical, kinetic and regulatory differences between the isoenzymes. The Km value of cFBPase and p-FBPase for F-1, 6-BP was 8.2μM and 23.6μM, respectively. The optimum pH of c-FBPase was in the range 7.5-7.8, whereas the p-FBPase was 6.7. The p-FBPase being more negatively charged than the c-FBPase. The c-FBPase is regulated by AMP, and F-2<6-BP, whereas the p-FBPase is slightly regulated by AMP.
