Publications (27) View all
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Article: Activation of adenosine A1 receptor-induced neural stem cell proliferation via MEK/ERK and Akt signaling pathways.
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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 -
Article: Heterogeneity of pluripotent marker gene expression in colonies generated in human iPS cell induction culture.
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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 -
Article: Phosphonate quinoxalinedione AMPA antagonists.
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ABSTRACT: In the Western world, over 350,000 deaths and $30 billion in medical costs are attributed annually to stroke. Head and spinal cord trauma cause an estimated 250,000 deaths annually and result in medical costs of $15 billion. Although stroke and head/spinal cord trauma are leading causes of disability and death in humans, no adequate neuroprotective treatment is available. Glutamate antagonists derived from the quinoxa-linedione scaffold are as drug candidates for neuroprotection in stroke and trauma. Quinoxalinedione derivatives such as 2,3-dihydroxy-6- nitro-7-sulfamoylbenzo(f)quinoxaline and 6-(1H-imidazol-1-yl)-7-nitro-2,3-(1H,4H)-quinoxalinedione failed clinical trials because of insolu-bility and resulting nephrotoxicity. Introduction of a phosphonate group into the quinoxalinedione skeleton improves solubility and leaves potency for the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor unchanged. Phosphonate quinoxalinedione derivatives ZK202000 and ZK200775 protected rodent brain against sequelae of permanent occlusion of the middle cerebral artery and head trauma. No major deleterious effects on motor coordination, cardiovascular, or respiratory systems were detected in doses required for neuroprotection. No psychotomimetic and no neurotoxic side effects, typical for N-methyl-D-aspartate antagonists, were observed following treatment with phosphonate quinoxalinediones.Restorative neurology and neuroscience 02/2000; 17(1):45-59. · 2.51 Impact Factor -
Article: Regenerative medicine and stem cell based drug discovery.
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ABSTRACT: As William Shakespeare beautifully described, increasing age often causes loss of tissue and organ function. The increase in average life expectancy in many countries is generating an aging society and an increase in age-related health problems. Regenerative medicine is expected to be a powerful actor in this drama, and stem cell technology may hold the key to the development of innovative treatments for acute and chronic degenerative conditions. This Review surveys the present situation and some future prospects for regenerative medicine and stem cell based drug discovery.Angewandte Chemie International Edition 02/2008; 47(31):5718-38. · 13.45 Impact Factor -
Article: The Promises and Challenges of Regenerative Medicine, October 20-22, 2004, Kobe, Japan.
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ABSTRACT: This report provides a brief summary of information presented at a workshop on regenerative medicine held in Kobe, Japan, on October 20-22, 2004. A major focus of the workshop was the identification and characterization of adult and embryonic stem cells, including approaches to manipulate these--in terms both of maintaining stemness and of driving differentiation toward a desired phenotype--and current developments toward their therapeutic use in regenerative medicine.Stem Cells 06/2005; 23(5):707-9. · 7.78 Impact Factor
