Yuta Ikawa

Chiba University, Tiba, Chiba, Japan

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Publications (2)5.06 Total impact

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    ABSTRACT: Transforming growth factor-β1 (TGFβ1) plays a pivotal role in fibrosis in various organs including the lung. Following pulmonary injury, TGFβ1 stimulates conversion of fibroblasts to myofibroblasts that are mainly characterized by up-regulation of α-smooth muscle actin (αSMA) expression, and the resulting excess production of extracellular matrix proteins causes fibrosis with loss of alveolar function. The present study was undertaken to define the role of the sphingosine-1-phosphate (S1P) pathway in TGFβ1-induced expression of αSMA in human fetal lung fibroblasts, HFL1 cells. Analysis of mRNA revealed the existence of S1P(1), S1P(2), and S1P(3) receptor mRNAs. Treatment with TGFβ1 increased sphingosine kinase (SphK) activity and S1P(3) receptor mRNA at 24h after stimulation, and pharmacological data showed the involvement of sphingomyelinase, SphK, and S1P(3) receptor in the TGFβ1-induced up-regulation of αSMA with and without serum. Treatment with pertussis toxin and S1P(1) receptor antagonist W146 enhanced αSMA expression by TGFβ1/serum, and S1P decreased and increased αSMA levels with and without serum, respectively. TGFβ1 increased cyclooxygenase-2 expression in a manner dependent on serum and the sphingomyelinase/SphK pathway, and the response was decreased by pertussis toxin. Prostaglandin E(2), formed by TGFβ1/serum stimulation, decreased the TGFβ1-induced expression of αSMA via EP prostanoid receptor. These data suggest that S1P formed by TGFβ1 stimulation has diverse effects on the expression of αSMA, inhibition via the S1P(1) receptor-mediated and serum-dependent expression of cyclooxygenase-2 and the resulting formation of prostaglandin E(2), and stimulation via the S1P(3) receptor in a serum-independent manner.
    No preview · Article · Oct 2012 · European journal of pharmacology
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    ABSTRACT: Increases in the level of cyclooxygenase (COX)-2 and prostanoids such as prostaglandin E(2) (PGE(2)) are considered biomarkers of colorectal cancer. Therefore, non-steroidal anti-inflammatory drugs (NSAID) have been used to reduce the risk of cancer development by reducing prostanoid biosynthesis as COX inhibitors. Along with their activity as COX inhibitors, NSAID have been reported to have other effects. One major NSAID, indomethacin, has been shown to have several effects independent of COX inhibition. To further examine the COX-inhibition-independent effects of indomethacin on colorectal cancer, we used human colon cancer LS174T cells, known to have express little COX-2 and have no detectable PGE(2) production. Here we show that indomethacin has a potential antagonizing effect on human EP(2) receptors. We believe this study raises the reasons to use indomethacin as a lead-compound for setting up another EP(2) receptor-specific antagonist as a relatively cost-efficient strategy for anti-cancer medication in the future.
    No preview · Article · Apr 2012 · European journal of pharmacology