T Tanabe

Osaka City University, Ōsaka-shi, Osaka-fu, Japan

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Publications (95)1008.42 Total impact

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    ABSTRACT: Although skin diseases are one of the target diseases for gene therapy, there has been no practical gene transfer method. First, we examined gene transfer efficiency of the spring-powered jet injector, Shima Jet, which was originally developed as a non-needle jet injector of insulin. Local gene expression was about 100 times higher when the luciferase plasmid was transferred by the Shima Jet than by a needle. Gene transfer of beta-galactosidase revealed gene expression in the epidermis. Based on these results, we then examined the potential of gene therapy using the Shima Jet for wound healing. An increase of cellular proliferation of the epidermis and the number of microvessels in the granulation tissue was observed after hepatocyte growth factor (HGF) gene transfer. An increase in blood flow around the wound was observed after prostacyclin synthase (PGIS) gene transfer. Moreover, promotion on wound healing was observed in HGF gene transferred group, and further promotion was observed in combined gene transferred group as assessed by measuring wound area. These results indicate that co-transfer of HGF and PGIS genes by the Shima Jet could be an effective strategy to wound healing.
    No preview · Article · Sep 2006 · Gene Therapy
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    T Hatae · M Wada · C Yokoyama · M Shimonishi · T Tanabe
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    ABSTRACT: Prostacyclin (PGI2) plays important roles in hemostasis both as a vasodilator and an endogenous inhibitor of platelet aggregation. PGI2 functions in these roles through a specific IP receptor, a G protein-coupled receptor linked to Gs and increases in cAMP. Here, we report that intracellular prostacyclin formed by expressing prostacyclin synthase in human embryonic kidney 293 cells promotes apoptosis by activating endogenous peroxisome proliferator-activated receptor δ (PPARδ). In contrast, treatment of cells with extracellular prostacyclin or dibutyryl cAMP actually reduced apoptosis. On the contrary, treatment of the cells with RpcAMP (adenosine 3′,5′-cyclic monophosphothioate, Rp-isomer), an antagonist of cAMP, enhanced prostacyclin-mediated apoptosis. The expression of an L431A/G434A mutant of PPARδ completely blocked prostacyclin-mediated PPARδ activation and apoptosis. These observations indicate that prostacyclin can act through endogenous PPARδ as a second signaling pathway that controls cell fate.
    Preview · Article · Jan 2002 · Journal of Biological Chemistry
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    ABSTRACT: It has been well established that overexpression of Cyclooxygenase-2 (Cox-2) in epithelial cells inhibits apoptosis and increases the invasiveness of malignant cells, favoring tumorigenesis and metastasis. However, the molecular mechanism that regulates Cox-2 expression has not been well defined in gastric carcinoma. In this study, we examined whether the Cox-2 expression could be regulated by hyper-methylation of the Cox-2 CpG island (spanning from -590 to +186 with respect to the transcription initiation site) in human gastric carcinoma cell lines. By Southern analysis, we found that three gastric cells (SNU-601, -620, and -719) without Cox-2 expression demonstrated hyper-methylation at the Cox-2 CpG island. A detailed methylation pattern using bisulfite sequencing analysis revealed that all of the CpG sites were completely methylated in SNU-601. Treatment with demethylating agents effectively reactivated the expression of Cox-2 and restored IL-1beta sensitivity in the previously resistant SNU-601. By transient transfection experiments, we demonstrate that constitutively active Cox-2 promoter activities were exhibited even without an exogenous stimulation in SNU-601. Furthermore, when the motif of the nuclear factor for interleukin-6 expression site, the cyclic AMP response element, or both was subjected to point mutation, the constitutive luciferase activity was markedly reduced. In addition, Cox-2 promoter activity was completely blocked by in vitro methylation of all of the CpG sites in the Cox-2 promoter region with SssI (CpG) methylase in SNU-601. Taken together, these results indicate that transcriptional repression of Cox-2 is caused by hyper-methylation of the Cox-2 CpG island in gastric carcinoma cell lines.
    Full-text · Article · Jul 2001 · Cancer Research
  • N Tohnai · T Tanabe

    No preview · Article · Mar 2001 · Nippon rinsho. Japanese journal of clinical medicine
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    H Maruoka · S Kitaoka · N Tohnai · Y Inaki · T Tanabe
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    ABSTRACT: Isopoly (S-carboxymethyl-L-cysteine) derivatives of nucleic acids bases were prepared as antisense compounds. In past study, we investigated the properties of these compounds in vitro, and revealed that these compounds in vivo regulated the cell death presumably due to the inhibition of protein production. In this study, western and northern blots were carried out in order to reveal the mechanism of this inhibition for N-methyl-D-aspartate receptor in neuroblastoma x glioma hybrid NG108-15 cell line. In addition, we investigated the resistance of these compounds against cell extract and the metabolism. In conclusion, we proved that these compounds inhibited the protein production by antisense mechanism.
    Preview · Article · Feb 2001 · Nucleic Acids Symposium Series
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    S Kitaoka · Y Inaki · H Maruoka · N Tohnai · T Hatae · T Tanabe
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    ABSTRACT: Antisense with L-cysteine derivative (CAS) can recognize DNA and forms the complementary duplex with DNA. So the properties of CAS in vitro and in vivo were examined in this study. CAS was resistant to proteinase K and stabilized RNA against RNase HI. Moreover using fluorescent CAS, the localization was observed by fluorescence microscope and confocal microscope. As a result, CASs were accumulated inside the nucleus in NG108-15.
    Preview · Article · Feb 2001 · Nucleic Acids Symposium Series
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    Full-text · Article · Apr 2000 · Neuron
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    ABSTRACT: Polycyclic aromatic hydrocarbons, such as benzo[a]pyrene (B[a]P) present in tobacco smoke and tar, have been implicated in the development of atherosclerosis as well as cancer. Increased expression of cyclooxygenase-2 (COX-2) has been detected both in atherosclerotic lesions and in epithelial cancers. To determine whether polycyclic aromatic hydrocarbons might directly affect COX expression in vascular cells, we investigated the effects of B[a]P on COX-2 expression in human and rat arterial smooth muscle cells (SMC). Treatment with B[a]P increased levels of COX-2 protein and mRNA and enhanced prostaglandin synthesis. Nuclear runoff assays and transient transfections revealed increased COX-2 gene transcription after treatment with B[a]P. Experiments were done to define the signaling mechanism by which B[a]P induced COX-2. B[a]P caused a rapid increase in phosphorylation of extracellular signal-regulated kinase (ERK); pharmacologic inhibition of mitogen-activated protein kinase kinase blocked B[a]P-mediated induction of COX-2. Depletion of the intracellular antioxidant, glutathione, with buthionine sulfoximine significantly increased B[a]P-mediated induction of COX-2 while exposure to N-acetylcysteine, a precursor of glutathione, suppressed the induction of COX-2 by B[a]P. Several lines of evidence suggest that the induction of COX-2 by B[a]P is mediated, at least in part, by NF-kappaB. Treatment with B[a]P increased binding of NF-kappaB to DNA. Moreover, B[a]P-mediated stimulation of COX-2 promoter activity was blocked when a construct containing a mutagenized NF-kappaB site was used. Pharmacological inhibitors of NF-kappaB blocked the induction of COX-2 protein and the stimulation of COX-2 promoter activity by B[a]P. Taken together, these data are likely to be important for understanding the atherogenic effects of tobacco smoke.
    No preview · Article · Mar 2000 · Journal of Biological Chemistry
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    H Maruoka · S Kitaoka · N Tohnai · Y Inaki · T Hatae · T Tanabe
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    ABSTRACT: Isopoly(S-carboxymethyl-L-cysteine) derivatives of nucleic acid bases were prepared as antisense compounds. These compounds in vitro have been found to form stable complex with oligo-DNA or RNA. This paper deals with effect of antisense compounds in vivo. The target in this paper is the sequence of the PSD-95 protein linked with NMDA receptor. Excess passing of calcium ions through the loss of the signal pathway without PSD-95 proteins caused by antisense compound. The cells detailing with L-cysteine derivatives showed the lowest percentage of 19.1%. The data were compared with that of phosphotioate antisense compound.
    Preview · Article · Feb 2000 · Nucleic Acids Symposium Series
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    ABSTRACT: Treatment of normal human epidermal keratinocytes (NHEK) with interferon-gamma (IFN-gamma) causes a 9-fold increase in the level of cyclooxygenase-2 (COX-2) mRNA expression. Nuclear run-off assays indicate that this induction is at least partly due to increased transcription. Activation of the epidermal growth factor receptor (EGFR) signaling pathway due to the enhanced transforming growth factor alpha (TGFalpha) expression plays an important role in the induction of COX-2 by IFN-gamma. This is supported by the ability of TGFalpha to rapidly induce COX-2 and the inhibition of the IFN-gamma-mediated COX-2 mRNA induction by an EGFR antibody and EGFR-selective kinase inhibitors. Deletion and mutation analysis indicates the importance of the proximal cAMP-response element/ATF site in the transcriptional control of this gene by TGFalpha. The increase in COX-2 mRNA by TGFalpha requires activation of both the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) pathways. Inhibition of p38 MAPK decreases the stability of COX-2 mRNA, while inhibition of MAPK/ERK kinase (MEK) does not. These results suggest that the p38 MAPK signaling pathway controls COX-2 at the level of mRNA stability, while the ERK signaling pathway regulates COX-2 at the level of transcription. In contrast to NHEK, IFN-gamma and TGFalpha are not very effective in inducing TGFalpha or COX-2 expression in several squamous carcinoma cell lines, indicating alterations in both IFN-gamma and TGFalpha response pathways.
    No preview · Article · Nov 1999 · Journal of Biological Chemistry
  • M Shimonishi · T Tanabe

    No preview · Article · Jul 1999 · Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme
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    ABSTRACT: We investigated the mechanisms by which caffeic acid phenethyl ester (CAPE), a phenolic antioxidant, inhibited the stimulation of prostaglandin (PG) synthesis in cultured human oral epithelial cells and in an animal model of acute inflammation. Treatment of cells with CAPE (2.5 microg/ml) suppressed phorbol ester (12-O-tetradecanoylphorbol-13-acetate; TPA) and calcium ionophore (A23187)-mediated induction of PGE2 synthesis. This relatively low concentration of CAPE did not affect amounts of cyclooxygenase (COX) enzymes. CAPE nonselectively inhibited the activities of baculovirus-expressed hCOX-1 and hCOX-2 enzymes. TPA- and A23187-stimulated release of arachidonic acid from membrane phospholipids was also suppressed by CAPE (4-8 microg/ml). Higher concentrations of CAPE (10-20 microg/ml) suppressed the induction of COX-2 mRNA and protein mediated by TPA. Transient transfections using human COX-2 promoter deletion constructs were performed; the effects of TPA and CAPE were localized to a 124-bp region of the COX-2 promoter. In the rat carrageenan air pouch model of inflammation, CAPE (10-100 mg/kg) caused dose-dependent suppression of PG synthesis. Amounts of COX-2 in the pouch were markedly suppressed by 100 mg/kg CAPE but were unaffected by indomethacin. These data are important for understanding the anticancer and anti-inflammatory properties of CAPE.
    Full-text · Article · Jun 1999 · Cancer Research
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    ABSTRACT: A disordered proliferative process in the vascular wall is thought to underlie the pathogenesis of restenosis after percutaneous transluminal angioplasty and carotid endarterectomy. A growth inhibitory property of overexpressed prostacyclin (PGI2) synthase (PGIS) was recently implicated in the pathological proliferation of vascular smooth muscle cells (VSMC) in vitro. Here, we investigated the effects of increased PGI2 synthesis on the pathological proliferation of VSMCs. The cDNA encoding human PGIS was transfected into endothelium-denuded rat carotid arteries after arterial balloon injury with the use of hemagglutinating virus Japan (HVJ). HVJ liposome vector complex without PGIS cDNA was used for vehicle control. The level of 6-keto PGF1alpha, a stable hydrolyzed metabolite of PGI2, the histological distribution of the immunoreactivity for human PGIS and the ratio of neointimal/medial area were analyzed. In the analyses of 6-keto PGF1alpha, the level in the carotid arteries was significantly elevated 3 days after PGIS expression-vector transfection compared with that in the arteries after vehicle transfection. Seven days after human PGIS expression-vector transfection, the PGIS cDNA-transfected neointimal cells were strongly positive for human PGIS immunoreactivity in 81% sections examined. Fourteen days after the injury, the ratio of neointimal/medial area was 1.2+/-0.4 in the PGIS expression-vector transfected group, which was significantly smaller than that of the vehicle control group, 1.7+/-0.5; P<0.01. It was thus demonstrated that the gene transfer of human PGIS expression-vector into rat carotid arteries resulted in the increased production of human PGI2 in the vascular wall, the expression of human PGIS in the developing neointima and significantly inhibited the neointimal formation generated after balloon injury.
    Full-text · Article · Mar 1999 · Stroke
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    S Kitaoka · N Tohnai · Y Inaki · T Hatae · T Tanabe
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    ABSTRACT: Isopoly(S-carboxymethyl-L-cysteine) derivatives of nucleic acid bases were found to form stable complex with oligo-DNA in vitro. Fluorescent probed isopoly(S-carboxymethyl cysteine) derivatives of nucleic acid bases were prepared as antisense oligomers. The transfection of the oligomer into cells was carried out by HVJ-liposome method. Fluorescence was observed from the cells treated with HVJ-liposome including fluorescent probed oligomers.
    Preview · Article · Feb 1999 · Nucleic Acids Symposium Series
  • S Takahashi · J.-I. Shigeta · H Inoue · T Tanabe · S Okabe
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    ABSTRACT: It has been reported that cyclooxygenase-2 (COX-2) may play a crucial role in gastric ulcer healing. We examined the localization of COX-2 and the regulation of COX-2 mRNA expression in acetic acid ulcers in rats. PGE2 production was elevated in ulcerated tissue but not in intact tissue. COX-2 mRNA expression was induced in only the ulcerated tissue, and COX-2 protein was found in fibroblasts, monocytes/macrophages, and granulocytes. A selective COX-2 inhibitor inhibited increased PGE2 production by the ulcerated tissue. Interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta1 (TGF-beta1) mRNAs were also expressed only in the ulcerated tissue. In a culture of isolated ulcer base, blockade of IL-1beta and TNF-alpha reduced COX-2 mRNA expression and PGE2 production. In contrast, COX-2 mRNA expression and PGE2 production were promoted by prevention of TGF-beta1 action. These results indicate that COX-2 protein is highly localized in the base of gastric ulcers in rats and that COX-2 mRNA expression might be regulated positively by IL-1beta and TNF-alpha and negatively by TGF-beta1.
    No preview · Article · Dec 1998 · The American journal of physiology
  • T Tanabe · T Sakai · W D Mi · A Matsuki
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    ABSTRACT: A 28-year old female schizophrenic patient underwent electroconvulsive therapy (ECT) under propofol anesthesia. She received ECT five times, and Bispectral Index (BIS) was recorded four times out of the five ECT. BIS values (mean +/- SD) were 95.3 +/- 1.3 before anesthesia, 38.0 +/- 13.1 after loss of consciousness, 45.3 +/- 12.7 immediately after ECT and 27.3 +/- 11.6 about two minutes after ECT. In conclusion, ECT may decrease BIS during continuous propofol infusion.
    No preview · Article · Oct 1998 · Masui. The Japanese journal of anesthesiology
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    J Nakai · T Tanabe · T Konno · B Adams · K G Beam
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    ABSTRACT: Skeletal and cardiac muscles express distinct isoforms of the dihydropyridine receptor (DHPR), a type of voltage-gated Ca2+ channel that is important for excitation-contraction (EC) coupling. However, entry of Ca2+ through the channel is not required for skeletal muscle-type EC coupling. Previous work (Tanabe, T., Beam, K. G., Adams, B. A., Niidome, T., and Numa, S. (1990) Nature346, 567–569) revealed that the loop between repeats II and III (II-III loop) is an important determinant of skeletal-type EC coupling. In the present study we have further dissected the regions of the II-III loop critical for skeletal-type EC coupling by expression of cDNA constructs in dysgenic myotubes. Because Ser687 of the skeletal II-III loop has been reported to be rapidly phosphorylatedin vitro, we substituted this serine with alanine, the corresponding cardiac residue. This alanine-substituted skeletal DHPR retained the ability to mediate skeletal-type EC coupling. Weak skeletal-type EC coupling was produced by a chimeric DHPR, which was entirely cardiac except for a small amount of skeletal sequence (residues 725–742) in the II-III loop. Skeletal-type coupling was stronger when both residues 725–742 and adjacent residues were skeletal (e.g. a chimera containing skeletal residues 711–765). However, residues 725–742 appeared to be critical because skeletal-type coupling was not produced either by a chimera with skeletal residues 711–732 or by one with skeletal residues 734–765.
    Preview · Article · Oct 1998 · Journal of Biological Chemistry
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    ABSTRACT: We determined whether resveratrol, a phenolic antioxidant found in grapes and other food products, inhibited phorbol ester (PMA)-mediated induction of COX-2 in human mammary and oral epithelial cells. Treatment of cells with PMA induces COX-2 and causes a marked increase in the production of prostaglandin E2. These effects were inhibited by resveratrol. Resveratrol suppressed PMA-mediated increases in COX-2 mRNA and protein. Nuclear run-offs revealed increased rates of COX-2transcription after treatment with PMA, an effect that was inhibited by resveratrol. PMA caused about a 6-fold increase in COX-2promoter activity, which was suppressed by resveratrol. Transient transfections utilizing COX-2 promoter deletion constructs and COX-2 promoter constructs, in which specific enhancer elements were mutagenized, indicated that the effects of PMA and resveratrol were mediated via a cyclic AMP response element. Resveratrol inhibited PMA-mediated activation of protein kinase C. Overexpressing protein kinase C-α, ERK1, and c-Jun led to 4.7-, 5.1-, and 4-fold increases in COX-2 promoter activity, respectively. These effects also were inhibited by resveratrol. Resveratrol blocked PMA-dependent activation of AP-1-mediated gene expression. In addition to the above effects on gene expression, we found that resveratrol also directly inhibited the activity of COX-2. These data are likely to be important for understanding the anti-cancer and anti-inflammatory properties of resveratrol.
    Preview · Article · Sep 1998 · Journal of Biological Chemistry
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    ABSTRACT: Cyclooxygenase-2 (Cox-2), the inducible form of cyclooxygenase, is up-regulated in tumors and transformed cells. Because this enzyme catalyzes the formation of prostaglandins from arachidonic acid, chemopreventive strategies that suppress its expression could be useful for preventing cancer. We investigated whether retinoids suppressed basal expression of Cox-2 or EGF-mediated induction of Cox-2 in human oral squamous carcinoma cells. Treatment with retinoids [all-trans-retinoic acid (all-trans-RA), 9-cis-RA, 13-cis-RA, and retinyl acetate] suppressed both basal levels of Cox-2 and EGF-mediated induction of Cox-2 protein and synthesis of prostaglandin E2. Retinoids also suppressed the induction of Cox-2 mRNA by EGF. Transient transfection experiments showed that EGF caused about a 100% increase in Cox-2 promoter activity, an effect that was suppressed by retinoids. Levels of epidermal growth factor receptor were unaffected by retinoids. Epidermal growth factor caused a nearly 10-fold increase in mitogen-activated protein kinase activity; this effect was not blocked by retinoids.
    Full-text · Article · Aug 1997 · Cancer Research
  • T Tanabe · M Ebina · H Ishihara · A Matsuki · S Oshima · S Fukushi
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    ABSTRACT: This study investigated the effect of preanesthetic meals on the volume and pH of gastric contents in forty elective surgical patients ranging in ages from 20 to 60 years. Twenty patients who were given either isotonic beverage 250 ml or apple juice 250 ml on the morning of the operative day were subjected as control group and twenty patients of the breakfast group took two slices of bread with the above drink. About seven hours following drinking and feeding, the mean values of gastric volume were 20.9 +/- 18.3 ml in the control group and 19.2 +/- 16.3 ml in the breakfast group. The mean values of gastric pH were 4.3 +/- 2.3 in the drink group and 4.6 +/- 2.3 in the breakfast group. There were no significant differences in the gastric volume and pH between the two groups. However, very small amount of the bread was detected in the gastric fluid of three patients in the breakfast group. As preanesthetic drinking and feeding are advantageous for reducing the anxieties of preoperative patients and also for their nutrition during operation, it is encouraging that eating two slices of bread did not induce a significant effect of gastric volume or pH. The minute fragment of bread seems to have no clinically significant effect.
    No preview · Article · Jul 1997 · Masui. The Japanese journal of anesthesiology

Publication Stats

14k Citations
1,008.42 Total Impact Points


  • 1999-2001
    • Osaka City University
      • Faculty of Engineering
      Ōsaka-shi, Osaka-fu, Japan
  • 1998-2000
    • Tokyo Medical and Dental University
      • • Department of Pharmacology and Neurobiology
      • • Department of Pharmacology
      Edo, Tōkyō, Japan
  • 1995-1997
    • Kyushu University
      • Division of Internal Medicine
      Hukuoka, Fukuoka, Japan
  • 1993-1997
    • National Cerebral and Cardiovascular Center
      • Department of Cardiovascular Medicine
      Ōsaka, Ōsaka, Japan
  • 1996
    • Hachinohe City Hospital
      八戸, Aomori, Japan
  • 1994-1995
    • Yale University
      • Department of Cellular and Molecular Physiology
      New Haven, Connecticut, United States
    • Stanford University
      • Department of Molecular and Cellular Physiology
      Palo Alto, California, United States
  • 1984-1995
    • Osaka University
      • Institute for Protein Research
      Suika, Ōsaka, Japan
  • 1992-1994
    • Colorado State University
      • • Department of Anatomy and Neurobiology
      • • College of Veterinary Medicine and Biomedical Sciences
      Fort Collins, Colorado, United States
  • 1984-1989
    • Kyoto University
      • Department of Medical Chemistry
      Kioto, Kyōto, Japan
  • 1983
    • Keio University
      Edo, Tōkyō, Japan