Taku Murata

Mie University, Tu, Mie, Japan

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Publications (35)78.28 Total impact

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    ABSTRACT: By catalyzing hydrolysis of cAMP and cGMP, cyclic nucleotide phosphodiesterases are critical regulators of their intracellular concentrations and their biological effects. Since these intracellular second messengers control many cellular homeostatic processes, dysregulation of their signals and signaling pathways initiate or modulate pathophysiological pathways related to various disease states, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication, chronic obstructive pulmonary disease, and psoriasis. Alterations in expression of PDEs and PDE-gene mutations (especially mutations in PDE6, PDE8B, PDE11A and PDE4) have been implicated in various diseases and cancer pathologies. PDEs also play important role in formation and function of multi-molecular signaling/regulatory complexes called signalosomes. At specific intracellular locations, individual PDEs, together with pathway-specific signaling molecules, regulators, and effectors, are incorporated into specific signalosomes, where they facilitate and regulate compartmentalization of cyclic nucleotide signaling pathways and specific cellular functions. Currently, only a limited number of PDE inhibitors (PDE3, PDE4, PDE5 inhibitors) are used in clinical practice. Future paths to novel drug discovery include the crystal structure-based design approach, which has resulted in generation of more effective family-selective inhibitors, as well as burgeoning development of strategies to alter compartmentalized cyclic nucleotide signaling pathways by selectively targeting individual PDEs and their signalosome partners.This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2014 · Oral Diseases
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    ABSTRACT: Cyclic nucleotide phosphodiesterases (PDEs) regulate the intracellular concentrations and effects of adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP). The role of PDEs in malignant tumor cells is still uncertain. The role of PDEs, especially PDE2, in human malignant melanoma PMP cell line was examined in this study. In PMP cells, 8-bromo-cAMP, a cAMP analog, inhibited cell growth and invasion. However, 8-bromo-cGMP, a cGMP analog, had little or no effect. PDE2 and PDE4, but not PDE3, were expressed in PMP cells. Growth and invasion of PMP cells were inhibited by erythro-9-(2-Hydroxy-3-nonyl) adenine (EHNA), a specific PDE2 inhibitor, but not by rolipram, a specific PDE4 inhibitor. Moreover, cell growth and invasion were inhibited by transfection of small interfering RNAs (siRNAs) specific for PDE2A and a catalytically-dead mutant of PDE2A. After treating cells with EHNA or rolipram, intracellular cAMP concentrations were increased. Growth and invasion were stimulated by PKA14-22, a PKA inhibitor, and inhibited by N(6)-benzoyl-c AMP, a PKA specific cAMP analogue, whereas 8-(4-chlorophenylthio)-2'-O-methyl-cAMP, an Epac specific cAMP analogue, did not. Invasion, but not growth, was stimulated by A-kinase anchor protein (AKAP) St-Ht31 inhibitory peptide. Based on these results, PDE2 appears to play an important role in growth and invasion of the human malignant melanoma PMP cell line. Selectively suppressing PDE2 might possibly inhibit growth and invasion of other malignant tumor cell lines.
    No preview · Article · Apr 2014 · Cellular Signalling
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    ABSTRACT: The prognosis for malignant melanoma is poor; therefore, new diagnostic methods and treatment strategies are urgently needed. Phosphodiesterase 2 (PDE2) is one of 21 phosphodiesterases, which are divided into 11 families (PDE1-PDE11). PDE2 hydrolyzes cyclic AMP (cAMP) and cyclic GMP (cGMP), and its binding to cGMP enhances the hydrolysis of cAMP. We previously reported the expression of PDE1, PDE3 and PDE5 in human malignant melanoma cells. However, the expression of PDE2 in these cells has not been investigated. Herein, we examined the expression of PDE2A and its role in human oral malignant melanoma PMP cells. Sequencing of RT-PCR products revealed that PDE2A2 was the only variant expressed in PMP cells. Four point mutations were detected; one missense mutation at nucleotide position 734 (from C to T) resulted in the substitution of threonine with isoleucine at amino acid position 214. The other three were silent mutations. An in vitro migration assay and a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay revealed that suppressing PDE2 activity with its specific inhibitor, erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA), had no impact on cell motility or apoptosis. Furthermore, the cytotoxicity of EHNA, assessed using a trypan blue exclusion assay, was negligible. On the other hand, assessment of cell proliferation by BrdU incorporation and cell cycle analysis by flow cytometry revealed that EHNA treatment inhibited DNA synthesis and increased the percentage of G2/M-arrested cells. Furthermore, cyclin A mRNA expression was downregulated, while cyclin E mRNA expression was upregulated in EHNA-treated cells. Our results demonstrated that the PDE2A2 variant carrying point mutations is expressed in PMP cells and may affect cell cycle progression by modulating cyclin A expression. Thus, PDE2A2 is a possible new molecular target for the treatment of malignant melanoma.
    Full-text · Article · Jan 2013 · Oncology Reports
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    ABSTRACT: Phosphodiesterases (PDEs) are important regulators of signal transduction processes. Eleven PDE gene families (PDE1-11) have been identified and several PDE isoforms are selectively expressed in various cell types. PDE4 family members specifically hydrolyze cyclic AMP (cAMP). Four genes (PDE4A-D) are known to encode PDE4 enzymes, with additional diversity generated by the use of alternative mRNA splicing and the use of different promoters. While PDE4 selective inhibitors show therapeutic potential for treating major diseases such as asthma and chronic obstructive pulmonary disease, little is known concerning the role of PDE4 in malignant melanoma. In this study, we examined the role of PDE4 in mouse B16-F10 melanoma cells. In these cells, PDE4 activity was found to be ∼60% of total PDE activity. RT-PCR detected only PDE4B and PDE4D mRNA. Cell growth was inhibited by the cAMP analog, 8-bromo-cAMP, but not by the specific PDE4 inhibitors, rolipram and denbufylline, which increased intracellular cAMP concentrations. Finally, migration of the B16-F10 cells was inhibited by the PDE4 inhibitors and 8-bromo-cAMP, while migration was increased by a protein kinase A (PKA) inhibitor, PKI(14-22), and was not affected by 8-pCPT-2'-O-Me-cAMP, which is an analog of exchange protein activated by cAMP (Epac). The inhibitory effect of rolipram on migration was reversed by PKI(14-22). Based on these results, PDE4 appears to play an important role in the migration of B16-F10 cells, and therefore may be a novel target for the treatment of malignant melanoma.
    No preview · Article · Aug 2012 · Experimental and therapeutic medicine
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    ABSTRACT: Eleven phosphodiesterase (PDE) gene families (PDE1-11) have been identified, and some PDE isoforms are selectively expressed in various cell types. Previously, we reported PDE1, PDE3 and PDE4 expressions in human malignant melanoma cells. However, the expression and role of PDE5 in malignant melanoma cells is not clear. Therefore, we characterized PDE5 in human malignant melanoma MAA cells. PDE5 activity and PDE5A mRNA expression were investigated in MAA cells. The full open reading frames for human PDE5A1 were sequenced. Effects of PDE5 inhibitors on cell growth were determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assays. PDE5 activity and PDE5A1 mRNA expression were detected in MAA cells. The nucleotide sequence of PDE5A1 was identical to that of human PDE5A1, previously published. Two PDE5 inhibitors inhibited the growth of cells. PDE5A1 mRNA is expressed and may play an important role in the growth of human malignant melanoma MAA cells.
    No preview · Article · Feb 2010 · Anticancer research
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    ABSTRACT: Cyclic adenosine 3'5'-monophosphate (cAMP) and cyclic guanosine 3'5'-monophosphate (cGMP) are critical intracellular messengers involved in transduction of signals generated by a wide variety of extracellular stimuli, including growth factors, cytokines, peptide hormones, light and neurotransmitters. These messengers modulate many fundamental biological processes, including myocardial contractility, platelet aggregation, vascular smooth muscle relaxation, proliferation and apoptosis, etc. Cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP, and are important in regulating intracellular concentrations and biological actions of these signal-transducing molecules. These enzymes contain at least 11 highly regulated and structurally related gene families (PDE1-11). In this review, we will discuss some general information of PDEs and then focus on PDE3 gene family, including the molecular biology, structure, function and potential as therapeutic targets. Furthermore, we show the possibilities of PDE3 as therapeutic targets in malignant tumor cells and salivary gland.
    No preview · Article · Aug 2009 · Cardiovascular & hematological agents in medicinal chemistry
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    ABSTRACT: Differentiation-inducing factor 1 [DIF-1; 1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) hexan-1-one] from Dictyostelium discoideum exhibits antiproliferative activity in mammalian cells. We have previously shown that phosphodiesterase 1 (PDE1) is a pharmacological target of DIF-1, but there are no reports of PDE1 in human malignant melanoma cells. Therefore, we characterized PDE1 in human malignant melanoma MAA cells. PDE1 mRNA expression was investigated in MAA cells. The full open reading frames for human PDE1C1 and PDE1C3 were cloned. Cell growth was determined by MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] assay. PDE1C mRNA expression was detected in MAA cells. The nucleotide sequence of PDE1C1 was identical to that of human PDE1C1, previously published. At nucleotide 2246 in PDE1C3, A was replaced by G, but this did not change the encoded amino acid. Cell growth was inhibited by the PDE1 inhibitor vinpocetin. PDE1C mRNA is expressed and may play an important role in human malignant melanoma MAA cells.
    No preview · Article · May 2009 · Anticancer research
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    ABSTRACT: Xeroderma pigmentosum is a rare, autosomal recessive genetic disease accompanied by abnormal DNA function due to damage by ultraviolet radiation. Xeroderma pigmentosum typically has general features of high light sensitivity and a high incidence of skin cancer in regions exposed to sunlight. We report the case of squamous cell carcinoma of the lower lip in an 82-year-old patient with xeroderma pigmentosum who was successfully treated with peplomycin after first receiving treatment for diabetes.
    No preview · Article · Dec 2007 · Asian Journal of Oral and Maxillofacial Surgery

  • No preview · Article · Jul 2007 · Journal of Oral and Maxillofacial Surgery
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    ABSTRACT: The activity, expression and function of phosphodiesterase 4 (PDE 4) were investigated in the HMG human gingiva-derived malignant melanoma cell line. A specific PDE4 inhibitor, rolipram, inhibited PDE activity in homogenates of HMG cells, and PDE4B and 4D mRNAs were detected by RT-PCR in RNA from HMG cells. Two specific PDE4 inhibitors, rolipram and Ro-20-1724, and an adenylate cyclase activator, forskolin, increased intracellular cAMP in HMG cells. Cell growth induced by rolipram, Ro-20-1724, and forskolin was inhibited by the H-89 protein kinase A (PKA) inhibitor. However, in contrast to effects of H-89, two other PKA inhibitors, KT5720 and PKI, did not inhibit rolipram-induced cell growth. A cAMP analogue that selectively activates Epac, 8-pCPT-2'-O-Me-cAMP, also promoted the growth of HMG cells. These findings suggested that PDE4, PDE4B and/or 4D regulate cell growth through cAMP targets in the HMG malignant melanoma cell line. There have been no previous studies of positive regulation of cell growth by PDE4 inhibition, suggesting that it may be possible to target PDE4 in therapy for human malignant melanoma.
    Preview · Article · May 2007 · Oncology Reports
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    ABSTRACT: Aim: Acromegaly is caused by excessive secretion of growth hormone (GH) usually associated with a pituitary adenoma. Acromegaly is associated with several oral complications. There are few reports of gingivitis in patients with acromegaly. This paper describes a case of intractable gingivitis in acromegaly. Materials and Methods: A 48-year-old Japanese woman was referred to our department in June 1998 complaining of gingival bleeding. The clinical diagnosis of marginal periodontitis was made. Extraction of loose teeth and scaling were performed and the patient was given brushing instructions. The gingiva of same region, however, swelled repeatedly. The patient visited the department of internal medicine for treatment of hypertension. The blood level of GH was high and a pituitary adenoma was discovered. The patient was diagnosed with a GH-producing pituitary adenoma-associated acromegaly. Administration of bromocriptine mesilate (Parlodel), a GH secretion inhibitor, was initiated. Results and Conclusions: Gingival swelling rapidly diminished and the gingival pocket was reduced. It is suggested that abnormal GH secretion should be included as a cause of intractable gingivitis.
    No preview · Article · Dec 2006 · The Endocrinologist
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    ABSTRACT: Phosphodiesterase (PDE) 3 has been characterized in isolated rat submandibular acini. PDE3 activity was detected in homogenates of isolated rat submandibular acini; little or no PDE3 activity was found in ducts. About 62% of PDE3 activity in the acini was recovered in the supernatant fractions; 38% in particulate fractions. In the acini, but not ducts, PDE3A mRNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR). The PDE3-specific inhibitor, cilostamide, increased the ratio of apomucin mRNA/18s rRNA, as quantified by real-time RT-PCR. Our results indicate that PDE3A may be important in regulating cAMP pools that control acini functions.
    No preview · Article · Mar 2006 · Archives of Oral Biology
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    Preview · Article · Jan 2005 · Journal of Hard Tissue Biology
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    ABSTRACT: We have been subculturing a human mandible-derived osteosarcoma cell line (HOSM-2) for approximately 15 years, and have compared the characters of early generations, which did not exhibit tumorigenicity, to those in the later generations. The shape and doubling time of the cells did not change during long-term culture. The number of chromosomes, however, changed from 59-81 in the 6th generation (modal number: 70) to 54-59 (modal number: 56 and 57), and the chromosomal structure also changed. In addition, the cell line in the later generations showed tumorigenicity in nude mice, and Codon 306 of the p53 gene was mutated to a stop codon due to a point mutation. HOSM-2 cells expressed osteoblast markers, thus confirming them to be osteoblastic osteosarcoma cells. These results showed that changes in certain genes in the HOSM-2 cells led to tumorigenicity in nude mice following long-term culture. In addition, as a mandible-derived cell line with characteristics different from those of limb-derived osteosarcoma cell lines, HOSM-2 cells may be a valuable model for mandibular osteosarcoma and osteoblasts.
    No preview · Article · Sep 2004 · Oral Oncology
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    ABSTRACT: The differentiation-inducing factor-1 (DIF-1) isolated from Dictyostelium discoideum is a potent antiproliferative agent that induces growth arrest and differentiation in mammalian cells in vitro. However, the specific target molecule(s) of DIF-1 has not been identified. In this study, we have tried to identify the target molecule(s) of DIF-1 in mammalian cells, examining the effects of DIF-1 and its analogs on the activity of some candidate enzymes. DIF-1 at 10-40 micro M dose-dependently suppressed cell growth and increased the intracellular cyclic AMP concentration in K562 leukemia cells. It was then found that DIF-1 at 0.5-20 micro M inhibited the calmodulin (CaM)-dependent cyclic nucleotide phosphodiesterase (PDE1) in vitro in a dose-dependent manner. Kinetic analysis revealed that DIF-1 acted as a competitive inhibitor of PDE1 versus the substrate cyclic AMP. Because DIF-1 did not significantly affect the activity of other PDEs or CaM-dependent enzymes and, in addition, an isomer of DIF-1 was a less potent inhibitor, we have concluded that PDE1 is a pharmacological and specific target of DIF-1.
    Full-text · Article · Apr 2004 · Cancer Research
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    ABSTRACT: The objective of this study was to assess the clinical significance of synovial proliferation in patients with painful temporomandibular disorders based on magnetic resonance imaging findings. The current study was conducted in 100 joints of 100 patients with unilateral painful temporomandibular disorders. One hundred joints on the contralateral side of patients with unilateral disease were used as nonpain group. Areas in the articular space that showed a low signal intensity on T1-weighted imaging, a high signal intensity on T2-weighted imaging, and high signal intensity on gadolinium-enhanced fat-suppressed T1-weighted imaging were judged to be regions of synovial proliferation. Synovial proliferation alone was observed in 8.0% of the pain group, but in none of the nonpain group. Synovial proliferation + effusion was observed in 33.0% of the pain group and in 7.0% of the nonpain group. Effusion alone was observed in 7.0% of the pain group and in 3.0% of the nonpain group. The mean visual analog scale value of pain was in the order of synovial proliferation alone > synovial proliferation + effusion > effusion alone. The incidence rates of anterior displacement of the disk were 100% for synovial proliferation alone, 93.9% for synovial proliferation + effusion, 57.1% for effusion alone, and 57.7% for "without synovial proliferation/effusion." Strong correlations were observed between synovial proliferation, pain, and disk displacement. It is considered that evaluating effusion alone provides only limited information on the disease state in painful temporomandibular disorders. Thus, it is essential to include enhanced T1-weighted imaging as a means to judge the disease state as well as to assess disease progression.
    No preview · Article · Jan 2004 · Journal of Computer Assisted Tomography
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    ABSTRACT: Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that HOSM-1 cells, an osteosarcoma cell line established from human mandible, expressed mRNA for osteoblastic markers, such as alkaline phosphatase, osteonectin, osteocalcin and parathyroid hormone receptor, thus exhibiting an osteoblastic phenotype. We have investigated a possible role of cyclic nucleotide phosphodiesterases (PDEs) in osteosarcoma cells. RT-PCR analysis revealed that HOSM-1 cells expressed mRNA for PDE4A, 4B and 4C. In addition, rolipram, a specific inhibitor of PDE4, inhibited HOSM-1 cell proliferation. The finding that PDE4 is involved in proliferation of osteosarcoma cells suggests the possibility that PDE4 may be a new target for antitumor therapy.
    No preview · Article · Jul 2003 · Anti-Cancer Drugs
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    ABSTRACT: This is a report of a 45-year-old woman in whom ameloblastoma recurred in the soft tissues 14 years after resection of the mandible. From the age of 14 years she had received conservative treatmentfor the recurrence of multiple intraosseous tumours.
    No preview · Article · Mar 2003 · Asian Journal of Oral and Maxillofacial Surgery
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    ABSTRACT: We have evaluated effects of a phosphodiesterase (PDE) 4 inhibitor on retinoic acid-increased alkaline phosphatase activity in the mouse fibroblastic C3H10T1/2 clone 8 (10T1/2) cell line. 10T1/2 cells were cultured in minimum essential medium (MEM) and 10% fetal bovine serum with or without 1 microM retinoic acid and/or the PDE 4 inhibitor, rolipram, and harvested at specific intervals before measurement of alkaline phosphatase activity, cAMP production in response to parathyroid hormone, osteocalcin synthesis and expression, and phosphodiesterase activity. Retinoic acid-increased alkaline phosphatase activity, and slightly enhanced cAMP production in response to parathyroid hormone. However, it did not affect osteocalcin synthesis and expression. In the presence of retinoic acid, PDE 4 activity was not changed. A PDE 4 inhibitor, rolipram, and cAMP analog, 8-bromo-cAMP dramatically increased retinoic acid's ability to induce alkaline phosphatase activity. This is the first report that PDE 4 may be involved in regulation of retinoic acid-increased alkaline phosphatase activity.
    No preview · Article · Feb 2003 · Archives of Oral Biology
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    ABSTRACT: Little is known concerning the expression, distribution and function of phosphodiesterase (PDE) 3s in malignant tumor cells, including human malignant melanoma HMG and osteosarcoma HOSM-1 cells. PDE3 activity was detected in homogenates of HMG cells; however, much less activity was found in HOSM-1 cells. In HMG cells, most of the PDE3 activity was in the particulate fraction. PDE3A and 3B mRNAs were detected by RT-PCR in RNA from HMG cells only. The nucleotide sequences of the fragments were identical to those of human PDE3A and 3B. The PDE3-specific inhibitors, trequinsin and cilostamide, did not inhibit the proliferation of HMG or HOSM-1 cells. Although two PDE3 isoforms may be expressed in human malignant melanoma cells, their functional importance is not known.
    No preview · Article · Nov 2002 · Anticancer research