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Volume 118 (2001)
- Issue 6 Pages 363-
- Issue 5 Pages 303-
- Issue 4 Pages 251-
- Issue 3 Pages 147-
- Issue 2 Pages 81-
- Issue 1 Pages 5-
Volume 118, Issue 3
Displaying 1-10 of 10 articles from this issue
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Reviews: Towards Understanding Mechanisms of Drug Action and Functions of the Body on Molecular Level
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Iwao OHTSUKISubject area: Others
2001 Volume 118 Issue 3 Pages 147-158
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSContraction of skeletal and cardiac muscles is regulated by Ca2+ through a specific Ca2+-receptive protein, troponin, regularly distributed along the thin filaments. This protein consists of three different subunits, troponins C, I and T. In this article, studies on the structural and biochemical aspects of the molecular mechanisms of Ca2+-regulation were first reviewed with particular reference to the regulatory role of troponin T. Several properties of the isoforms of troponin from fast and slow skeletal and cardiac muscles were discussed, based on the findings obtained by the use of troponin-exchange techniques under physiological conditions. Recent findings on the functional consequence of mutations in human cardiac troponins T and I found in familial hypertrophic cardiomyopathy were also presented. The results clarified the increase in Ca2+-sensitivity of contraction to be the critical consequence due to this genetic disorder.View full abstractDownload PDF (2078K) -
Takehiko WATANABESubject area: Others
2001 Volume 118 Issue 3 Pages 159-169
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSI have been studying the functions of the histaminergic neuron system in the brain, the location and distribution of which we elucidated with antibody raised against L-histidine decarboxylase (a histamineforming enzyme) as a marker in 1984. For this purpose, we used two methods employing (1) pharmacological agents like α-fluoromethylhistidine, an HDC inhibitor, and agonists and antagonists of H1, H2 and H3 receptors and (2) knockout mice of the HDC- and H1- and H2-receptor genes. In some cases, we used positron emission tomography (PET) of H1 receptors in living human brains. It turned out that histamine neurons are involved in many brain functions, and particularly, histamine is one of the neuron systems to keep awakefulness. Histamine also plays important roles in bioprotection against various noxious or unfavorable stimuli (convulsion, nociception, drug sensitization, ischemic lesions, stress and so on). Finally, I briefly described interesting phenotypes found in peripheral tissues of HDC-KO mice; the most striking finding is that mast cells in HDC-KO mice are fewer in number, smaller in size and less dense in granule density than those of wild type mice, indicating that histamine is related to the proliferation and differentiation of mast cells. In conclusion, histamine is important not only in the central and peripheral systems as studied so far but also may be related to some new functions that are now under investigation in our laboratories.View full abstractDownload PDF (1873K) -
Koichi ISHIKAWA, Gozoh TSUJIMOTOSubject area: Others
2001 Volume 118 Issue 3 Pages 170-176
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSReal advances in biotechnology made it possible to complete human whole genome sequencing within a short duration. Although the genome includes a huge amount of information about biological functions and the interest is now directed to the study using genomic information, the genomic strategy is not clearly understood. The following 4 studies were therefore presented and discussed about the strategy after the completion of the genomic sequence in the 74th Annual Meeting of Japanese Pharmacological Society: 1) Asthma and atopic dermatitis: models for genetic and genomic investigations of complex genetic diseases, by W.C.O. Cookson (University of Oxford, Asthma Genetics Group, Wellcome Trust Centre for Human Genetics); 2) Molecular classification by global gene expression profiling: application on oncogenomic research, by H. Aburatani (Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo); 3) Functional genomic search of disease-related genes using microarrays with normalized rat cDNA library, by G. Tsujimoto, et al. (Department of Molecular, Cell Pharmacology, National Children’s Medical Research Center: and 4) Acute ischemic change of mRNA expression in the hippocampus by GeneChip array analysis: a starting point for post-genome strategy, by S. Asai, et al. (Department of Pharmacology, Nihon University School of Medicine).View full abstractDownload PDF (868K) -
Akikazu FUJITA, Tetsuro MATSUOKA, Kenji MATSUSHITA, Yoshihisa KURACHISubject area: Others
2001 Volume 118 Issue 3 Pages 177-186
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSThe ATP-sensitive K+ channels (KATP) are composed of Kir6.0 sbunits and sulfonylurea receptors (SUR1, 2A and 2B). SUR2A and SUR2B are splice variants and differ only in the C-terminal 42 amino acid residue (C42). SURs are supposed to be the subunit that determines the different response of KATPs to intracellular nucleotides, K+ channel openers and inhibitors. In this study, we report that C42 of SURs plays critical roles in differential activation of various KATPs by ADP and K+ channel openers such as diazoxide and nicorandil. KATPs containing distinct SURs and Kir6.2 were receonstructed on HEK293T cells. Much higher concentrations of ADP were necessary to activate channels which SUR1 or SUR2B. In all KATPs containing different SUR, diazoxide increased the potency of ADP for channel activity without affecting its efficacy. From the electrophysiological data obtained from C-terminal chimeras and point mutants in the second nucleotide binding domain (NBDs), we developed the homology model of each SUR-NBD2 based on the crystallgraphically determined structure of HisP, a member of the ABC protein superfamily. In this model, C42 is located just beneath the Walker A motif of NBD2 and regulates the binding of nucleotide to NBD2 by affecting the 3-D construct of NBD2. This homology model well explains the different response of KATPs to ADP. Based on this model, it will be possible to develop new ligands for KATPs.View full abstractDownload PDF (1429K) -
Hiroshi OZAKI, Yuji IMAIZUMI, Kazuhiko OISHI, Kazuhiro KOHAMASubject area: Others
2001 Volume 118 Issue 3 Pages 187-196
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSHigh Throughput Screening (HTS) now plays an important role in the discovery of new lead compounds for novel therapeutic targets. The advantage of HTS over the conventional method, now termed as Low Throughput Screening (LTS), is that valuable compounds can be selected rapidly from a large number of samples with minimal human involvement. In spite of the growing awareness of HTS, the importance of the LTS in the drug discovery and development is still not changed. Advances in pharmacogenomics will also provide us many pharmacological targets, and thus increase the number of compounds that should be assayed by HTS and LTS. In this review, we will first describe the outline of HTS. We will next describe new approaches to develop and brush up the LTS: 1) screening method of drugs acting on ion channels by voltage-sensitive fluorescent dye, 2) functional assay method using reconstituted smooth muscle fiber, and 3) organ culture method as a useful model of vascular proliferative disease. These approaches, which work cooperatively with HTS, will contribute greatrly to the development of new drugs.View full abstractDownload PDF (1879K) -
Keiichi HISHIKAWA, Toshio NAKAKISubject area: Others
2001 Volume 118 Issue 3 Pages 197-202
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSThe transcription factor NF-κB has attracted widespread interest based on its unusual regulation, the variety of stimuli that activate it, the diverse genes and biological responses that it controls, the striking evolutionary conservation of structure and function among family members, and its apparent involvement in a variety of human diseases. Recently NF-κB has been shown to be the target of new drug discovery. Here, we discuss the so-called NF-κB inhibitors and consider the development of new therapeutic agents.View full abstractDownload PDF (1074K)
Technical Note
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Tsutomu NISHIHARA, Jun-ichi NISHIKAWAArticle type: Others
Subject area: Others
2001 Volume 118 Issue 3 Pages 203-210
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSOne of the urgent tasks in understanding endocrine disruptors (EDs) is to compile a list of suspected substances among the huge number of chemicals by using the screening test method. An in vitro screening test is a more useful tool for primary selection of suspected EDs. We have developed an assay for EDs using the yeast two-hybrid system. The assay is based on the ligand-dependent interaction of two proteins, a hormone receptor and a coactivator, and the hormonal activity is detected by β-galactosidase activity. This assay is a very simple and inexpensive test method with high repeatability to detect the agonist, and it is applicable for the detection of antagonist and active compounds after metabolism. Accordingly, it has been used in more than 40 laboratories in Japan. To date, we have tested the estrogenic activity of more than 500 chemicals including natural substances, medicines, pesticides and industrial chemicals. Sixty-four compounds were evaluated as positive and most of these possessed a common structure: phenol with a hydrophobic moiety at the para-position without bulky groups at the ortho-position. These results are expected to facilitate further risk assessment of chemicals, especially EDs.View full abstractDownload PDF (1343K)
Review on New Drug
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Shigemi TAKEUCHI, Minoru MURAKAMIArticle type: Others
Subject area: Others
2001 Volume 118 Issue 3 Pages 211-218
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSLevofolinate and fluorouracil regimen (l-leucovorin and 5 fluorouracil regimen) is a biochemical modulation of 5 fluorouracil (5FU) by leucovorin (LV). In the USA and Europe d,l-LV and 5FU regimen is frequently administered for colorectal cancer treatment and recognized as the standard regimen. In Japan, multi-institutional clinical trials of l-leucovorin (l-LV), a bioactive diastereomer of leucovorin, and 5FU combination were conducted for the treatment of advanced gastrointestinal cancer with comparable results to the US/Europe data. This l-LV and 5FU regimen was approved in August 1999 for the indications of advanced gastric cancer and colorectal cancer. The dosage and administration is referred to the weekly method developed at RPMI. Recently, the irinotecan (CPT-11) or oxariplatin plus LV and 5FU combination showed higher antitumor activities than the LV and 5FU combination with increased progression-free survival. These regimens, however, are not yet properly established because clinical trial results with Japanese patients are not completed for agreement of the dosage and administration schedule. For the l-LV and 5FU regimen diarrhea and leukocytopenia, including grade 3 and higher, were reported as the major adverse events. Administration for eligible patients with periodical monitoring of diagnostic data is necessary.View full abstractDownload PDF (587K)
Drug Development Now
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Hideo NAKAMURASubject area: Others
2001 Volume 118 Issue 3 Pages 219-230
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSAspirin was developed as a non-steroidal anti-inflammatory drug (NSAID) in 1899. During the century after that, aspirin has been found to show its anti-inflammatory, analgesic and anti-pyretic activities by reducing prostaglandins biosynthesis through inhibition of cyclooxygenase (COX); and then COX was found to be constituted of two isoforms, constitutive COX-1 and inducible COX-2. Currently, novel NSAIDs, acting through selective inhibition of COX-2, that have efficacy as excellent as excellent as aspirin with significantly lower incidence of gastrointestinal adverse effects are available in America and some other countries, but not in Japan. Physiological and pathophysiological roles of COX-1 and COX-2 have been explained from studies in experimental animals, but there are many differences in species and diseases between animals and humans. Thus, physiological and pathophysiological roles of COX-2 were considered from the standpoint of clinical effects of the two latest COX-2 selective inhibitors, celecoxib and rofecoxib, on inflammation, pain, fever and colorectal cancer together with their adverse effects on gastrointestinal, renal and platelet functions; and the usefulness and limits of COX-2-selective inhibitors were discussed with the trends of new NSAIDs development.View full abstractDownload PDF (1912K)
Original Article
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Kuniko HARA, Masatoshi KOBAYASHI, Yasuhiro AKIYAMASubject area: Others
2001 Volume 118 Issue 3 Pages 231-240
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSDifferent types of therapeutic agents for osteoporosis are often simultaneously prescribed for the same patient, but limited experimental findings indicate the significance of combined treatment. In the present study, the inhibitory effect of combined vitamin K2(K2) and 1α-(OH)-vitamin D3(D3) treatment on bone loss was compared to that of K2 or D3 alone in overiectomized rats. Female rats (20-week-old) were ovariectomized and divided into 4 groups as follows: they were treated for 8 weeks with vehicle, K2 (30 mg/kg), D3 (0.3 μg/kg) and K2 and D3 (K2+D3) at the respective doses. K2 was given as a dietary supplement and D3 was orally administered 3 times a week. Bone density of the femurs was measured by peripheral quantitative computed tomography. Ovariectomy resulted in decreased bone density in proximal metaphysis, especially in the trabecular region, and treatment with K2, D3 or K2+D3 inhibited this decrease. Moreover, in the K2+D3 group, bone density and mineral content in the trabecular region in proximal metaphysis and cortical bone width in diaphysis were significantly higher than those in the D3 group. Consistent with these observations, bone strength in the femoral midshaft tended to increase only in the K2+D3 group compared to that in the vehicle group. These findings indicate that combined K2 and D3 treatment is more effective for bone loss than that with K2 or D3 alone.View full abstractDownload PDF (979K)
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