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Volume 127, Issue 4
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Symposium Reviews
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Kazuo NITTAArticle type: Foreword
2007 Volume 127 Issue 4 Pages 551-552
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
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Kazuo NITTA, Tasuku KAWANO, Shigeki SUGAWARA, Masahiro HOSONOArticle type: Review
2007 Volume 127 Issue 4 Pages 553-561
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSSilurus asotus (catfish) egg lectin (SAL) has potent affinity to Gal α-linked carbohydrate chains of not only glycoproteins but also glycosphingolipids such as globotriaosylceramide (Gb3). SAL selectively bound to Gb3 localized in glycosphingolipid-enriched microdomain (GEM) of Gb3-expressing (Gb3+) Burkitt's lymphoma cells. Since treatment of Gb3+ cells with SAL caused an increase in externalization of phosphatidylserine via activation of P-glycoprotein, and apoptotic volume decrease via activation of G-protein activated K+ channel-1, SAL may function as an inducer of early apoptotic signal; however, neither caspase-8 and -3 activation nor DNA fragmentation was observed. We therefore investigated whether cell proliferation and viability were altered in SAL-treated Raji cells. SAL caused reduction of Raji cell proliferation without cytotoxicity. Although SAL did not induce apoptotic cell death to Gb3-expressing cells, it functionally behaved as a regulator of cell proliferation. SAL activated the suppression system of cell proliferation, such as down-regulation of c-myc and cdk4, and up-regulation of p21 and p27, inducing G1 arrest of the cell cycle, and consequently inhibited cell proliferation of Raji cells. Therefore, we conclude that SAL leads the cells to early apoptotic status but not late apoptotic (necrotic) status via binding to Gb3 existing in GEM, and that this binding is a prerequisite condition to induce cell cycle stop signal.
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Hideyoshi HIGASHIArticle type: Review
2007 Volume 127 Issue 4 Pages 563-570
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSGangliosides and proteoglycans with various sugar chains exist abundantly in the brain. They participate in intercellular recognition by revealing the sugar chains on the cell surface, and some of them show neurite-extension activity. Several recognition features that are mediated by the sugar chains are known such as saccharide-saccharide interaction and cell-surface sugar-chain receptor-mediated recognition. Experiments on animals lacking the sugar-chain synthetic system with the technique of gene targeting suggest that phylogenetically “old” sugar chains such as chondroitin sulfate appear necessary for early development of the organism while relatively “new” sugar chains such as gangliosides, which appear with further development of the brain, are necessary for differentiation maturity processes. On the other hand, research using primary cultured neurons showed similar effects of the gangliosides and chondroitin sulfate on cell differentiation. It is possible that these sugar chains share the glyco-receptor-mediated signal transduction system.
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Jianguo GUArticle type: Review
2007 Volume 127 Issue 4 Pages 571-578
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSIntegrins are cell surface transmembrane glycoproteins that function as adhesion receptors in cell-ECM interactions and link matrix proteins to the cytoskeleton. Integrins play an important role in cytoskeleton organization and in the transduction of intracellular signals, regulating various processes such as proliferation, differentiation, apoptosis, and cell migration. Although integrin-mediated adhesion is based on the binding of α and β subunits to a defined peptide sequence, the strength of this binding is modulated by various factors including the status of glycosylation of integrin. Glycosylation reactions are catalyzed by the catalytic action of glycosyltransferases, such as N-acetylglucosaminyltransferase III, V and α1,6 fucosyltransferase, etc., which catalyze the formation of glycosidic bonds. In this talk we will briefly overview the N-glycan structures of integrins, such as α3β1 and α5β1, and their related functions arising from recent studies, which provide insight into some long-standing questions concerning N-glycosylation functions.
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Jin-ichi INOKUCHIArticle type: Review
2007 Volume 127 Issue 4 Pages 579-586
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSMembrane microdomains (lipid rafts) are now recognized as critical for proper compartmentalization of insulin signaling, but their role in the pathogenesis of insulin resistance has not been investigated. Detergent-resistant membrane microdomains (DRMs), isolated in the low density fractions, are highly enriched in cholesterol, glycosphingolipids and various signaling molecules. TNFα induces insulin resistance in type 2 diabetes, but its mechanism of action is not fully understood. We have found a selective increase in the acidic glycosphingolipid ganglioside GM3 in 3T3-L1 adipocytes treated with TNFα, suggesting a specific function for GM3. We were able to extend these in vitro observations to living animals using obese Zucker fa/fa rats and ob/ob mice, in which the GM3 synthase mRNA levels in the white adipose tissues are significantly higher than in their lean controls. In the DRMs from TNFα-treated 3T3-L1 adipocytes, GM3 levels were doubled, compared to results in normal adipocytes. Additionally, insulin receptor (IR) accumulations in the DRMs were diminished, while caveolin and flotillin levels were unchanged. GM3 depletion was able to counteract the TNFα-induced inhibition of IR accumulation into DRMs. Together, these findings provide compelling evidence that in insulin resistance the insulin metabolic signaling defect can be attributed to a loss of IRs in the microdomains due to an accumulation of GM3.
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Akira YAMAMOTOArticle type: Foreword
2007 Volume 127 Issue 4 Pages 587
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
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Kazutaka HIGAKI2007 Volume 127 Issue 4 Pages 589-599
Published: 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSThe development of combinatorial chemistry and high-throughput screening techniques has made it possible to generate many new drug candidates very rapidly, but it has also resulted in a number of poorly soluble and/or poorly absorbable candidates. A new trend in drug development based on pharmacogenomics or the development of molecular-targeted drugs is also spurring the tendency, and it does not necessarily lead to good output in terms of the development of new drugs. It is attractive to improve membrane permeability as well as solubility by using adjuvants, because this method could be applicable for various drugs. However, the practical use of absorption-enhancing adjuvants has been limited because of the potential local toxicity. Therefore suppressing the potential local toxicity would lead to the successful development of safe preparations with improved absorption using adjuvants. Our biochemical and histopathologic studies showed that several amino acids such as taurine and L-glutamine had cytoprotective activity, and it has been found that the combinatorial use of sodium laurate (C12) with these amino acids could maintain the absorption-enhancing ability of C12. A suppository preparation containing C12 and taurine remarkably improved the rectal absorption of rebamipide, classified as BCS class IV, and the preparation was safe to the rectal mucosa. For the mechanisms of cytoprotective action by these amino acids, it has been found that they suppress the intracellular calcium level, induce the expression of heat-shock protein 70, and inhibit the release of histamine and apoptosis.
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Masuo KONDOH, Makiko FUJII, Kiyohito YAGI, Yoshiteru WATANABEArticle type: Review
2007 Volume 127 Issue 4 Pages 601-609
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSPassing of drugs across epithelial cell sheets and endothelial cell sheets is an obligatory step in the absorption of a drug. The passing routes of drugs are classified into transcellular and paracellular pathways. The transcellular route has been widely investigated and is used in clinical therapy. In contrast, drug delivery using the paracellular route has never been fully developed. Sodium caprate is the only absorption-enhancer of drugs that uses the paracellular route. Tight junctions (TJs) exist between adjacent cells in epithelial and endothelial cell sheets, and they play a role in sealing the cell sheets. Therefore, we must modulate the TJ barrier for drug delivery using paracellular route. In this review, we describe barriology, including very recent topics, and overview absorption-enhancers from the perspective of barriology.
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Teruko IMAIArticle type: Review
2007 Volume 127 Issue 4 Pages 611-619
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSProdrug is a useful approach for improving the bioavailability of therapeutic agents through increased passive transport. Carboxylesterases (CESs, EC.3.1.1.1.) that show ubiquitous expression profiles play an important role in the biotransformation of ester-containing prodrugs into their therapeutically active forms in the body. High levels of CESs are found in the liver, small intestine and lungs where prodrugs are firstly hydrolyzed before entering the systemic circulation. Rat intestine single-pass perfusion experiments have shown that CES is involved in the intestinal first-pass hydrolysis. Extensive pulmonary first-pass hydrolysis has been observed in accordance to the substrate specificity of CES1 isozyme. Hydrolysis in the human liver and lungs is mainly catalyzed by hCE1 (a human CES1 family isozyme), whereas that in the small intestine is predominantly mediated by hCE2 (a human CES2 family isozyme). hCE2 preferentially hydrolyzes substrates with a small acyl moiety such as CPT-11, due to conformational steric hindrance in its active site. In contrast, hCE1 is able to hydrolyze a variety of substrates due to spacious and flexible substrate binding region in its active site. In addition, hCE1 has been found to catalyze transesterification. Caco-2 cells mainly expresses CES1 isozyme but not CES2 isozyme. Because of the differences in substrate specificity between CES1 and CES2 enzymes, Caco-2 cell monolayer is not suitable for predicting intestinal absorption of prodrugs. These findings indicate that identification of substrate specificity of CES isozymes and development of an in vitro experimental method are essential to support rational design of prodrug.
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Akira YAMAMOTOArticle type: Review
2007 Volume 127 Issue 4 Pages 621-630
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSIn this study, we examined the effectiveness of chitosan capsules for the colon-specific delivery of prednisolone in rats. We also evaluated the effectiveness and side effects of prednisolone using chitosan capsules compared with the conventional dosage form (gelatin capsules). We found a significant increase in the concentration of prednisolone in the large intestinal mucosa when prednisolone was administered orally using chitosan capsules, as compared with the case using gelatin capsules. On the other hand, the plasma concentrations of prednisolone after oral administration using chitosan capsules were much lower than those in the case of gelatin capsules. We also assessed the effectiveness of prednisolone for the healing of trinitrobenzene sulfonic acid-induced colitis by measuring myeloperoxidase (MPO) activity and colon wet weight/body weight (C/B) ratio. MPO activities and C/B ratios were significantly reduced when prednisolone was administered orally using chitosan capsules, in comparison with the case of gelatin capsules. Moreover, the weight of the thymus, which is an index of the side effects of prednisolone, markedly decreased after oral administration of prednisolone using gelatin capsules, whereas its weight did not change as much when prednisolone was administered orally using chitosan capsules. These findings indicate that chitosan capsules might be useful for the colon-specific delivery of prednisolone and its enhanced effectiveness for the healing of colitis in rats. Moreover, chitosan capsules might be also effective in reducing the side effects of prednisolone due to its decreased intestinal transfer to the systemic circulation.
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Keigo YAMADAArticle type: Review
2007 Volume 127 Issue 4 Pages 631-641
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSIn general, drugs are well absorbed from the lung, and the pulmonary absorption of therapeutic protein and peptide drugs, which are poorly absorbed from the gastrointestinal tract, was observed. However, locally acting drugs including antiasthmatic agents, bronchodilators, and expectorants should be localized for a long period in the lung tissues. In this study, the effects of various viscous vehicles on the absorption of theophylline and fluticasone propionate after intrapulmonary administration were examined in rats. Carrageenans were effective in regulating the absorption rate of these drugs. On the other hand, the bioavailability of therapeutic protein and peptide drugs with relatively high molecular weights from the pulmonary route is still poor when compared with the parenteral route. Therefore we examined the effects of chitosan and chitosan oligomers on the pulmonary absorption of interferon-α and salmon calcitonin in rats. Chitosan oligomers were effective in improving the pulmonary absorption of these drugs, and chitosan hexamer appeared to be markedly more effective than other oligomers. Furthermore, the present study indicated that chitosan oligomers did not cause any membrane damage to rat pulmonary tissues. In conclusion, it is suggested that various pharmaceutical excipients achieved the sustained pulmonary absorption of locally acting drugs and the improved pulmonary bioavailability for therapeutic protein and peptide drugs.
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Hirokazu OKAMOTO, Kazumi DANJOArticle type: Review
2007 Volume 127 Issue 4 Pages 643-653
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSThe pulmonary route has recently attracted attention as a noninvasive administration route for peptide and protein drugs, and an insulin powder for inhalation was approved by authorities in Europe and the USA. The present study examined usefulness of insulin and gene powders for systemic and local inhalation therapy. We prepared several dry insulin powders by spray drying to examine the effect of additives on insulin absorption. Citric acid appears to be a safe and potent absorption enhancer for insulin in dry powder. However, in the powder with citric acid (MIC0.2 SD) insulin was unstable compared with the other powders examined. To improve insulin stability, a combination of insulin powder and citric acid powder was prepared (MIC Mix). MIC Mix showed hypoglycemic activity comparable to MIC0.2 SD while the insulin stability was much better than that of MIC SD. Next, dry insulin powders with mannitol were prepared with supercritical carbon dioxide (SCF); the powder thus prepared reduced blood glucose level rapidly and was more effective than that prepared by spray drying. Chitosan-pDNA complex powders as a pulmonary gene delivery system were also prepared with SCF and their in vivo activity was evaluated. The addition of chitosan suppressed the degradation of pCMV-Luc during preparation and increased the storage stability. The luciferase activity in mouse lung was evaluated after pulmonary administration of the powders. The chitosan-pDNA powder with an N/P ratio=5 increased the luciferase activity to 27 times that of the pCMV-Luc solution. These results suggest that gene powder with chitosan is a useful pulmonary gene delivery system.
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Naruhito HIGOArticle type: Review
2007 Volume 127 Issue 4 Pages 655-662
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSThe potential of transdermal drug delivery systems has been demonstrated in recent years with the approval of several medicines for use by patients who are unable to use conventional dosage routes, like oral administration or injection. To enhance the TDDS (Transdermal Drug Delivery System) potential to include other drug candidates, many researchers have been exploring enhancement approaches to increase the permeability of various drugs through the skin. Recently, physical enhancement systems are being reported as having big potential by many researchers. In particular, iontophoresis is a very attractive way of delivering ionized drugs by the application of an electric field to the skin. This has been marketed with some topical and systemic drugs (lidocaine and fentanyl). Sonophoresis is also an attractive method to deliver a drug through the skin using ultrasound. Besides these technologies, various physical approaches are under study. Such technologies can be expected to deliver not only small MW compounds but also macromolecules like peptides. In this article, after looking back through the history of TDDS development, I would like to summarize with new physical and chemical approaches and outline of the new trend of TDDS development with those enhancement system.
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Shinji KOIZUMIArticle type: Review
2007 Volume 127 Issue 4 Pages 663-664
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
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Nobuhiko MIURA, Shinji KOIZUMIArticle type: Review
2007 Volume 127 Issue 4 Pages 665-673
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSMetallothioneins (MTs) are proteins known to be involved in defense mechanisms against heavy metals and reactive oxygen species. In human, more than ten MT isoform genes have been identified, in contrast to much fewer isoforms in other mammalian species. The increased number of isoforms in human may have some biological significance; for example, isoforms may have been functionally differentiated to deal with various environmental factors in the evolutional process. However, we know little about the functions of the individual MT isoforms. To clarify functional differences between human MT isoforms, we developed a method to determine individual isoform mRNA levels using real-time polymerase chain reaction (PCR), and studied responses of the isoform genes against heavy metals (Zn, Cd, Cu) and As in HeLa cells. These metals induced all MT isoforms except for MT-1A by Cu, though their induced levels were different. Furthermore, these metals preferentially induced isoforms MT-2A and MT-1X suggesting that these isoforms may be important in protecting from their cytotoxicity.
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Fuminori OTSUKA, Shotaro OHNO, Kaoru SUZUKI, Kazuko TAKAHASHI, Motoyas ...Article type: Review
2007 Volume 127 Issue 4 Pages 675-684
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSTranscriptional activation of metallothionein (MT) genes by heavy metals is a valuable system for understanding the functions of MT as well as the cellular response against heavy metals. Although it is now known that heavy metal signals culminating in MT induction converge upon a transcription factor MTF-1, the mechanism underlying the MTF-1 response to heavy metals has not been elucidated. To address this issue, we investigated various aspects of the in vivo response of MTF-1 against heavy metals. Chromatin immunoprecipitation assay showed that heavy metal-dependent DNA binding of MTF-1 is the critical step in vivo. MTF-1 is primarily localized in the nucleus so that heavy metal-depend- ent nuclear translocation demonstrated by other groups does not seem to be universal and hence may not be critical for activation of MTF-1. In the six Zn finger motifs, the hallmark of MTF-1, the third and the fourth fingers are essential for the nuclear localization of MTF-1. Furthermore, all fingers except the last are important for transcriptional activation function of MTF-1, suggesting their key role for MTF-1 function. Also, a cysteine cluster structure located in the C-terminal region of MTF-1 is critical for transactivating function of MTF-1. These results suggest a central role of the Zn-finger domain and intramolecular cooperation through a structural change of MTF-1 for its response to heavy metal challenge.
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Cytokine-induced Metallothionein Expression and Modulation of Cytokine Expression by MetallothioneinNorio ITOH, Tomoki KIMURAArticle type: Review
2007 Volume 127 Issue 4 Pages 685-694
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSA multifunctional protein metallothionein (MT) is induced by various chemicals and cytokines. We have found novel functions of MT as follows: 1) Cytokine expression such as IL-1α, IL-6, and TNFα responding to lipopolysaccharide is reduced in MT-deficient macrophages compared with in wild-type cells. 2) Nitric oxide production responding to TNFα and LPS is reduced in MT-deficient macrophages compared with in wild-type cells. 3) M-CSF expression responding to zinc is reduced in MT-deficient fibroblasts compared with in wild-type cells, and increased in MT-overexpressed fibroblasts compared with in control cells. 4) LIF, a STAT3 activating cytokine, protects the heart from ischemia/reperfusion injury. Transgenic mice overexpressing STAT3 have tolerance to ischemia/reperfusion-induced damage, whereas MT-null mutation cancels the myocardial protection. In this review, we discuss the relation of MT and stress responses from the point of view of cytokine-induced expression of MT and modulation of cytokine expression by MT.
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Kyong-Son MINArticle type: Review
2007 Volume 127 Issue 4 Pages 695-702
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSMetallothionein (MT), a ubiquitous family of low-molecular weight metal-binding proteins, comprises 30% cysteine residues. Although all of the thiol residues in MT are bound to metals, it still remains active to reactive oxygen species. Each cysteine residue in MT is more effective at protecting DNA from hydroxyl radical attack than the glutathione cysteine in vitro. Prooxidative agents such as paraquat and carbon tetrachloride induce MT synthesis mediated by some responsive elements. MT demonstrates strong antioxidant properties, yet the physiological relevance of its antioxidant action is not clear. An injection of ferric nitrilotriacetate (Fe-NTA), which produces reactive oxygen species, caused transcriptional induction of MT synthesis in the liver and kidney. Pretreatment of mice with Zn attenuated nephrotoxicity induced by Fe-NTA. After a Fe-NTA injection, a loss of Cd-binding properties of preinduced MT was observed only in kidneys of Zn-pretreated mice but not in liver. MT-enriched hepatocytes are resistant to Fe-NTA toxicity, oxidative DNA, and cell damage during conditions of glutathione depletion. In glutathione-depleted cells, but not in non-treated cells, Cd-binding properties of cellular MT decreased with increasing concentration of Fe-NTA. Moreover, Cd released from MT after an injection of Fe-NTA induced new MT protein again. Thus MT may act as a secondary antioxidant in cellular protection system against oxidative stress.
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Masao SATO, Shinya SUZUKIArticle type: Review
2007 Volume 127 Issue 4 Pages 703-708
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSMuch attention has been paid to lifestyle-related diseases including type 2 diabetes mellitus, cardiovascular disease, hypertension, and hyperlipidemia because the incidence rates of these diseases are increasing in developed countries. Elucidation of factors contributing to the development of obesity and insulin resistance is needed. Metallothionein (MT), a ubiquitous metal-binding protein, is induced not only by heavy metals but also by various kinds of stresses. Endoplasmic reticulum (ER) stress is caused by accumulation of misfolded proteins in ER. Recently, increased ER stress by obesity and impairment of insulin action by ER stress have been reported. Exposure to ER stress increased induction of MT synthesis, and an enhanced response to ER stress evaluated as expression of Bip/GRP78mRNA was observed in the liver of MT-null mice, suggesting that MT attenuates expression of ER stress. MT may prevent ER stress and thereby modulate the development of obesity and insulin resistance. A possible role of metallothionein in response reaction for ER stress is discussed.
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Masahiko SATOHArticle type: Review
2007 Volume 127 Issue 4 Pages 709-717
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSTwo research groups produced metallothionein (MT)-I/II knockout mice with null mutation of MT-I and MT-II genes. In 1993, Choo et al. produced MT-I/II knockout mice with a mixed genetic background of 129 Ola and C57BL/6 strains. Palmiter et al. also produced MT-I/II knockout mice with a genetic background of 129/Sv strain in 1994. Subsequently, MT-I/II knockout mice have been used to clarify the biological function and physiological role of MT by many research groups. We were also provided MT-I/II knockout mice from Dr. Choo (Australia). F1 hybrid mice were mated with C57BL/6, and their offspring were back-crossed to C57BL/6 for ten generations. MT-I/II knockout (MT-/-) mice and wild-type (MT+/+) mice were obtained by mating of those heterozygous (MT+/-) mice. We have been investigating the susceptibility of MT-I/II knockout mice to toxicity of harmful factors and some diseases. Our present studies found that MT-I/II knockout mice have an increased sensitivity to harmful metals such as cadmium, mercury, and arsenic, oxidative stress, chemical carcinogenesis and neurodegenerative diseases. These results clearly indicate that MT plays an important role in defense of these toxicities. In this review, we present our findings and summarize recent reports with MT-I/II knockout mice concerning the role of MT as a biological protective factor.
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Yukiko IWATANIArticle type: Review
2007 Volume 127 Issue 4 Pages 719
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
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Hiroshi HAMA, Nobufumi ONO, Masayoshi ABEArticle type: Review
2007 Volume 127 Issue 4 Pages 721-727
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSThe complement system, which plays an important role in inmate immunity, is considered to be important in the pathophysiology of allergic asthma. A patient with allergic asthma shows the reversible characteristic system of bronchoconstriction, increased mucus secretion, and complicated airway inflammation. Various cytokines secreted from Th2 cells contribute to the system. Cysteinyl-leukotrienes (CysLTs) are also considered to be one of the important mediators involved in asthmatic pathophysiology. However, the effects of a drug on humans may not be the same as those on animals due to species differences in complement-related molecules. In this series of experiments, we tried to establish a model in which the effects of a drug on the production of CysLTs from human lung preparations were evaluated following an anaphylactic reaction. CysLT production increased when the passively sensitized lung tissues were stimulated with anti-IgE antibody. The coaddition of anaphylatoxin, C5a, with the anti-IgE antibody potentiated CysLT production. The response to C3a was weaker when compared with that to C5a. In addition, increased production of CysLTs by adding serum at a specific ratio was dose dependently inhibited by nonpeptide C5a receptor antagonist, W-54011, or a novel complementary peptide inhibitor of C5a, acetyl peptide A. From these results, it is suggested that C5a potentiates cysLT production from human lung tissues and contributes to allergic inflammation like asthma, and thus acetylated peptide A and W-54011 are useful for suppressing allergic inflammation in the lungs.
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Yukiko IWATANI, Hiromi NUMA, Saori ATAGI, Fusako TAKAYAMA, Mitsunobu M ...Article type: Review
2007 Volume 127 Issue 4 Pages 729-733
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSWe reported that vasodilator responses to various vasodilator agents were augmented by endothelium removal. To explain this mechanism, we hypothesized that endothelium removal eliminates the release of endothelium-derived contracting factor EDCF, which counteracts the vasodilation. However, the underlying mechanism is unknown. Therefore the present study investigated the second messenger system further to investigate the mechanisms underlying enhanced vasodilator response after endothelium removal in rat mesenteric resistance arteries. Mesenteric vascular beds isolated from Wistar rats were perfused and perfusion pressure was measured. The vascular endothelium was removed by 30-s perfusion of sodium deoxycholate. Vasodilator responses to sodium nitroprusside (SNP) perfusion were markedly augmented and prolonged by endothelium removal. In preparations with intact endothelium and active tone, 5-min perfusion of sodium azide (non-specific guanylate cyclase (GC) activator), ANP (membrane-linked GC activator), and 8-Br-cGMP (cGMP analogue) caused a concentration-dependent vasodilation that was markedly augmented by endothelium removal. However, vasodilation induced by YC-1 and BAY41-2272 (selective soluble GC activator) was not augmented by endothelium removal. When methylene blue (soluble GC inhibitor) was present in the medium, SNP caused a concentration-dependent vasodilation in the preparation with intact endothelium, which was less augmented by endothelium removal compared with control (preparation without methylene blue). These findings suggest that endothelium removal affects intracellular cGMP-mediated signal transduction system in vascular smooth muscle cells.
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Bingjin LI, Katsuya SUEMARU, Yoshihisa KITAMURA, Ranji CUI, Yutaka GOM ...2007 Volume 127 Issue 4 Pages 735-742
Published: 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSIn recent years, depression studies have focused on morphological changes associated with depression. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor that plays an important role in the morphological changes associated with depression and the mechanisms of antidepressants. On the other hand, hyperfunction of the hypothalamic-pituitary-adrenal axis has been link to pathophysiology of depression. In our previous studies, ACTH-treated rats served as a valuable animal model of tricyclic antidepressant-resistant depressive conditions. However, few neuroanatomic studies have been done. In the present study, we investigated mechanisms underling ACTH-treated rat serving an imipramine treatment-resistant depression model using c-Fos as a marker. The c-Fos immunohistochemical study indicated that the medial prefrontal cortex is an action site of imipramine in ACTH-treated rats. Electroconvulsive therapy is considered an effective treatment for treatment-resistant depression. However, the mechanisms causing treatment-resistant depressive conditions are unknown. We investigated the effect of repeated electrical convulsive shock (ECS)-treatment using the forced swim test, a screening method for antidepressant-like activity, and hippocampal BDNF protein levels in ACTH-treated rats. Findings showed that repeated ECS treatment decreased the immobility time during forced swim test. Furthermore, the ECS treatment also markedly increased the hippocampal BDNF levels in the rat tricyclic antidepressant-resistant depression model. In addition, the repeated ECS treatment showed long-lasting effects on forced swim test and increased of hippocampal BDNF levels in normal rats. These findings suggest that BDNF plays a key role in the antidepressant-like effect of ECS and that increased BDNF may be involved in promoting the long-lasting effect.
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Feng HAN, Kohji FUKUNAGAArticle type: Review
2007 Volume 127 Issue 4 Pages 743-748
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSMicrosphere embolism-induced up-regulation of endothelial nitric oxide synthase (eNOS) in endothelial cells of brain microvessels was found after brain ischemia. The eNOS induction preceded disruption of the blood-brain barrier following ischemia. In vascular endothelial cells, microsphere embolism-induced eNOS expression was associated with protein tyrosine nitration, which is a marker of generation of peroxynitrite. To determine whether eNOS expression and protein tyrosine nitration in vascular endothelial cells mediates the blood-brain barrier disruption in the microsphere embolism brain, we tested the effect of a novel calmodulin-dependent NOS inhibitor, DY-9760e, which inhibits eNOS activity and in turn protein tyrosine nitration. Concomitant with inhibition of protein tyrosine nitration in vascular endothelial cells, DY-9760e significantly inhibited BBB disruption as assessed by Evans blue excretion. DY-9760e also inhibited cleavage of poly(ADP-ribose) polymerase as a marker of the apoptotic pathway in vascular endothelial cells. Taken together with previous evidence in which DY-9760e inhibited brain edema, microsphere embolism-induced eNOS expression in vascular endothelial cells likely mediates BBB disruption and in turn brain edema.
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Review
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Sanae MURAOKA, Toshiaki MIURAArticle type: Review
2007 Volume 127 Issue 4 Pages 749-756
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSNon-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammatory diseases including rheumatoid arthritis and gout. The anti-inflammatory action of NSAIDs is due to the inhibition of prostaglandin synthesis by preventing cyclooxygenase (COX) activity of prostaglandin H synthase (PGS). However, administration of NSAIDs causes gastrointestinal mucosal lesions and a decrease of granulocytes as side effects. PGS catalyzes two distinct enzyme reactions: (1) bis-dioxygenation of arachidonic acid catalyzed by COX activity of PGS to form PGG2; and (2) reduction of the hydroperoxide group in PGG2 by PGS hydroperoxidase. Most NSAID are oxidized by peroxidases to produce NSAID radicals that damage biological components such as lipids and enzymes. Indomethacin, phenylbutazone, and piroxicam are more toxic under aerobic conditions than anaerobic conditions during the interaction with peroxidase. We discuss the contribution of peroxidases in the formation of gastrointestinal mucosal lesions induced by NSAIDs.
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Regular Article
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Tomoko OHASHI, Tetsuya SATOH, Minoru KUWATA, Taira FUJIMURA, Shigeru T ...Article type: Regular Article
2007 Volume 127 Issue 4 Pages 757-764
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSWe examined the systematic assay of the reporter gene for the assessment of heavy metals and organic chemical pollutants using the reporter plasmids carrying stress-responsive elements fused to the green fluorescence protein (GFP) gene as follows: metallothionein (MTIIA), heme oxigenase-1 (HO-1), quinone reductase (ARE), and c-fos genes. The treatment of COS7 cells in which the c-fos gene promoter-, ARE-, or HO-1 enhancer-fused GFP with a low concentration of NaAsO2 was introduced led to the detection of the fluorescent cells, and an agrichemical paraquat enhanced the fluorescence of ARE or HO-1 enhancer-transfected cells. The cells in which the plasmid carrying the MT-IIA gene promoter (the -765 bp upstream from the transcription initiation site) was introduced highly expressed GFP on treatment with CdCl2, ZnSO4, or CuCl2. The plasmid carrying seven metal-responsive elements of the MT-IIA gene increased the response of the fluorescence intensity to these heavy metals. These results indicated that the use of the gene promoters and enhancers of the stress-responsive genesfused to GFP contributes to the visualization of pollutant-responsive mammalian cells and can be applied to biomonitoring of environmental pollution.
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Notes
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Hidenori SAGARA, Hideki NAWA, Toshiaki SENDO, Yutaka GOMITAArticle type: Note
2007 Volume 127 Issue 4 Pages 765-772
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSIn examining assessment methods used for evaluating training, there have so far been no studies reporting any differences between the visual analogue scale (VAS) evaluation method, based on a rating scale, and evaluation methods based on an ordinal scale. Here we report the findings of an examination into differences and discrepancies between the results of the VAS method and a 5-point evaluation. Following the end of their training period, seven trainees carried out a self-evaluation regarding their level of understanding and performance using the 5-point evaluation and VAS methods. We then compared the average results of both assessment methods and examined the correlation between the two sets of figures. We found no differences between the 5-point evaluation method and VAS method in evaluating training for dispensing drugs, administering injections, pharmacy preparation, and medication management and instruction. There was also a significant correlation between average values for the 5-point evaluation and VAS method in evaluating training for dispensing drugs, administering injections, pharmacy preparation, and medication management and instruction. This led us to the conclusion that both the 5-point evaluation method and VAS method give similar results and outcomes in assessing the results of practical training.
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Hirofumi MORINO, Akane MATSUBARA, Toshiaki FUKUDA, Takashi SHIBATAArticle type: Note
2007 Volume 127 Issue 4 Pages 773-777
Published: April 01, 2007
Released on J-STAGE: April 01, 2007
JOURNAL FREE ACCESSThe efficacy of chlorine dioxide (ClO2) gas at very low concentrations for hyphal growth of Alternaria alternata related to fungal allergy was evaluated using a fungus detector. The fungus detector is a plastic sheet with a drop of spore-suspending medium, and it makes possible clear observations of hyphal growth with a light microscope. ClO2 gas (average 0.075 ppm, 0.21 μg/l) inhibited hyphal growth of the fungus, but not germination of fungal spores. The hyphal length was more than 1780 μm under air conditions (control) and 49±17 μm under ClO2 gas conditions for 72 h. According to the international chemical safety card, threshold limit values for ClO2 gas are 0.1 ppm as an 8-h time-weight average and 0.3 ppm as a 15 min short-term exposure limit. From these data, we propose that treatment with ClO2 gas at very low concentrations in space is a useful tool for the growth inhibition of fungi in the fields of food, medicine, etc. without adverse effects.
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