Journal of Pharmacological Sciences
Online ISSN : 1347-8648
Print ISSN : 1347-8613
ISSN-L : 1347-8613
Volume 97 , Issue 1
Showing 1-23 articles out of 23 articles from the selected issue
Current Perspective
  • Ana Olariu, Kiyofumi Yamada, Toshitaka Nabeshima
    2005 Volume 97 Issue 1 Pages 1-5
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 15, 2005
    JOURNALS FREE ACCESS
    Amyloid β-protein (Aβ) is one of the most studied peptides in human neurodegenerative disorders. Although much has been learned about the biochemistry of this peptide, fundamental questions such as when and how the Aβ becomes pathologic remain unanswered. In this article we review the recent findings on the biology and pathology of Aβ and the role protein kinase C (PKC) plays in these processes. The potential neuroprotective role of PKC and the possible therapeutic effects of PKC activators in Alzheimer’s disease (AD) will be discussed. Briefly, comments will be also addressed on the role of PKC in cell death and neurogenesis in AD.
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Forum Minireview
  • Masahiro Nishibori
    2005 Volume 97 Issue 1 Pages 7
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 15, 2005
    JOURNALS FREE ACCESS
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  • Morley D. Hollenberg
    2005 Volume 97 Issue 1 Pages 8-13
    Published: 2005
    Released: January 21, 2005
    JOURNALS FREE ACCESS
    Proteinases like thrombin and trypsin, long known for their ability to activate the coagulation cascade or to act as digestive enzymes for many protein targets, are now recognized as hormone-like regulators of cell function. These serine proteinases activate cell signaling by triggering a novel family of G-protein-coupled receptors, termed proteinase-activated receptors (PARs). This article summarizes the unique mechanisms involved in PAR activation and outlines the many different settings in which the PARs act to regulate tissue function. The PARs can be seen to play a role in inflammatory processes in large part via a neurogenic mechanism. Apart from activating PARs to cause their physiological effects in tissues, proteinases can also mediate cell signaling via a number of other mechanisms, including the activation of growth factor receptors, like the one for insulin. Thus, this article also points out the non-PAR mechanisms whereby proteinases can have hormone-like actions in cells and tissues.
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  • Yoshinori Itoh, Toshiaki Sendo, Ryozo Oishi
    2005 Volume 97 Issue 1 Pages 14-19
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 15, 2005
    JOURNALS FREE ACCESS
    Proteinase-activated receptor-2 (PAR-2) plays important roles in a variety of pathophysiological functions, including inflammatory responses and nociception. In this minireview, we describe the role of PAR-2 in acute inflammatory responses in lungs associated with iodinated radiographic contrast medium (RCM). Intravenous injection of RCM to rats induces lung injury characterized by vascular hyperpermeability, edema, and respiratory depression. Nafamostat, which is found to be the most potent and specific tryptase inhibitor, prevents RCM-induced lung injury. In cultured endothelial cells of human pulmonary artery and bovine aorta, RCM, when applied in combination with mast cells, disrupts barrier function evaluated by the permeability of Evans blue through a monolayer of cultured cells, which is blocked by nafamostat and mimicked by tryptase and PAR-2-activating peptide. The tryptase-induced barrier dysfunction is blocked completely by a phospholipase C inhibitor and partially inhibited by a IP3 receptor blocker, protein kinase C inhibitor, or Rho kinase inhibitor. Morphological observations reveal the formation of actin stress fibers and disappearance of the intercellular meshwork structure of vascular endothelial-cadherin after application of RCM or PAR-2 ligands. Therefore, the release of mast cell tryptase and subsequent activation of endothelial PAR-2 are involved in acute lung injury induced by RCM.
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  • Atsufumi Kawabata, Naoyuki Kawao
    2005 Volume 97 Issue 1 Pages 20-24
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 15, 2005
    JOURNALS FREE ACCESS
    Proteinase-activated receptors (PARs), a family of G protein-coupled receptors, are widely distributed in the mammalian body, playing a variety of physiological/pathophysiological roles. In the respiratory systems, PARs, particularly PAR-2 and PAR-1, are expressed in the epithelial and smooth muscle cells. In addition to the Gq/11-mediated activation of the phospholipase C β pathway, epithelial PAR activation causes prompt and/or delayed prostanoid formation, leading to airway smooth muscle relaxation and/or modulation of an inflammatory process. PAR-2 present in the epithelium and smooth muscle is considered primarily pro-inflammatory in the respiratory system, although PAR-2 may also be anti-inflammatory under certain conditions. In the lung epithelial cells, PAR-2 can also be activated by exogenous proteinases including house dust mite allergens, in addition to various possible endogenous agonist proteinases. Clinical evidence also suggests possible involvement of PARs, particularly PAR-2, in respiratory diseases. PARs thus appear to play critical roles in the respiratory systems, and the agonists/antagonists for PARs may serve as the novel therapeutic strategy for treatment of certain respiratory diseases including asthma.
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  • Masahiro Nishibori, Shuji Mori, Hideo K. Takahashi
    2005 Volume 97 Issue 1 Pages 25-30
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 15, 2005
    JOURNALS FREE ACCESS
    Proteinase-activated receptor-2 (PAR-2) has been demonstrated to be highly expressed in the gastrointestinal tract. In the present minireview, we summarize the effects of PAR-1 and PAR-2 stimulation using their activating peptides and agonist proteinases on the calcium signaling and the cell proliferation in DLD-1 cell, a human colon cancer cell line. PAR-2 but not PAR-1 stimulation induced the enhancement of cell proliferation, whereas both PAR-1 and PAR-2 stimulation induced the transient increase in [Ca2+]i. PAR-2 stimulation induced the phosphorylation of MEK1/2 and ERK1/2, but PAR-1 stimulation did not. The inhibition of MEK1/2 by PD98059 completely abolished the proliferative response to PAR-2 stimulation. Thus, MEK-ERK activation plays major role in the PAR-2-mediated proliferative response. The coupling of PARs to calcium signaling and MEK-ERK activation may be independent, and varied dependent on cell types.
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  • Katsuya Hirano, Tatsuya Yufu, Mayumi Hirano, Junji Nishimura, Hideo Ka ...
    2005 Volume 97 Issue 1 Pages 31-37
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 15, 2005
    JOURNALS FREE ACCESS
    The level of receptors expressed on the cell surface determines the cellular responsiveness to agonists. Proteinase-activated receptors (PARs) have been reported to be either up-regulated or down-regulated in response to various types of stimulation and pathological situations. In addition, the transcriptional regulation plays a major role in the alteration of the expression of PARs under pathological conditions, while post-translational mechanisms such as phosphorylation, arresting-binding, internalization, and lysosomal degradation, which desensitize activated PARs and terminate intracellular signaling, also play an important role in regulating the expression of PARs and the cellular responsiveness to the agonists. Elucidating the mechanisms related to the expression of PARs is a critical step to understand the pathophysiology of various diseases and establish new therapeutic strategies. However, the molecular mechanism regulating the expression of PARs still remains to be elucidated. This minireview discusses our current understanding of the mechanisms regulating the expression of PARs. The transcription factors and the regulatory elements in the promoter regions, and the proteins that interact with the receptors and thereby regulate their trafficking and desensitization are the main problems that need to be elucidated.
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  • Toru Kanke, Toshiaki Takizawa, Mototsugu Kabeya, Atsufumi Kawabata
    2005 Volume 97 Issue 1 Pages 38-42
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 15, 2005
    JOURNALS FREE ACCESS
    PAR-2 is the second member of the family of proteinase-activated receptors activated by trypsin, tryptase, and several other serine proteinases. In order to evaluate the therapeutic potential for PAR-2, we have performed studies on PAR-2-mediated signal transduction and investigated the effects of PAR-2 gene deficiency in disease models. In addition to the G-protein-coupled receptor-mediated common signal transduction pathways, inositol 1,4,5-trisphosphate production and mobilization of Ca2+, PAR-2 can also activate multiple kinase pathways, ERK, p38MAPK, JNK, and IKK, in a cell-type specific manner. The studies using PAR-2-gene-deficient mice highlighted critical roles of PAR-2 in progression of skin and joint inflammation. We also describe the development and evaluation of potent and metabolically stable PAR-2 agonists in multiple assay systems both in vitro and in vivo. The structure-activity relationship analysis indicated the improved potencies of furoylated peptides. Furthermore, the resistance of the furoylated peptide against aminopeptidase contributed to the highly potent and sustained effects of the peptide in vivo. These studies suggest the potential therapeutic importance of PAR-2 in inflammatory diseases. Also, the PAR-2-gene-deficient mice and the potent and metabolically stable agonists are shown to be useful tools for evaluating the potency of PAR-2 as a therapeutic target.
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Full Papers
  • Toru Nishinaka, Chihiro Yabe-Nishimura
    2005 Volume 97 Issue 1 Pages 43-51
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 15, 2005
    JOURNALS FREE ACCESS
    Transcription factor Nrf2 regulates gene expression of drug metabolizing enzymes such as glutathione S-transferase via the antioxidant response element, ARE. Aldose reductase (AR), a member of the aldo-keto reductase (AKR) superfamily, metabolizes various endogenous and exogenous aldehydes. The AR gene 5'-flanking region contains a multiple stress response region (MSRR) composed of two putative AREs (ARE1 and ARE2), an AP1 site, and a tonicity response element (TonE). As this region is highly conserved among species, we examined the involvement of Nrf2 in transcriptional regulation of the AR gene. β-Naphthoflavone, an Nrf2 activator, elevated the level of AR mRNA in HepG2 cells and increased the promoter activity of the mouse AR (AKR1B3) gene. The promoter activity of the AKR1B3 gene, containing MSRR, was also augmented by overexpression of Nrf2. Deletion and mutation analyses indicated that both ARE1 and the AP1 site were essential for the responsiveness to Nrf2, while ARE2 was nonfunctional. The presence of an ARE1 binding protein complex was revealed by electrophoretic mobility shift assay. These findings indicate that Nrf2 regulates the AKR1B3 promoter activity via ARE1 and the AP1 site.
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  • Naoto Tadano, Sachio Morimoto, Akira Yoshimura, Makoto Miura, Kimitomo ...
    2005 Volume 97 Issue 1 Pages 53-60
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 08, 2005
    JOURNALS FREE ACCESS
    We investigated the effects of the agent SCH00013 on Ca2+-induced force generation in rabbit skinned cardiac muscle fibers and in vivo cardiac function in high-pacing-induced heart failure dogs. The Ca2+-induced force generation in skinned cardiac muscle fibers was determined at pH 6.2 – 7.4, and SCH00013 was found to have a significant Ca2+ sensitizing effect at pH 7.2 to 7.4. There was no significant difference in the Ca2+ sensitizing action between the enantiomers of SCH00013. The Ca2+ sensitizing effect of SCH00013 was dependent on the sarcomere length, being significant only at a long sarcomere length. SCH00013 elicited a positive inotropic effect at more than 0.3 and 1 mg/kg, i.v. in normal and heart failure dogs, respectively, with no chronotropic action. These results strongly suggested that SCH00013 is a novel Ca2+ sensitizer that elicits a positive inotropic and no chronotropic effect in heart failure, probably through enhancing the Frank-Starling mechanism.
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  • Murat Kesim, Erdem N. Duman, Mine Kadioglu, Ersin Yaris, Nuri I. Kalyo ...
    2005 Volume 97 Issue 1 Pages 61-66
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 15, 2005
    JOURNALS FREE ACCESS
    Serotonin (5-HT) is known to be an important mediator in pain modulation. Some centrally acting agents, like selective serotonin reuptake inhibitors (SSRIs), modulate pain. Activation of the endogenous opioid mechanisms or potentiation of analgesic effect by serotonergic and/or noradrenergic pathways might be involved in antinociception of SSRIs. However, peripheral mechanisms of nociception are not clear. In this study, the antinociceptive effect of paroxetine, its interaction with the opioidergic system and serotonin receptors were tested using the writhing test in mice. Paroxetine (5, 10, 20 mg/kg) induced an antinociceptive effect following i.p. administration in writhing test. For the groups in which the antagonists were tested, the dose of paroxetine that caused a significant and equipotent analgesic effect similar to 0.5 mg/kg morphine was selected. Naloxone significantly antagonized the antinociceptive effects of both paroxetine and morphine in a similar pattern and magnitude. Ketanserin (5-HT2-receptor antagonist) or ondansetron (5-HT3-receptor antagonist) alone did not alter the nociceptive action of acetic acid. While the antinociceptive effect of paroxetine was highly potentiated by ketanserin, ondansetron reduced that antinociception. In conclusion, our results indicate that the antinociceptive effect of paroxetine mainly depends on central opioidergic and serotonergic mechanisms. Peripheral serotonergic mechanisms/receptors may contribute to this antinociceptive effect, especially by 5-HT3-receptor subtypes.
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  • Kana Kunieda, Akiyoshi Someya, Syunji Horie, Hirofusa Ajioka, Toshihik ...
    2005 Volume 97 Issue 1 Pages 67-74
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 15, 2005
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    Lafutidine, a histamine H2 receptor antagonist, exerts gastroprotective effects in addition to gastric antisecretory activity. The gastrointestinal protective effects of lafutidine are mediated by capsaicin-sensitive neurons, where capsaicin excites neurons by opening a member of the transient receptor potential channel family (TRPV1). Since the effect of lafutidine on the intracellular Ca2+ concentration ([Ca2+]i) in cells has not been elucidated, we investigated the lafutidine response to [Ca2+]i in rat pheochromocytoma PC12 and human endothelial cells. Lafutidine at pharmacological concentrations greater than 1 mM induced a sustained increase in [Ca2+]i in the presence of extracellular CaCl2 in PC12 cells, while capsaicin showed dual effects on [Ca2+]i in PC12 cells, where it activated TRPV1 and inhibited store-operated Ca2+ entry. The thapsigargin (an activator of store-operated Ca2+ entry)-induced increase in [Ca2+]i in PC12 cells was inhibited by capsaicin and SKF96365, an inhibitor of store-operated Ca2+ entry, and the lafutidine response was inhibited by capsaicin but not by SKF96365. In endothelial cells, lafutidine induced an increase in [Ca2+]i in a SKF96365-insensitive manner. These results suggest that lafutidine stimulates Ca2+ entry via the capsaicin-sensitive pathway but not the SKF96365-sensitive pathway. The possible role of store-operated Ca2+ entry induced by lafutidine on gastrointestinal function is also discussed.
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  • Mototaka Nakama-Kitamura
    2005 Volume 97 Issue 1 Pages 75-82
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 08, 2005
    JOURNALS FREE ACCESS
    I and coauthor previously reported the memory facilitation effect of morphine. The main purpose of this study was to evaluate the involvement of the N-methyl-D-aspartate (NMDA) receptor in associative tolerance to morphine by a contextual procedure. Antinociceptive response latency was measured by the tail-pinch method during repeated morphine (5 mg/kg, s.c.) injection for four consecutive days with pretreatment by dizocilpine (0.01, 0.05, 0.1 mg/kg, i.p.) at 30 min prior to morphine injection in the training phase and before and after morphine injection in the test phase. The nociceptive response latency was shortened by the single administration of dizocilpine (0.05 to 0.25 mg/kg, i.p.). Pretreatment by dizocilpine at 0.05 or 0.1 mg/kg weakened the antinociception to morphine on Day 1, but decreased the tolerance throughout the training phase. In the test phase, the animals were allocated into the same and different contexts. In the test phase, hyperalgesia before morphine injection in the same context and antinociception after morphine injection in the different context were evident in the saline-pretreated group in the training phase, but they were not observed in those contexts in the dizocilpine-pretreated groups. These results suggest that memory dysfunction with dizocilpine inhibits the recovery of associative tolerance to morphine by contextual change.
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  • Ryoko Taniguchi, Toshio Kumai, Naoki Matsumoto, Minoru Watanabe, Koji ...
    2005 Volume 97 Issue 1 Pages 83-90
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 15, 2005
    JOURNALS FREE ACCESS
    Paclitaxel is widely used for treatment of malignant tumors. Paclitaxel is metabolized by CYP2C8 and CYP3A4, and these enzymes are known to differ between individuals, although the details have not been clarified. Recent progress in pharmacogenetics has shown that genetic polymorphisms of metabolic enzymes are related to these individual differences. We investigated the effect of the polymorphisms on paclitaxel metabolism by analyzing metabolic activities of CYP2C8 and CYP3A4 and expressions of mRNA and protein. Production of 6α-hydroxypaclitaxel, a metabolite of CYP2C8, was 2.3-fold larger than 3'-p-hydroxypaclitaxel, a metabolite of CYP3A4. Significant inter-individual differences between these two enzyme activities were shown. The expressions of mRNA and protein levels correlated well with the enzyme activities, especially with CYP3A4. Although it was previously reported that CYP2C8*3 showed lower activity than the wild type, two subjects that had the CYP2C8*3 allele did not show lower activities in our study. Inter-individual differences in paclitaxel metabolism may be related to CYP2C8 and CYP3A4 mRNA expression. CYP2C8 is the primary metabolic pathway of paclitaxel, but there is a “shifting phenomenon” in the metabolic pathway of paclitaxel in the liver of some human subjects.
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  • Kaori Waseda, Tadayoshi Takeuchi, Mayuko Ohta, Yutaka Okishio, Akikazu ...
    2005 Volume 97 Issue 1 Pages 91-100
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 08, 2005
    JOURNALS FREE ACCESS
    A role of ATP in nonadrenergic, noncholinergic (NANC) relaxations was examined in the Wistar rat jejunum. Electrical field stimulation (EFS) induced NANC relaxation of longitudinal muscle of the jejunal segments in a frequency-dependent manner. A purinoceptor antagonist, adenosine 3'-phosphate 5'-phosphosulfate (A3P5PS, 100 μM) inhibited the relaxation: relaxations induced by EFS at lower or higher frequencies were either completely or partially inhibited, respectively. After the jejunal segments had been desensitized to ATP, the relaxations were decreased to the same extent as those inhibited by A3P5PS. An inhibitor of small conductance Ca2+-activated K+ channels (SK channels), apamin (100 nM), completely inhibited EFS-induced relaxations. Treatment of the segments with an inhibitor of sarcoplasmic reticulum Ca2+-ATPase, thapsigargin (1 μM), significantly inhibited the relaxations. The exogenous ATP-induced relaxation of longitudinal muscle occurred with a concomitant decrease in intracellular Ca2+ levels. Apamin and thapsigargin abolished these ATP-induced responses. A3P5PS significantly inhibited the inhibitory junction potentials which were induced in the longitudinal muscle cells. In addition, apamin significantly inhibited the hyperpolarization that was induced by exogenous ATP in the cells. These findings in the Wistar rat jejunum suggest that ATP participates in the NANC relaxation via activation of SK channels induced by Ca2+ ions that are released from the thapsigargin-sensitive store site.
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  • Yoshioki Satoh, Atsushi Sugiyama, Akira Takahara, Kentaro Ando, Kai Wa ...
    2005 Volume 97 Issue 1 Pages 101-106
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 15, 2005
    JOURNALS FREE ACCESS
    Electropharmacological effect of the antipsychotic and antiemetic drug prochlorperazine was assessed using the halothane-anesthetized in vivo canine model (n = 5). Up to 10 times higher than the clinically relevant doses of prochlorperazine (≤ 3 mg/kg, i.v.) did not induce cardiohemodynamic collapse in the model. Meanwhile, clinically relevant to supratherapeutic doses (0.3 – 3 mg/kg, i.v.) prolonged the ventricular repolarization period in a dose-related and reverse-use dependent manner that could become proarrhythmic substrates. Thus, caution has to be paid on the use of prochlorperazine particularly for patients with risks of the elevated plasma drug concentration, compromised cardiac repolarization, and/or frequent ventricular premature beats.
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  • Wei Xia, Jing Li, Meiyu Geng, Xianliang Xin, Jian Ding
    2005 Volume 97 Issue 1 Pages 107-115
    Published: 2005
    Released: January 21, 2005
    JOURNALS FREE ACCESS
    Marine algae-derived sulfated polymannuroguluronate (SPMG), a candidate drug for AIDS treatment, was intraperitoneally injected into normal mice for 6 weeks, and the in vivo and in vitro mechanisms of SPMG for immunomodulation were investigated in isolated lymphocytes by MTT assay, flow cytometry, and surface plasmon resonance assay. SPMG treatment at 5 and 10 mg/kg enhanced concanavalin A (ConA)-induced T cell proliferation, cellular levels of CD69, interleukin-2 (IL-2), and interferon-γ (IFN-γ), as well as CD4/CD8 ratio, while decreasing tumor necrosis factor-α (TNF-α) level in T cells of peripheral blood mononuclear cells. In addition, 1 molecule of SPMG bound to 2/3 molecules of IL-2 with a KD of 9.53 × 107 M. Heparin prevented SPMG binding to IL-2 by 72.2%; thus, to a large extent, SPMG and heparin share common binding sites on IL-2. In contrast, other glycosaminoglycans (e.g., chondroitin sulfate and dermatan sulfate) had little effect on SPMG and IL-2 interaction, suggesting the requirement of a defined sequence within the sugar chain for specific recognition of IL-2. Concomitant treatment of IL-2 and SPMG augmented lymphocyte proliferation, compared with IL-2 alone; in contrast, SPMG alone had no proliferative effect. Taken together, our findings demonstrated for the first time that SPMG exerted its immunomodulation by direct activation of T cell function, accompanied by simultaneous modulation of cytokine function, which suggests that SPMG would show great promise for use in anti-AIDS therapy.
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  • Kazuyoshi Tomita, Susumu Okabe
    2005 Volume 97 Issue 1 Pages 116-123
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 15, 2005
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    Results from a limited number of studies suggest a potential role for endogenous histamine in regulating tumor growth in immunocompetent cells. The present study examined the effects of exogenous histamine on colorectal cancer growth and the immune response against tumor tissue in mice. Histamine was administered for 21 days to Colon 38 mouse colon adenocarcinoma-implanted syngeneic mice and tumor volume was measured throughout the experiment. Systemic administration of histamine for 21 days caused a significant increase in tumor implant growth compared with the vehicle. At the end of histamine administration, the interferon (IFN)-γ / interleukin (IL)-4 ratio in peripheral lymphocytes, as well as histamine and cytokine levels in tumor implants were determined. Histamine levels in tumor implants remained unchanged after exogenous histamine delivery. Mice with tumor implants exhibited significantly elevated IFN-γ / IL-4 ratios compared with mice lacking tumors. Nonetheless, the increased IFN-γ / IL-4 ratios were markedly suppressed by histamine administration compared with vehicle. In addition, histamine delivery significantly decreased IFN-γ and IL-12 mRNA expression, but increased IL-10 mRNA expression in tumor implants. It was concluded that exogenous histamine dysregulates the balance between T-helper 1 (Th1) and T-helper 2 (Th2) cells, attenuating anti-tumor cytokine expression in the tumor microenvironment, thus resulting in stimulated colorectal cancer growth.
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  • Ji Hyun Kim, Dae Hyun Hahm, Deck Chun Yang, Jang Hyun Kim, Hye Jung Le ...
    2005 Volume 97 Issue 1 Pages 124-131
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 15, 2005
    JOURNALS FREE ACCESS
    The anti-obesity effects of crude saponin (CS) of Korean red ginseng (KRG) were investigated in the rat fed a high-fat (HF) diet. Male Sprague-Dawley (SD) rats became obese by feeding the HF diet over 5 weeks, while the control rats were fed a normal diet, and then both groups were treated with CS (200 mg/kg, i.p.) for 3 weeks. The body weight, food consumption, adipose tissues, and expression of appetite peptides such as leptin and neuropeptide Y (NPY) were investigated in rats fed normal and HF diet after treatment of CS. Administration of CS reduced body weight, food intake, and fat content in HF diet rats in a manner similar to those of the normal diet fed rats. The hypothalamic NPY expression and serum leptin level were reduced in HF diet rats after CS treatment. Our results suggest that CS may be useful in the treatment of obesity and related disorders as anti-obesity agents.
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  • Takayuki Seki, Tsuyoshi Ishimoto, Takanobu Sakurai, Yoshiko Yasuda, Ka ...
    2005 Volume 97 Issue 1 Pages 132-137
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 15, 2005
    JOURNALS FREE ACCESS
    The present study examined the contribution of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) in cyclosporine A (CsA)-induced renal nephrotoxicity. Treatment of rats with CsA (50 mg/kg) for 9 days induced renal damage as indicated by marked increase in urine flow (from 9.0 ± 0.3 ml/day to 46.6 ± 7.1 ml/day) and a 3 – 5-fold rise in blood urea nitrogen (BUN) levels. The urinary excretion of 20-HETE increased from 164 ± 5 ng/day (N = 5) to 2432 ± 290 ng/day (N = 5, P<0.01) after 9 days of CsA treatment. The increase in the urinary excretion of 20-HETE in the CsA treated rats was highly correlated with the increase in BUN levels (r = 0.819, P<0.001) and urine volume (r = 0.832, P<0.001). Immunohistochemical examination of kidney revealed that expression of cytochrome P450 4A (CYP4A) protein was markedly enhanced in the proximal tubules of CsA-treated rats. These results indicate that CsA-induced nephrotoxicity in rats is associated with a marked elevation in the renal production of 20-HETE and that 20-HETE may contribute to the pathophysiological condition of CsA-induced nephrotoxicity.
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  • Joon-Bae Kim, Hyun-Na Koo, Hyun-Ja Joeng, Yeoung-Su Lyu, Sang-Goo Park ...
    2005 Volume 97 Issue 1 Pages 138-145
    Published: 2005
    Released: January 21, 2005
    [Advance publication] Released: January 15, 2005
    JOURNALS FREE ACCESS
    Gagam-whanglyun-haedoktang (GWH) is a newly designed herbal drug formula based on the traditional oriental pharmacological knowledge for the purpose of treating tumorous diseases. Apoptosis is an evolutionarily conserved suicide program residing in cells. In the present study, apoptosis inducing activities of the decocted water extract of GWH were studied. Results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that GWH had a strong cytotoxic effect on HL-60 cells. The number of live cells was less than 20% after exposure to 1 mg/ml GWH for 48 h. GWH increased cytotoxicity of HL-60 cells in a dose- and time-dependent manner. The percentage of apoptotic cells by flow cytometric analysis of the DNA-stained cells increased to 28%, 31%, and 37% at 24 h and to 37%, 44%, and 81% at 48 h after treatment with 0.01, 0.1, and 1 mg/ml GWH, respectively. DNA fragmentation also occurred in apoptosis and was characterized by a ladder pattern on agarose gel. In addition, GWH increased the secretion of tumor necrosis factor-α. GWH-induced apoptosis was accompanied by activation of caspase-3. These results suggest that GWH induces activation of caspase-3 and eventually leads to apoptosis.
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  • Hirohito Hikiba, Eiko Watanabe, J. Carl Barrett, Takeki Tsutsui
    2005 Volume 97 Issue 1 Pages 146-152
    Published: 2005
    Released: January 21, 2005
    JOURNALS FREE ACCESS
    To assess the genotoxicity of 14 chemical agents used in dental practice, the ability of these agents to induce chromosome aberrations was examined using Syrian hamster embryo (SHE) cells. Statistically significant increases in the frequencies of chromosome aberrations were induced in SHE cells treated with 7 of 10 chemical agents used as endodontic medicaments, that is, carbol camphor, m-cresol, eugenol, guaiacol, zinc oxide, hydrogen peroxide, and formaldehyde. The other 3 chemical agents, that is, thymol, glutaraldehyde, and iodoform, did not increase the levels of chromosome aberrations. Of the 4 chemical agents that are used as an antiseptic on the oral mucosa, chromosome aberrations were induced by iodine, but not by the other 3 antiseptics, benzalkonium chloride, benzethonium chloride, and chlorhexidine. Among the 6 chemical agents exhibiting a negative response in the assay, only thymol induced chromosome aberrations in the presence of exogenous metabolic activation. Our results indicate that chemical agents having a positive response in the present study are potentially genotoxic to mammalian cells and need to be studied further in detail.
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