Journal of Pharmacological Sciences
Online ISSN : 1347-8648
Print ISSN : 1347-8613
ISSN-L : 1347-8613
Volume 117 , Issue 3
Showing 1-9 articles out of 9 articles from the selected issue
Full Papers
  • Xinhui Wang, Junichi Hasegawa, Yoshiyuki Kitamura, Zhongzhi Wang, Akik ...
    2011 Volume 117 Issue 3 Pages 129-138
    Published: 2011
    Released: November 15, 2011
    [Advance publication] Released: October 07, 2011
    JOURNALS FREE ACCESS
    The protective effects of hesperidin against hypercholesterolemia and fatty liver were examined in male Wistar rats fed a high-cholesterol diet for 12 weeks. Compared with a standard diet, a high-cholesterol diet not only increased body weights, liver weights, and serum concentration of cholesterol, but also induced the fatty degeneration (steatosis) of liver. Hesperidin (0.08%) reduced levels of hepatic steatosis, adipose tissue and liver weights (P < 0.05), serum total cholesterol and retinol binding protein (RBP) 4 concentrations (P < 0.05) in rats fed with high-cholesterol diet, while reduction in low-density lipoprotein cholesterol levels and triglyceride concentrations was not significant. It also attenuated the marked changes in mRNA expression of lipid metabolism–related proteins: RBP, heart fatty acid–binding protein (H-FABP), and cutaneous fatty acid–binding protein (C-FABP), in liver and adipose tissue. According to the results of gas chromatography, serum concentrations of total cholesterol and biomarkers of cholesterol synthesis (lathosterol) and absorption (campesterol, β-sitosterol) were lower, and concentrations of cholesterol in feces were higher in the rats given hesperidin (P < 0.05). Hesperidin may improve hypercholesterolemia and fatty liver by inhibiting both the synthesis and absorption of cholesterol and regulating the expression of mRNA for RBP, C-FABP, and H-FABP.
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  • Takanobu Tabuchi, Xiao-Fang Che, Katsuya Hiraishi, Masakazu Adachi, Ke ...
    2011 Volume 117 Issue 3 Pages 139-148
    Published: 2011
    Released: November 15, 2011
    [Advance publication] Released: October 25, 2011
    JOURNALS FREE ACCESS
    The present research investigated the effect of the oxidative phenoxazines, 2-amino-4,4α-dihydryo-4α-7H-phenoxazine-3-one (Phx-1) and 2-amino-phenoxazine-3-one (Phx-3) on apoptosis induction and apoptosis-related early events in human neutrophils. When Phx-1 or Phx-3 was administered to freshly drawn human blood for 18 h, these phenoxazines caused apoptotic cell death morphologically characterized by condensation of the nucleus in neutrophils, without causing it in lymphocytes and monocytes. Apoptosis, which was detectable by microscopic analysis and by using flow-cytometry, occurred significantly in human neutrophils isolated from freshly drawn blood, 6 h after the administration of 50 μM Phx-1 and Phx-3. After 24 h, every isolated neutrophil treated with Phx-1 or Phx-3 fell into apoptosis or lost its morphology, while many of the neutrophils without these phenoxazines remained alive, with normal morphology. Apoptosis-related early events including a decrease in intracellular pH (pHi) and depolarization of the mitochondria occurred in the isolated neutrophils, 30 min and 6 h after the administration of Phx-1 or Phx-3, respectively. Superoxide generation from the isolated neutrophils mimicked by phorbol myristate acetate (PMA) was very markedly inhibited by 100 μM Phx-1 or Phx-3. This result could be explained, in part, by the fact that the insufficient supply of NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) was caused by pHi decrease in neutrophils treated with Phx-1 or Phx, because NADPH is necessary for NADPH oxidase responsible for generating superoxide in the cells. The present results suggest that Phx-1 and Phx-3 have the capacity of selectively inducing apoptosis in human neutrophils and that these phenoxazines may be useful as specific drugs to induce apoptotic cell death of human neutrophils and thereby prevent inflammation caused by these phagocytic cells.
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  • Masaki Honda, Jumpei Kiyokawa, Mitsuyasu Tabo, Tomoaki Inoue
    2011 Volume 117 Issue 3 Pages 149-159
    Published: 2011
    Released: November 15, 2011
    [Advance publication] Released: October 25, 2011
    JOURNALS FREE ACCESS
    Cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs) hold great promise for development of in vitro research tools to assess cardiotoxicity, including QT prolongation. In the present study, we aimed to clarify the electrophysiological/pharmacological characteristics of hiPS-CMs using the patch-clamp technique. The hiPS cells were differentiated into beating cardiomyocytes by the embryoid body method. The expression of genes related to cardiac ion channels and differentiation markers in cardiomyocytes were detected by RT-PCR. Whole-cell patch-clamp recordings were performed using single hiPS-CMs dispersed from beating colonies. We confirmed voltage-dependence of major cardiac ion currents (INa, ICa, IKr, and IKs) and pharmacological responses to ion-channel blockers. Action potential duration (APD) was prolonged by both IKr/hERG and IKs blockers, whereas it was shortened by an ICa blocker, indicating that these ion current components contribute to action potential generation in hiPS-CMs. As for multiple ion channel blockers, terfenadine prolonged APD, but verapamil did not, results which were identical to clinically relevant pharmacological responses. These data suggest that patch-clamp assay using hiPS-CMs could be an accurate method of predicting the human cardiac responses to drug candidates. This study would be helpful in establishing an electrophysiological assay to assess the risk of drug-induced arrhythmia using hiPS-CMs.
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  • Yuan-Chao Ye, Lu Yu, Hong-Ju Wang, Shin-ichi Tashiro, Satoshi Onodera, ...
    2011 Volume 117 Issue 3 Pages 160-169
    Published: 2011
    Released: November 15, 2011
    [Advance publication] Released: October 25, 2011
    JOURNALS FREE ACCESS
    Tumor necrosis factor alpha (TNFα) has been reported to induce necroptosis and autophagy, but its mechanisms remain unclear. In this study, we found that TNFα significantly induced necroptosis and autophagy in murine fibrosarcoma L929 cells. The necroptosis inhibitor necrostatin-1 (Nec-1) completely blocked TNFα-induced necroptosis and autophagy, but inhibition of autophagy with 3-methyladenine (3MA) or Beclin 1 small interfering RNA (siRNA) promoted necroptosis, indicating that autophagy acted as a negative regulator of TNFα-induced necroptosis. The cytotoxicity of TNFα was accompanied by decreased expressions of phosphorylated p38 mitogen-activated protein kinase (p-p38) and nuclear factor-kappa B (NF-κB), and inhibition of p38 and NF-κB activation by chemical inhibitors or siRNA augmented these necroptotic and autophagic responses to TNFα in the cells. The pan-caspase inhibitor z-VAD-fmk (zVAD) exacerbated TNFα-induced necroptosis and autophagy. Combined treatment with TNFα and zVAD further decreased the expressions of p-p38 and NF-κB compared with TNFα alone treatment. Consequently, these results indicated that suppression of the p38–NF-κB survivial signaling pathway promoted necroptotic and autophagic cell death in TNFα-treated L929 cells.
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  • Jingxian Zeng, Shuxuan Xia, Wa Zhong, Jie Li, Liling Lin
    2011 Volume 117 Issue 3 Pages 170-179
    Published: 2011
    Released: November 15, 2011
    [Advance publication] Released: October 29, 2011
    JOURNALS FREE ACCESS
    The question about how intravenous anesthetic reagents affect the development and function of dendritic cell subsets still has no comprehensive answers. Bone marrow cells differentiated with FMS-like tyrosine kinase 3 ligand in vitro represented the steady-state dendritic cell subsets. The effects of ketamine on the generation and function of dendritic cell subsets were investigated. We found that dendritic cell subsets responded to the anesthetic reagent ketamine in several aspects: 1) The in vitro and in vivo development of plasmacytoid dendritic cells were inhibited by ketamine at high concentrations; 2) The endocytosis of dendritic cells were not influenced by ketamine at concentrations from 50 – 200 μM; 3) The maturation markers of conventional dendritic cells were not changed by ketamine upon LPS or CpG stimulation, although the cytokines mRNA profiles were affected; 4) The allogenic-stimulatory activity of dendritic cells was suppressed by ketamine. In conclusion, ketamine hampered plasmacytoid dendritic cell subset development both in vivo and in vitro. The dendritic cells maturation and downstream responses towards different toll-like receptor stimuli were differently regulated by ketamine treatment.
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  • Yuko Akasaka, Atsushi Sakai, Kumiko Takasu, Michiko Tsukahara, Akira H ...
    2011 Volume 117 Issue 3 Pages 180-188
    Published: 2011
    Released: November 15, 2011
    [Advance publication] Released: October 28, 2011
    JOURNALS FREE ACCESS
    Glycyrrhetinic acid (GA), an aglycone of glycyrrhizin, isolated from the licorice root (Glycyrrhizia), and its semi-synthetic derivatives have a wide range of pharmacological effects. To investigate whether GA derivatives may be used as a new class of analgesics, we examined the effects of these compounds on human tachykinin receptors expressed in CHO-K1 cells. Among the GA derivatives examined, the disodium salt of olean-11,13(18)-dien-3β,30-O-dihemiphthalate inhibited the mobilization of [Ca2+]i induced by substance P, neurokinin A, and neurokinin B in CHO-K1 cells expressing the human NK1, NK2, and NK3 tachykinin receptors, respectively. In an inflammatory pain model, Compound 5 suppressed the capsaicin-induced flinching behavior in a dose-dependent manner. Compound 5 was also effective in suppressing pain-related behaviors in the late phase of the formalin test and reducing thermal hyperalgesia in the neuropathic pain state caused by sciatic nerve injury. Collectively, Compound 5 may be an analgesic candidate via tachykinin receptor antagonism.
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  • Masatoshi Inden, Yoshihisa Kitamura, Kazunori Takahashi, Kazuyuki Taka ...
    2011 Volume 117 Issue 3 Pages 189-203
    Published: 2011
    Released: November 15, 2011
    [Advance publication] Released: October 29, 2011
    JOURNALS FREE ACCESS
    DJ-1, Parkinson’s disease PARK7, acts as an oxidative stress sensor in neural cells. Recently, we identified the DJ-1 modulator UCP0054278 by in silico virtual screening. However, the effect of the peripheral administration of UCP0054278 on an in vivo Parkinson’s disease (PD) model is unclear. Therefore, in the present study, we examined the effects of the peripheral administration of UCP0054278 on both 6-OHDA–microinjected rats and rotenone-treated mice as acute and chronic animal models of PD, respectively. The peripheral administration of UCP0054278 prevented 6-OHDA– and rotenone-induced dopaminergic neural cell death and restored the defect in locomotion in these models of PD. In addition, 6-OHDA– or rotenone-induced neural cell death and the production of reactive oxygen species were significantly inhibited by UCP0054278 in normal SH-SY5Y cells, but not in DJ-1–knockdown cells. These results suggest that UCP0054278 interacts with endogenous DJ-1 and then produces antioxidant and neuroprotective responses in both in vivo and in vitro models of PD. The present study raises the possibility that DJ-1 stimulatory modulators, such as UCP0054278, may be a new type of dopaminergic neuroprotective drug for the treatment of PD.
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Short Communications
  • Yoshikazu Mikami, Naoto Suzuki, Tomihisa Takahashi, Kichibee Otsuka, H ...
    2011 Volume 117 Issue 3 Pages 204-207
    Published: 2011
    Released: November 15, 2011
    [Advance publication] Released: October 25, 2011
    JOURNALS FREE ACCESS
    Streptococcus mutans is a bacterial cause of dental caries that is resistant to bacitracin. The aim of this study was to elucidate the mbrABCD-related bacitracin resistance mechanism of S. mutans. Transcriptome data demonstrated that the expression levels of 33 genes were induced more than twofold by bacitracin. Fourteen genes were selected from the upregulated genes, and defective mutants of these genes were constructed for measurement of their sensitivity to bacitracin. Among the mutants, only the mbrA- or mbrB-deficient mutants exhibited 100- to 121-fold greater sensitivity to bacitracin when compared with the wild-type strain. Moreover, knockout of the mbrC and mbrD genes abolished the bacitracin-induced mbrAB upregulation. These results suggest that both mbrC and mbrD are required for mbrAB upregulation that confers the bacitracin-resistant phenotype on S. mutans.
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  • Koichi Kawada, Masayuki Kaneko, Yasuyuki Nomura, Seisuke Mimori, Hiros ...
    2011 Volume 117 Issue 3 Pages 208-212
    Published: 2011
    Released: November 15, 2011
    [Advance publication] Released: October 25, 2011
    JOURNALS FREE ACCESS
    Neural stem/progenitor cells (NSCs) reside in the subventricular zone (SVZ) and subgranular zone of the hippocampal dentate gyrus in adult mammals. The ubiquitin ligase HRD1 is associated with degradation of amyloid precursor protein and believed to be specifically expressed in neurons and not in astrocytes. We investigated expression of HRD1 using immunohistochemistry and found colocalization of HRD1 with the NSC marker protein nestin and glial fibrillary acidic protein in the NSCs of the SVZ (the SVZ astrocytes) but not in the hippocampus. In the hippocampal dentate gyrus, HRD1 is localized in the nucleus of nestin-positive cells.
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