Journal of Pharmacological Sciences
Online ISSN : 1347-8648
Print ISSN : 1347-8613
ISSN-L : 1347-8613
Volume 108 , Issue 3
Showing 1-20 articles out of 20 articles from the selected issue
Critical Review
  • Koji Aoyama, Masahiko Watabe, Toshio Nakaki
    2008 Volume 108 Issue 3 Pages 227-238
    Published: 2008
    Released: November 21, 2008
    [Advance publication] Released: November 13, 2008
    JOURNALS FREE ACCESS
    The brain is among the major organs generating large amounts of reactive oxygen species and is especially susceptible to oxidative stress. Glutathione (GSH) plays critical roles as an antioxidant, enzyme cofactor, cysteine storage form, the major redox buffer, and a neuromodulator in the central nervous system. GSH deficiency has been implicated in neurodegenerative diseases. GSH is a tripeptide comprised of glutamate, cysteine, and glycine. Cysteine is the rate-limiting substrate for GSH synthesis within neurons. Most neuronal cysteine uptake is mediated by sodium-dependent excitatory amino acid transporter (EAAT) systems, known as excitatory amino acid carrier 1 (EAAC1). Previous studies demonstrated EAAT is vulnerable to oxidative stress, leading to impaired function. A recent study found EAAC1-deficient mice to have decreased brain GSH levels and increased susceptibility to oxidative stress. The function of EAAC1 is also regulated by glutamate transporter associated protein 3-18. This review focuses on the mechanisms underlying GSH synthesis, especially those related to neuronal cysteine transport via EAAC1, as well as on the importance of GSH functions against oxidative stress.
    Download PDF (425K)
Full Papers
  • Chien-Chuan Wang, Pao-Yun Cheng, Yie-Jen Peng, Edwin SC Wu, Hsiao-Ping ...
    2008 Volume 108 Issue 3 Pages 239-247
    Published: 2008
    Released: November 21, 2008
    JOURNALS FREE ACCESS
    Naltrexone, an opioid receptor antagonist, has been claimed to have anti-inflammatory and immunomodulatory effects both in vitro and in vivo. Thus, the aim of this study was to evaluate the effects of naltrexone on acute hepatitis induced by intraperitoneal (i.p.) administration of lipopolysaccharide (LPS, 20 μg/kg)/D-galactosamine (D-gal, 700 mg/kg) in conscious ICR mice. Results demonstrated that post-treatment with naltrexone (20 mg/kg, i.p.) significantly attenuated the deleterious liver function in mice treated with LPS/D-gal. It was also found that naltrexone significantly inhibited the elevation of plasma tumor necrosis factor-α (TNF-α) caused by LPS/D-gal. The overproduction of nitric oxide (NO) and superoxide anions induced by LPS/D-gal were also significantly reduced by naltrexone. Moreover, infiltration of neutrophils into the liver of mice 12 h after treatment with LPS/D-gal was also decreased by naltrexone. In conclusion, the beneficial effects of naltrexone on LPS/D-gal–induced hepatitis result from its inhibition of pro-inflammatory factors and antioxidant effects. Thus, naltrexone is of therapeutic potential for treating liver injury.
    Download PDF (718K)
  • Masayuki Yamamoto, Toshihiro Unno, Hayato Matsuyama, Masanobu Kohda, N ...
    2008 Volume 108 Issue 3 Pages 248-257
    Published: 2008
    Released: November 21, 2008
    [Advance publication] Released: November 06, 2008
    JOURNALS FREE ACCESS
    The present study, aiming to elucidate ion channel mechanisms underlying muscarinic receptor–induced depolarization, has characterized membrane currents induced by carbachol in single guinea-pig urinary bladder myocytes. Application of carbachol to cells that were voltage-clamped at −50 mV produced an atropine-sensitive, biphasic inward current consisting of an initial peak followed by a smaller sustained phase. Replacing the extracellular Na+ and intracellular Cl with impermeable tris+ and glutamate, respectively, demonstrated that the biphasic current is entirely composed of cation currents. Its initial peak phase was abolished by buffering intracellular Ca2+ to a constant level of 100 nM or depleting intracellular Ca2+ stores, and it was mimicked by the Ca2+ releaser caffeine. Ca2+ entry evoked by voltage steps in the sustained phase induced no noticeable change, indicating that this phase of cation current is insensitive to a rise of [Ca2+]i. These results demonstrate that muscarinic receptor stimulation invokes the openings of two types of cation channel, a Ca2+-activated and a receptor-operated type; the former channels are gated by a rise in [Ca2+]i upon intracellular Ca2+ release, and the latter are gated through other muscarinic receptor–coupled signal transduction mechanisms.
    Download PDF (673K)
  • Hidemi Nomura, Hideyuki Yamawaki, Masashi Mukohda, Muneyoshi Okada, Yu ...
    2008 Volume 108 Issue 3 Pages 258-265
    Published: 2008
    Released: November 21, 2008
    [Advance publication] Released: November 06, 2008
    JOURNALS FREE ACCESS
    Pioglitazone is a widely used anti-type 2 diabetic drug. Beside its insulin-sensitizing effects, pioglitazone exerts preventive roles against ischemic heart disease. Since one possible explanation is anti-hypertensive action, we examined effects of pioglitazone on contractility of isolated blood vessel. Endothelium-intact [End (+)] or -removed [End (−)] rat aorta is isolated and isometric tension is recorded. In both End (+) and End (−) aorta, pretreatment with pioglitazone (3 – 10 μM, 30 min) inhibited noradrenaline (NA) (1 nM – 1 μM)-induced contraction. In NA (100 nM)-pre-contracted aorta, pioglitazone (1 – 10 μM) directly induced a relaxation. The relaxant effect is higher in End (−) aorta than in End (+) aorta. In End (+) aorta, NG-nitro-L-arginine methyl ester (100 μM) significantly inhibited the relaxation. In End (−) aorta, neither indomethacin nor cimetidine affected the relaxation, but tetraethylammonium (10 mM) inhibited it. Furthermore, the relaxation was significantly inhibited by a voltage-dependent K+ (KV)-channel blocker, 4-aminopyridine (1 mM), or an inward rectifying K+ (KIR)-channel blocker, BaCl2 (1 mM). GW9662 (2 μM), a blocker of peroxisome proliferator-activated receptor (PPAR)-γ was ineffective against the relaxation. The present study demonstrated that pioglitazone causes PPAR-γ–independent relaxation. While endothelium-dependent relaxation is mediated via nitric oxide, the endothelium-independent one is responsible for smooth muscle K+ (KV, KIR)-channel opening.
    Download PDF (772K)
  • Atsushi Sasaki, Kenichi Serizawa, Tsugunobu Andoh, Kimiyasu Shiraki, H ...
    2008 Volume 108 Issue 3 Pages 266-273
    Published: 2008
    Released: November 21, 2008
    [Advance publication] Released: November 06, 2008
    JOURNALS FREE ACCESS
    In the present study, we investigated whether dynamic and static allodynia would be developed in the affected dermatome in murine models of herpetic pain and postherpetic neuralgia and pharmacologically characterized the allodynia. Inoculation with herpes simplex virus type-1 on the femur induced skin lesions in the dermatome including the plantar region of the hind paw from day 5 to day 21 after inoculation. Dynamic allodynia became apparent in the hind paw from day 3 to at least day 42. Static allodynia was not obvious during the stage of herpetic pain and gradually increased after the lesion healing. Mexiletine hydrochloride (30 mg/kg, p.o.) and ketamine hydrochloride (50 mg/kg, i.p.) produced a moderate attenuation of static but not dynamic allodynia. Diclofenac sodium (50 mg/kg, i.p.) did not affect both static and dynamic allodynia. Gabapentin (30 mg/kg, p.o.) markedly inhibited both static and dynamic allodynia. Developmental and pharmacological differences between static and dynamic allodynia suggest that independent mechanisms are responsible for dynamic and static allodynia. This murine model may be useful for the study of the mechanisms of dynamic allodynia of herpetic pain or postherpetic neuralgia and the development of new analgesics effective against the dynamic allodynia.
    Download PDF (492K)
  • Makoto Shigeto, Masashi Katsura, Masafumi Matsuda, Seitaro Ohkuma, Koh ...
    2008 Volume 108 Issue 3 Pages 274-279
    Published: 2008
    Released: November 21, 2008
    [Advance publication] Released: November 06, 2008
    JOURNALS FREE ACCESS
    Glucagon-like peptide-1 (GLP-1) induces pancreatic insulin secretion via the cAMP-dependent protein kinase (PKA) pathway. However, the GLP-1 concentration used in the previous in vitro experiments was far from the in vivo concentrations. Alteration of plasma GLP-1 concentration at pM order lowers blood glucose concentration. In this study, we examined the GLP-1 action mechanism at a physiological concentration on insulin secretion. A high concentration of GLP-1 (10 nM) stimulated intracellular cAMP accumulation and insulin secretion was significantly inhibited by KT5720, a selective inhibitor of PKA. Low GLP-1 concentrations (1 pM) also increased insulin secretion without significant accumulation of intracellular cAMP, and KT5720 did not affect insulin secretion. Insulin secretion stimulated by 1 pM GLP-1 was reduced by inhibitors of calcium action, including verapamil, dantrolene, and BAPTA. Thus, we concluded that relatively low GLP-1 concentrations–comparable to in vivo blood concentrations–promoted insulin secretion independent of the cAMP-PKA pathway. This effect was dependent on intracellular Ca2+ concentration. The results of the present study may further the understanding of the dose-dependent response of GLP-1 signal transducing pathways and the complicated mechanism of insulin secretion. Studies of GLP-1 at physiologic concentrations may lead to new developments in studies of pancreatic β-cell function.
    Download PDF (309K)
  • Sirirat Amonpatumrat, Hiroyuki Sakurai, Pattama Wiriyasermkul, Narakor ...
    2008 Volume 108 Issue 3 Pages 280-289
    Published: 2008
    Released: November 21, 2008
    JOURNALS FREE ACCESS
    Methylmercury (MeHg) is a well-known environmental toxicant. With its lipophilic nature and high reactivity to sulfhydryl groups, it is widely distributed and accumulated in the body to damage cells. Oxidative stress is proposed as a major mechanism underlying the cytotoxic action of MeHg. In the present study, we found that L-glutamate (L-Glu) concentration-dependently increased MeHg cytotoxicity in HeLa S3 cells. The enhancement of the toxicity was accompanied by enhanced apoptosis, increased production of reactive oxygen species, and decreased glutathione level. An anti-oxidant N-acetylcysteine largely alleviated the cytotoxicity, suggesting enhanced oxidative stress behind L-Glu-elicited increase of MeHg toxicity. The effect was specific to L-Glu and L-α-aminoadipate, whereas D-Glu, L-aspartate, and D-aspartate were not effective. In addition, the cystine uptake by the cells was mostly mediated by a L-Glu/L-α-aminoadipate–sensitive amino acid transport system xC. All these results suggest that the inhibition of system xC by L-Glu underlies the enhancement of MeHg cytotoxicity. The enhancement was highly synergistic because MeHg and L-Glu alone had little toxic effect in the conditions used. This synergism was confirmed in neural cells (neuroblastoma cell lines). It is proposed that similar mechanisms may underlie the neural toxicity of MeHg, particularly in the locality of lesions characteristic of MeHg toxicity.
    Download PDF (547K)
  • Li-Ying Hao, Jian-Jun Xu, Etsuko Minobe, Asako Kameyama, Masaki Kameya ...
    2008 Volume 108 Issue 3 Pages 290-300
    Published: 2008
    Released: November 21, 2008
    JOURNALS FREE ACCESS
    The roles of calmodulin (CaM)-dependent protein kinase II (CaMKII) in the maintenance of basal activity and the reversion of run-down of L-type Ca2+ channels were studied in guinea-pig ventricular myocytes by the patch-clamp technique. In the cell-attached configuration, the Ca2+-channel activity was inhibited to 82% – 26% by 1 – 10 μM KN-93 and to 92% – 66% by 0.1 – 1 μM autocamtide-2–related inhibitory peptide (AIP) myristoylated. In the inside-out configuration, the bovine cardiac cytoplasm recovered Ca2+-channel activity to 87% of that recorded in the cell-attached configuration, while the CaMKII inhibitor 281-301 at 10 μM reduced the recovery effect to 19%. CaM + ATP recovered the channel activity to 93% and 28% of that recorded in the cell-attached configuration when applied at 1 and 5 min after run-down, respectively, showing a time-dependent attenuation. However, in the presence of 0.33 μM CaMKII, this attenuation was abolished, showing 85% and 75% recovery when applied at 1 and 5 min after run-down, respectively. This recovery effect was suppressed by 10 μM AIP, applied at 5 min, but not at 1 min after run-down. We concluded that CaMKII activation is required in the maintenance of basal activity of L-type Ca2+ channels.
    Download PDF (797K)
  • Kaichiro Kamiya, Ryoko Niwa, Mikio Morishima, Haruo Honjo, Michael C. ...
    2008 Volume 108 Issue 3 Pages 301-307
    Published: 2008
    Released: November 21, 2008
    [Advance publication] Released: November 06, 2008
    JOURNALS FREE ACCESS
    Block of cardiac hERG K+ channels by the antihistamine terfenadine and the prokinetic agent cisapride is associated with prolonged ventricular repolarization and an increased risk of ventricular arrhythmia. Here, we used a site-directed mutagenesis approach to determine the molecular determinants of hERG block by terfenadine and cisapride. Wild-type and mutant hERG channels were heterologously expressed in Xenopus laevis oocytes and characterized by measuring whole cell currents with two-microelectrode voltage clamp techniques. Mutation of T623, S624, Y652, or F656 to Ala reduced channel sensitivity to block by terfenadine. The same mutations reduced sensitivity to cisapride. These data confirm our previous findings that polar residues (T623, S624) located near the base of the pore helix and aromatic residues (Y652, F656) located in the S6 domain are key molecular determinants of the hERG drug binding site. Unlike methanesulfonanilides (dofetilide, MK-499, E-4031, ibutilide) or clofilium, mutation of V625, G648, or V659 did not alter the sensitivity of hERG channels to terfenadine or cisapride. As previously proposed by molecular modeling studies (Farid R, et al. Bioorg Med Chem. 2006;14:3160–3173), our findings suggest that different drugs can adopt distinct modes of binding to the central cavity of hERG.
    Download PDF (1048K)
  • Minoru Hojo, Yuka Sudo, Yuko Ando, Koichiro Minami, Masafumi Takada, T ...
    2008 Volume 108 Issue 3 Pages 308-319
    Published: 2008
    Released: November 21, 2008
    [Advance publication] Released: November 13, 2008
    JOURNALS FREE ACCESS
    Interactions between μ-opioid receptor (μOR) and cannabinoid CB1 receptor (CB1R) were examined by morphological and electrophysiological methods. In baby hamster kidney (BHK) cells coexpressing μOR fused to the yellow fluorescent protein Venus and CB1R fused to the cyan fluorescent protein Cerulean, both colors were detected on the cell surface; and fluorescence resonance energy transfer (FRET) analysis revealed that μOR and CB1R formed a heterodimer. Coimmunoprecipitation and Western blotting analyses also confirmed the heterodimers of μOR and CB1R. [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO) or CP55,940 elicited K+ currents in Xenopus oocytes expressing μOR or CB1R together with G protein activated-inwardly rectifying K+ channels (GIRKs), respectively. In oocytes coexpressing both receptors, either of which was fused to the chimeric Gα protein Gqi5 that activates the phospholipase C pathway, both DAMGO and CP55,940 elicited Ca2+-activated Cl currents, indicating that each agonist can induce responses through Gqi5 fused to either its own receptor or the other. Experiments with endogenous Gi/o protein inactivation by pertussis toxin (PTX) supported the functional heterodimerization of μOR/CB1R through PTX-insensitive Gqi5(m) fused to each receptor. Thus, μOR and CB1R form a heterodimer and transmit a signal through a common G protein. Our electrophysiological method could be useful for determination of signals mediated through heterodimerized G protein–coupled receptors.
    Download PDF (900K)
  • Kou Takahashi, Akiyoshi Saitoh, Misa Yamada, Yoshiaki Maruyama, Norita ...
    2008 Volume 108 Issue 3 Pages 320-334
    Published: 2008
    Released: November 21, 2008
    JOURNALS FREE ACCESS
    We investigated the effects of antidepressants on the gene expression profile and behavior of olfactory-bulbectomized (OBX) rats. Removal of the main olfactory bulbs in rats alters neuronal function in brain areas involved in emotional regulation, resulting in maladaptive behavioral patterns similar to the symptoms of patients with depression. Previously, we found that OBX-induced behavioral and neuronal abnormalities were completely rescued by chronic treatment with SNC80, an opioid delta agonist, as well as with classical monoaminergic antidepressants. Thus, to determine the basis for this effect, we analyzed gene expression in OBX rat frontal cortex using a GeneChip® rat Genome oligonucleotide array after imipramine or SNC80 treatment. We found that imipramine and SNC80 induced the following systematic changes in OBX rats: zinc ion binding; hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides; protein serine/threonine kinase activity; N-acetyltransferase activity; protein modification process; regulation of cellular process; and regulation of neurotransmitter levels. Defining the roles of candidate neuronal systems in antidepressant-induced neural changes are likely to transform the course of research on the biological basis of mood disorders.
    Download PDF (962K)
  • Tadatsugu Tarumi, Azusa Mikami, Kenichi Shimada, Chiaki Kamei
    2008 Volume 108 Issue 3 Pages 335-340
    Published: 2008
    Released: November 21, 2008
    [Advance publication] Released: November 13, 2008
    JOURNALS FREE ACCESS
    The effect of [pGlu4,Cyt6,Arg8]-vasopressin fragment 4-9 (AVP4-9) on group I metabotropic glutamate (mGlu1) receptor antagonist–induced memory deficits was studied using 8-arm radial maze performance with 4 arms baited. In addition, the participation of the cholinergic system in the ameliorating effect of AVP4-9 on mGlu1 receptor antagonist–induced memory deficits was also investigated. Intrahippocampal injection of (R,S)-1-aminoindan-1,5-dicarboxylic acid (AIDA), an mGlu1-receptor antagonist, significantly increased total error, reference memory error, and working memory error at a dose of 20 nmol/side. AVP4-9 (0.1 and 1.0 μg/kg, s.c.) showed a significant ameliorative effect on AIDA-induced memory deficits. Improvement of AIDA-induced memory deficit in response to AVP4-9 treatment was significantly antagonized by scopolamine (5 nmol/side) but not by mecamylamine (200 nmol/side) at a dose that caused no effect on performance when injected separately. These findings indicate that the ameliorating effect of AVP4-9 on AIDA-induced memory deficit may be closely associated with the muscarinic receptor.
    Download PDF (299K)
  • Takehiko Maeda, Norikazu Kiguchi, Yuka Kobayashi, Masanobu Ozaki, Shir ...
    2008 Volume 108 Issue 3 Pages 341-347
    Published: 2008
    Released: November 21, 2008
    [Advance publication] Released: November 13, 2008
    JOURNALS FREE ACCESS
    To clarify the role of peroxisome proliferator activated receptor γ (PPARγ) in neuropathic pain, we examined the effect of pioglitazone, a PPARγ agonist, on tactile allodynia and thermal hyperalgesia in a neuropathic pain model. Mice were subjected to partial sciatic nerve ligation (PSL) and given pioglitazone (1 – 25 mg/kg, p.o.) once daily. PPARγ was distributed in the neurons of the dorsal root ganglion and the dorsal horn of the spinal cord and in the adipocytes at the epineurium of the sciatic nerve in naive mice. PSL elicited tactile allodynia and thermal hyperalgesia for two weeks. Administration of pioglitazone for the first week after PSL attenuated thermal hyperalgesia and tactile allodynia, which was dose-dependent and blocked by GW9662 (2 mg/kg, i.p.), a PPARγ antagonist. Administration of pioglitazone for the second week also relieved tactile allodynia, but administration one week before PSL had no effect. A single administration of pioglitazone to mice on day 7 of PSL did not alter tactile allodynia and thermal hyperalgesia. PSL-induced upregulation of tumor necrosis factor-α and interleukin-6, which are essential for neuropathic pain, was suppressed by pioglitazone for the first week. This suggests that pioglitazone alleviates neuropathic pain through attenuation of proinflammatory cytokine upregulation by PPARγ stimulation.
    Download PDF (663K)
  • Kenji Hayata, Katsuichi Sakano, Shigeyuki Nishinaka
    2008 Volume 108 Issue 3 Pages 348-354
    Published: 2008
    Released: November 21, 2008
    [Advance publication] Released: November 13, 2008
    JOURNALS FREE ACCESS
    To obtain compounds that promote glucose uptake in muscle cells, the novel cell lines A31-IS derived from Balb/c 3T3 A31 and C2C12-IS from mouse myoblast C2C12 were established. In both cell lines, glucose consumption was induced by insulin and suppressed by the addition of Akt-activating kinase inhibitor. The A31-IS cells highly express the insulin receptor β chains, Glut4, and uncoupling protein-3, as compared to the parent Balb/c 3T3 A31 cells, and C2C12-IS cells highly express the insulin receptor β chain as compared to its parent cell line. Using A31-IS cells, we screened our library compounds and obtained three compounds, DF-4394, DF-4451, and DG-5451. These compounds dose-dependently promoted glucose consumption in A31-IS cells and facilitated [3H]-2-deoxyglucose uptake in differentiated C2C12-IS cells. The compounds that we obtained from the library screening will be good candidates for improving insulin resistance in muscle cells.
    Download PDF (419K)
  • Masayuki Ishizaki, Hiroyuki Tanaka, Daisuke Kajiwara, Tatsuyuki Toyoha ...
    2008 Volume 108 Issue 3 Pages 355-363
    Published: 2008
    Released: November 21, 2008
    [Advance publication] Released: November 14, 2008
    JOURNALS FREE ACCESS
    To clarify the involvement of serine proteases in the development of allergic airway inflammation, we investigated the effect of nafamostat mesilate, a serine protease inhibitor, in a murine model of allergic asthma. Mice were sensitized to ovalbumin (OA) with alum and then exposed to 1% OA for 30 min, three times every 4th day. Nafamostat mesilate was administered orally for 10 days during the allergen challenge. In sensitized mice, repeated allergen challenge induced an increase in tryptase proteolytic activity in bronchoalveolar lavage fluid (BALF). In addition, marked increases in the numbers of inflammatory cells, levels of T helper type 2 (Th2) cytokines and eotaxin in BALF, numbers of goblet cells in the epithelium, and level of OA-specific IgE in serum were observed after repetitive allergen inhalation. Treatment with nafamostat mesilate significantly inhibited not only increased proteolytic activities, but also increases in the numbers of eosinophils and lymphocytes in the BALF. Nafamostat mesilate also dose-dependently inhibited increases in the levels of interleukin-13 and eotaxin in BALF and goblet cell hyperplasia. These findings suggest that increased serine protease activity in the airways is involved in the development of antigen-induced allergic eosinophilic inflammation and epithelial remodeling in bronchial asthma.
    Download PDF (564K)
  • Tomoaki Kahyo, Shuji Ichikawa, Takahiro Hatanaka, Maki K. Yamada, Mits ...
    2008 Volume 108 Issue 3 Pages 364-371
    Published: 2008
    Released: November 21, 2008
    [Advance publication] Released: November 13, 2008
    JOURNALS FREE ACCESS
    SIRT1 is one of seven mammalian orthologs of yeast silent information regulator 2 (Sir2), and it functions as a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase. Recently, resveratrol and its analogues, which are polyphenols, have been reported to activate the deacetylase activity of SIRT1 in an in vitro assay and to expand the life-span of several species through Sir2 and the orthologs. To find activators or inhibitors to SIRT1, we examined thirty-six polyphenols, including stilbenes, chalcones, flavanones, and flavonols, with the SIRT1 deacetylase activity assay using the acetylated peptide of p53 as a substrate. The results showed that 3,2',3',4'-tetrahydroxychalcone, a newly synthesized compound, inhibited the SIRT1-mediated deacetylation of a p53 acetylated peptide and recombinant protein in vitro. In addition, this agent induced the hyperacetylation of endogenous p53, increased the endogenous p21CIP1/WAF1 in intact cells, and suppressed the cell growth. These results indicated that 3,2',3',4'-tetrahydroxychalcone had a stronger inhibitory effect on the SIRT1-pathway than sirtinol, a known SIRT1-inhibitor. Our results mean that 3,2',3',4'-tetrahydroxychalcone is a novel inhibitor of SIRT1 and produces physiological effects on organisms probably through inhibiting the deacetylation by SIRT1.
    Download PDF (392K)
  • Kyung-Jong Won, Seung Hwa Park, Taekyu Park, Chang-Kwon Lee, Hwan Myun ...
    2008 Volume 108 Issue 3 Pages 372-379
    Published: 2008
    Released: November 21, 2008
    JOURNALS FREE ACCESS
    Cofilin, an actin-binding protein, is essential for a variety of cell responses. In this study, we investigated the correlation between proliferation and cofilin phosphorylation in response to platelet-derived growth factor (PDGF) in rat aortic smooth muscle cells (RASMCs). The phosphorylation of cofilin and activity of mitogen-activated protein kinase (MAPK) were measured by Western analyses and proliferation in RASMCs was measured by BrdU incorporation assays. The phosphorylation of cofilin in RASMCs was decreased by PDGF-BB treatment at 10 min, but recovered to the level of the quiescent state at 60 min. PDGF-BB–induced dephosphorylation of cofilin was inhibited by pretreatment with piceatannol (a spleen tyrosine kinase [Syk] inhibitor), PP2 (a Src inhibitor), or SP600125 (a c-Jun N-terminal kinase [JNK] inhibitor), but not by PD98059, an inhibitor of extracellular signal-regulated kinase 1/2. PDGF-BB increased JNK activity and proliferation, and these responses were suppressed by kinase inhibitors and small interference RNA-cofilin. The results suggest that PDGF-BB–induced dephosphorylation of cofilin can be promoted via the JNK pathway, which is regulated by both Syk and Src kinases and that cofilin dephosphorylation may be involved in PDGF-BB–induced RASMC proliferation.
    Download PDF (924K)
Short Communications
  • Junzo Kamei, Shigeo Miyata, Takayuki Sunohara, Atsuko Kamei, Masahiko ...
    2008 Volume 108 Issue 3 Pages 381-384
    Published: 2008
    Released: November 21, 2008
    [Advance publication] Released: November 06, 2008
    JOURNALS FREE ACCESS
    We examined the effect of the novel atypical antipsychotic drug aripiprazole alone or in combination with the selective serotonin reuptake inhibitor fluoxetine in the mouse tail suspension test. We also investigated the effect of aripiprazole on glucose metabolism. Combined treatment with aripiprazole and a sub-effective dose of fluoxetine significantly decreased the duration of immobility in the tail suspension test. Aripiprazole by itself did not affect the duration of immobility. While olanzapine significantly increased blood glucose level in the glucose tolerance test, aripiprazole did not affect glucose metabolism. We suggest that aripiprazole augments the antidepressant-like effect of fluoxetine without affecting glucose metabolism.
    Download PDF (225K)
  • Kenichiro Tsujii, Tsugunobu Andoh, Jung-Bum Lee, Yasushi Kuraishi
    2008 Volume 108 Issue 3 Pages 385-388
    Published: 2008
    Released: November 21, 2008
    [Advance publication] Released: November 06, 2008
    JOURNALS FREE ACCESS
    Proteinase-activated receptor-2 (PAR2) participates in itch, but the role of the other subtypes of this receptor remain unknown. To investigate this issue, scratching, an itch-related behavior, was observed following intradermal injections of the activating peptides of PAR1–4 in mice. Activating peptides of PAR1, PAR2, and PAR4, but not PAR3, induced scratching. The antihistamine terfenadine suppressed scratching elicited by activating peptides of PAR1 and PAR4, but not PAR2. These results suggest that PAR1, PAR2, and PAR4 are involved in itch and that histamine is a cause of itch related to PAR1 and PAR4, but not PAR2.
    Download PDF (186K)
  • Takashi Orido, Hiromichi Fujino, Yuta Hasegawa, Kaori Toyomura, Tatsuo ...
    2008 Volume 108 Issue 3 Pages 389-392
    Published: 2008
    Released: November 21, 2008
    [Advance publication] Released: November 06, 2008
    JOURNALS FREE ACCESS
    Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the incidence of colorectal cancer. However, evidence is accumulating that NSAIDs have anti-cancer effects in addition to inhibiting cyclooxygenase (COX)-mediated prostanoid biosynthesis. We now show that indomethacin, a popular NSAID, significantly reduced the [3H]-arachidonic acid uptake in HCA-7 human colon cancer cells. Interestingly, no decrease in the uptake of [3H]-arachidonic acid occurred when the cells were treated with aspirin, diclofenac, and sulindac even though the concentrations of these NSAIDs were high enough to inhibit COX-2 activity. These findings suggest that indomethacin has a novel anti-cancer effect that may be independent of COX-2 inhibition.
    Download PDF (569K)
feedback
Top