Journal of Pharmacological Sciences
Online ISSN : 1347-8648
Print ISSN : 1347-8613
ISSN-L : 1347-8613
Volume 119 , Issue 3
Showing 1-13 articles out of 13 articles from the selected issue
Current Perspective
  • Junichi Kikuta, Masaru Ishii
    2012 Volume 119 Issue 3 Pages 193-197
    Published: 2012
    Released: July 18, 2012
    [Advance publication] Released: June 13, 2012
    JOURNALS FREE ACCESS
    Intravital multiphoton microscopy has opened a new era in the field of biological imaging. Focal excitation of fluorophores by simultaneous attack of multiple (normally “two”) photons generates images with high spatial resolution, and use of near-infrared lasers for multiphoton excitation allows penetration of thicker specimens, enabling biologists to visualize living cellular dynamics deep inside tissues and organs without thin sectioning. Moreover, the minimized photo-bleaching and toxicity associated with multiphoton techniques is beneficial for imaging of live specimens for extended observation periods. Here we focus on recent findings using intravital multiphoton imaging of dynamic biological systems such as the immune system and bone homeostasis. The immune system comprises highly dynamic networks, in which many cell types actively travel throughout the body and interact with each other in specific areas. Therefore, real-time intravital imaging represents a powerful tool for understanding the mechanisms underlying this dynamic system.
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  • Koichiro Kuwahara, Toshio Nishikimi, Kazuwa Nakao
    2012 Volume 119 Issue 3 Pages 198-203
    Published: 2012
    Released: July 18, 2012
    [Advance publication] Released: June 13, 2012
    JOURNALS FREE ACCESS
    Reactivation of the fetal cardiac gene program in adults is a reliable marker of cardiac hypertrophy and heart failure. Normally, genes within this group are expressed in the fetal ventricles during development, but are silent after birth. However, their expression is re-induced in the ventricular myocardium in response to various cardiovascular diseases, and potentially plays an important role in the pathological process of cardiac remodeling. Thus, analysis of the molecular mechanisms that govern the expression of fetal cardiac genes could lead to the discovery of transcriptional regulators and signaling pathways involved in both cardiac differentiation and cardiac disease. In this review we will summarize what is currently known about the transcriptional regulation of the fetal cardiac gene program.
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Full Paper
  • Ashok Kumar Sharma, Saurabh Bharti, Rajiv Kumar, Bhaskar Krishnamurthy ...
    2012 Volume 119 Issue 3 Pages 205-213
    Published: 2012
    Released: July 18, 2012
    [Advance publication] Released: June 21, 2012
    JOURNALS FREE ACCESS
    Syzygium cumini (SC) is well known for its anti-diabetic potential, but the mechanism underlying its amelioration of type 2 diabetes is still elusive. Therefore, for the first time, we investigated whether SC aqueous seed extract (100, 200, or 400 mg/kg) exerts any beneficial effects on insulin resistance (IR), serum lipid profile, antioxidant status, and/or pancreatic β-cell damage in high-fat diet / streptozotocin–induced (HFD–STZ) diabetic rats. Wistar albino rats were fed with HFD (55% of calories as fat) during the experiment to induce IR and on the 10th day were injected with STZ (40 mg/kg, i.p.) to develop type 2 diabetes. Subsequently, after confirmation of hyperglycemia on the 14th day (fasting glucose level > 13.89 mM), diabetic rats were treated with SC for the next 21 days. Diabetic rats showed increased serum glucose, insulin, IR, TNF-α, dyslipidemia, and pancreatic thiobarbituric acid-reactive substances with a concomitant decrease in β-cell function and pancreatic superoxide dismutase, catalase, and glutathione peroxidase antioxidant enzyme activities. Microscopic examination of their pancreas revealed pathological changes in islets and β-cells. These alterations reverted to near-normal levels after treatment with SC at 400 mg/kg. Moreover, hepatic tissue demonstrated increased PPARγ and PPARα protein expressions. Thus, our study demonstrated the beneficial effect of SC seed extract on IR and β-cell dysfunction in HFD–STZ-induced type 2 diabetic rats.
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  • Fen Yang, Wen-Dan Chen, Rong Deng, Dan-Dan Li, Ke-Wei Wu, Gong-Kan Fen ...
    2012 Volume 119 Issue 3 Pages 214-220
    Published: 2012
    Released: July 18, 2012
    [Advance publication] Released: June 13, 2012
    JOURNALS FREE ACCESS
    Hirsutanol A is a novel sesquiterpene compound purified from the marine fungus Chondrostereum sp in the coral Sarcophyton tortuosum. Our previous studies had demonstrated that hirsutanol A exerted potent cytotoxic effect in many kinds of cancer cell lines. Here, the anticancer molecular mechanisms of hirsutanol A were investigated in breast cancer MCF-7 cells. The results showed that hirsutanol A could inhibit cell proliferation, elevate reactive oxygen species (ROS) level, and induce apoptosis and autophagy. Co-treatment with the potent antioxidant agent N-acetyl-L-cysteine could effectively reverse the effect of enhanced ROS production, which in turn, reduces growth inhibition, apoptosis, and autophagy mediated by hirsutanol A. In addition, blocking autophagy by bafilomycin A1 or Atg7-siRNA could synergistically enhance the antiproliferative effect and apoptosis induced by hirsutanol A. These data suggested that hirsutanol A could induce apoptosis and autophagy via accumulation of ROS and co-treatment with an autophagy inhibitor could sensitize MCF-7 cells to hirsutanol A.
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  • Irena Lavrnja, Danijela Savic, Ivana Bjelobaba, Sanja Dacic, Iva Bozic ...
    2012 Volume 119 Issue 3 Pages 221-232
    Published: 2012
    Released: July 18, 2012
    [Advance publication] Released: June 28, 2012
    JOURNALS FREE ACCESS
    Experimental autoimmune encephalomyelitis (EAE) is an animal model of CNS inflammatory and demyelinating disease multiple sclerosis. Microglia and astrocytes represent two related cell types involved in the brain pathology in EAE. Accumulations of hypertrophic reactive astrocytes, intensely stained with glial fibrillary acidic protein (GFAP), which also expressed vimentin, are prominent features of EAE lesions. Recent studies from our laboratory reported that ribavirin attenuated the disease process in EAE by reducing clinical and histological manifestations. EAE was induced in genetically susceptible Dark Agouti rats with syngeneic spinal cord homogenate in complete Freund’s adjuvant. Real time PCR and immunohistochemistry were used for determination of GFAP and vimentin gene and tissue expression. We have observed the increased gene and tissue expression of GFAP and vimentin in EAE rats. Ribavirin treatment significantly decreased the number of reactive astrocytes at the peak of disease. At the end of the disease, we have observed reactive GFAP+ and vimentin+ astrocytes in both immunized and ribavirin-treated groups, accompanied by increased level of GFAP mRNA. The present study indicates that ribavirin may have the ability to attenuate astrocyte proliferation and glial scaring at the peak of the disease and modulate the astroglial response to EAE during the time-course of the disease.
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  • Shigeru Hishinuma, Yuko Sato, Chizuru Akatsu, Masaru Shoji
    2012 Volume 119 Issue 3 Pages 233-242
    Published: 2012
    Released: July 18, 2012
    [Advance publication] Released: June 21, 2012
    JOURNALS FREE ACCESS
    We examined the regulatory mechanisms of the affinity of Gq protein-coupled histamine H1-receptors for histamine after histamine pretreatment in intact human U373 MG astrocytoma cells. In control cells, the displacement curves for histamine against the binding of 5 nM [3H]mepyramine, a radioligand for H1-receptors, showed the presence of two binding sites for histamine, that is, high and low affinity sites. Pretreatment with 0.1 mM histamine for 30 min at 37°C induced a significant reduction in the percentage of high affinity sites for histamine and a concomitant increase in the percentage of low affinity sites with no change in their pIC50 values. These histamine-induced changes were insensitive to 30 μM KN-62, an inhibitor of Ca2+/calmodulin-dependent protein kinase II, but they were completely inhibited either by 0.4 mM ZnCl2, an inhibitor of G protein-coupled receptor kinases (GRKs), or under hypertonic conditions, where clathrin-mediated endocytosis is known to be inhibited. These results suggest that histamine-induced conversion of high to low affinity sites for histamine is predominantly regulated by GRK/clathrin-mediated internalization of H1-receptors in human astrocytoma cells.
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  • Kumi Yamada, Hisae Niki, Hitoshi Nagai, Masakuni Nishikawa, Haruto Nak ...
    2012 Volume 119 Issue 3 Pages 243-250
    Published: 2012
    Released: July 18, 2012
    [Advance publication] Released: June 28, 2012
    JOURNALS FREE ACCESS
    To clarify the involvement of 5-hydroxytryptamine (5-HT) in promotion of thrombogenesis in diabetes, we examined the inhibitory effect of sarpogrelate, a 5-HT2A receptor antagonist, on thrombus formation in diabetic rats. In streptozotocin-induced diabetic rats, polyethylene tube–induced thrombus formation was enhanced compared with that in normal rats. The thrombogenesis was inhibited by sarpogrelate; cilostazol, a PDE3 inhibitor; and aspirin, a COX inhibitor, by 75.8%, 42.3%, and 34.3%, respectively. The inhibition by sarpogrelate was more pronounced in diabetic rats than normal ones. High glucose and 5-HT increased the expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs) and combination of both high glucose and 5-HT further potentiated the effect. Sarpogrelate but not aspirin inhibited the increase in VCAM-1 expression induced by high glucose and 5-HT. These findings suggest that 5-HT mediates the enhanced thrombogenesis in diabetes and suggests that a 5-HT2A receptor antagonist may have novel therapeutic potential for the treatment of diabetic complications.
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  • Yasuhiro Ishihara, Norio Shimamoto
    2012 Volume 119 Issue 3 Pages 251-259
    Published: 2012
    Released: July 18, 2012
    [Advance publication] Released: June 28, 2012
    JOURNALS FREE ACCESS
    We previously reported the administration of a potent cytochrome P450 inhibitor, sulfaphenazole (SPZ), to suppress oxidative stress and the extension of myocardial infarct size in a rat model of cardiac ischemia–reperfusion (I/R). The aim of this study was to investigate the effects of SPZ on the myocardial cell apoptosis induced by I/R in rats. I/R injury was evoked by ligation of the left anterior descending coronary artery for 1 h, followed by reperfusion for 3 h. TUNEL-positive nuclei were detected and nucleosomal DNA fragmentation was observed 3 h after reperfusion. The administration of SPZ largely suppressed the cardiac DNA fragmentation induced by I/R. A pan-caspase inhibitor, z-VAD-fmk, had no effect on DNA fragmentation. Caspase-3/7 was not activated 3 h after reperfusion. Decreases in the mitochondrial membrane potential and cytochrome c release from the mitochondria to cytosol were detected 3 h after reperfusion. The expression levels of BimEL and Noxa were elevated 3 h after reperfusion. These phenomena were suppressed by the administration of SPZ. Taken together, treatment with SPZ could attenuate the myocardial cell apoptosis accompanied with I/R by inhibiting the mitochondrial dysfunction due to decreases in the expression of BimEL and Noxa.
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  • Hiroki Fujiwara, Narumi Hashikawa-Hobara, Yoshihiro Wake, Shingo Takat ...
    2012 Volume 119 Issue 3 Pages 260-270
    Published: 2012
    Released: July 18, 2012
    [Advance publication] Released: June 28, 2012
    JOURNALS FREE ACCESS
    Rat mesenteric arteries were maintained by both adrenergic vasoconstrictor nerves and calcitonin gene–related peptide (CGRP) vasodilator nerves. However, functions of these nerves in a pathophysiological state have not fully been analyzed. The use of disease models developed genetically in mice is expected to clarify neural function of perivascular nerves. Thus, we investigated basic mouse vascular responses. Mesenteric vascular beds isolated from male C57BL/6 mouse were perfused with Krebs solution and perfusion pressure was measured. Periarterial nerve stimulation (PNS, 8 – 24 Hz) induced frequency-dependent vasoconstriction, which increased flow rate–dependently. PNS-induced vasoconstriction was abolished by tetrodotoxin (neurotoxin) and guanethidine (adrenergic neuron blocker) and blunted by prazosin (α1-adrenoceptor antagonist). Injection of norepinephrine caused vasoconstriction, which was abolished by prazosin. In preparations with active tone, PNS (1 – 8 Hz) induced frequency-dependent vasodilation, which was inhibited by tetrodotoxin, capsaicin (CGRP depletor), and CGRP8-37 (CGRP-receptor antagonist). Injections of CGRP, acetylcholine, and sodium nitroprusside induced vasodilations. Vasodilator response to CGRP was inhibited by CGRP8-37. Immunohistochemical study showed innervation of tyrosine hydroxylase- and CGRP-immunopositive fibers in mesenteric arteries and veins. These results suggest that male mouse mesenteric vascular beds are useful for studying neural regulation of mesenteric arteries, which are innervated by adrenergic and CGRPergic nerves regulating vascular tone.
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  • Yoshiyuki Tanabe, Maki Saito-Tanji, Yuki Morikawa, Akihisa Kamataki, T ...
    2012 Volume 119 Issue 3 Pages 271-281
    Published: 2012
    Released: July 18, 2012
    [Advance publication] Released: June 29, 2012
    JOURNALS FREE ACCESS
    Excessive stretching of the vascular wall in accordance with pulmonary arterial hypertension (PAH) induces a variety of pathogenic cellular events in the pulmonary arteries. We previously reported that indoxam, a selective inhibitor for secretory phospholipase A2 (sPLA2), blocked the stretch-induced contraction of rabbit pulmonary arteries by inhibition of untransformed prostaglandin H2 (PGH2) production. The present study was undertaken to investigate involvement of sPLA2 and untransformed PGH2 in the enhanced contractility of pulmonary arteries of experimental PAH in rats. Among all the known isoforms of sPLA2, sPLA2-X transcript was most significantly augmented in the pulmonary arteries of rats with monocrotaline-induced pulmonary hypertension (MCT-PHR). The pulmonary arteries of MCT-PHR frequently showed two types of spontaneous contraction in response to stretch; 27% showed rhythmic contraction, which was sensitive to indoxam and SC-560 (selective COX-1 inhibitor), but less sensitive to NS-398 (selective COX-2 inhibitor); and 47% showed sustained incremental tension (tonic contraction), which was insensitive to indoxam and SC-560, but sensitive to NS-398 and was attenuated to 45% of the control. Only the rhythmically contracting pulmonary arteries of MCT-PHR produced a substantial amount of untransformed PGH2, which was abolished by indoxam. These results suggest that sPLA2-mediated PGH2 synthesis plays an important role in the rhythmic contraction of pulmonary arteries of MCT-PHR.
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Short Communication
  • Lin Ma, Jun Nagai, Yuki Sekino, Yoshitaka Goto, Shinji Nakahira, Hiros ...
    2012 Volume 119 Issue 3 Pages 282-286
    Published: 2012
    Released: July 18, 2012
    [Advance publication] Released: June 28, 2012
    JOURNALS FREE ACCESS
    Botulinum toxin type A is a unique candidate for inhibition of pain transmission. In the present study we attempted to see the beneficial actions of A2 neurotoxin (NTX), an active subunit of botulinum toxin type A. Intraplantar injection of A2 NTX significantly suppressed mechanical allodynia and hypersensitivities to A-fiber stimuli in the diabetic neuropathic pain model. Spinal application of A2 NTX also showed a potent suppression of thermal hyperalgesia and mechanical allodynia in the spinal cord injury–induced neuropathic pain model. A2 NTX seems to be a long-lasting treatment for diabetic and spinal cord injury–induced neuropathic pain.
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  • Yayoi Tsuneoka, Yuka Kobayashi, Yoriko Honda, Iyuki Namekata, Hikaru T ...
    2012 Volume 119 Issue 3 Pages 287-292
    Published: 2012
    Released: July 18, 2012
    [Advance publication] Released: June 29, 2012
    JOURNALS FREE ACCESS
    We recorded the electrical activity from the myocardial layer of isolated mouse pulmonary veins with the glass microelectrode technique. Spontaneous electrical activity was observed in about half of the preparations, which appeared either as constant firing or as repetitive bursts. Noradrenaline enhanced, while acetylcholine reduced, automatic activity. The action potentials evoked in quiescent preparations showed a resting membrane potential less negative than the atria and an extremely rapid early repolarization followed by a late plateau. The present study revealed that the mouse pulmonary vein myocardium shows diverse electrical activity, which is influenced by autonomic neurotransmitters.
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  • Maho Tsubota-Matsunami, Yumi Noguchi, Yasumasa Okawa, Fumiko Sekiguchi ...
    2012 Volume 119 Issue 3 Pages 293-296
    Published: 2012
    Released: July 18, 2012
    [Advance publication] Released: June 28, 2012
    JOURNALS FREE ACCESS
    Luminal hydrogen sulfide (H2S), a gasotransmitter, causes colonic pain / referred hyperalgesia in mice, most probably via activation of T-type Ca2+ channels. Here we analyzed the mechanisms for H2S-induced facilitation of colonic pain signals. Intracolonic administration of NaHS, an H2S donor, evoked visceral pain−like nociceptive behavior and referred hyperalgesia in mice, an effect abolished by NNC 55-0396, a selective T-type Ca2+-channel blocker, or by knockdown of Cav3.2. AP18, a TRPA1 blocker, also prevented the NaHS-induced colonic pain and referred hyperalgesia. These findings demonstrate that H2S-induced colonic pain and referred hyperalgesia require activation of both Cav3.2 and TRPA1 channels in mice.
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