• Title/Summary/Keyword: protein kinase C inhibitor

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Isolation and Biological Activity of Verbascoside, A Potent Inhibitor of Protein Kinase C from the Calyx of Campsis grandiflora (능소화의 꽃받침으로부터 Protein Kinase C 저해물질인 Verbascoside의 분리 및 그 생물활성)

  • 이현선;박문수;오원근;안순철;김보연;김환묵;오구택;민태익;안종석
    • YAKHAK HOEJI
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    • v.37 no.6
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    • pp.598-604
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    • 1993
  • The calyx extract of Campsis grandiflora displayed inhibitory activity against protein kinase C from the bovine brain. Separation guided by protein kinase C enzyme assay and bleb forming assay led to isolation of a potent protein kinase C inhibitor that was identified as a known phenylpropanoid glycoside, verbascoside. It suppressed completely bleb-formation of K562 cell surface induced by phorbol 12,13-dibutylate at the concentration of 60 $\mu\textrm{g}$/ml and IC$_{50}$ of the protein kinase C occured at 20 $\mu{M}$. This compound was tested for cytotoxic activity against ten human tumor cell lines in vitro. it exhibited moderate cytotoxic activity against skin tumor cell line M14 (IC$_{50}$ 2.2 $\mu\textrm{g}$/ml) and very weak cytotoxicity against other cell lines (IC$_{50}$>10 $\mu\textrm{g}$/ml)

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Antagonists of NMDA Receptor, Calcium Channel and Protein Kinase C Potentiate Inhibitory Action of Morphine on Responses of Rat Dorsal Horn Neuron

  • Shin, Hong-Kee;Kim, Yeon-Suk;Jun, Jong-Hun;Lee, Seo-Eun;Kim, Jae-Hwa
    • The Korean Journal of Physiology and Pharmacology
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    • v.7 no.5
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    • pp.251-254
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    • 2003
  • The present study was designed to examine whether the co-application of morphine with $Ca^{2+}$ channel antagonist $(Mn^{2+},\;verapamil)$, N-methyl-D-aspartate (NMDA) receptor antagonist (2-amino-5-phosphonopentanoic acid$[AP_5]$, $Mg^{2+}$) or protein kinase C inhibitor (H-7) causes the potentiation of morphine-induced antinociceptive action by using an in vivo electrophysiological technique. A single iontophoretic application of morphine or an antagonist alone induced weak inhibition of wide dynamic range (WDR) cell responses to iontophoretically applied NMDA and C-fiber stimulation. Although there was a little difference in the potentiating effects, the antinociceptive action of morphine was potentiated when morphine was iontophoretically applied together with $Mn^{2+}$, verapamil, $AP_5$, $Mg^{2+}$ or H-7. However, the potentiating action between morphine and each antagonist was not apparent, when the antinociceptive action evoked by morphine or the antagonist alone was too strong. These results suggest that the potentiating effect can be caused by the interaction between morphine and each antagonist in the spinal dorsal horn.

MT-2007, Protein Kinase C Inhibitor from Aetinomycetes Isolate No. 2007-18 (방선균 분리주 No 2007-18이 생산하는 Protein Kinase C 저해물질, MT-2007)

  • 안종석;박문수;박찬선;윤병대;민태익;안순철;오원근;이현선;윤병대
    • Microbiology and Biotechnology Letters
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    • v.21 no.1
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    • pp.54-58
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    • 1993
  • During the screening of inhibitors against protein kinase CCPKC) and the bleb formation of K562 cell induced by phorbol ester from microbial secondary metabolites, MT-2007 was purified by solvent extraction, and chromatographic techniques from Actinomycetes isolate No. 2007-18. It showed completely suppression of bleb formation of K562 cell surface induced by phorbol 12.13dibutylate at the concentration of 503.9 11M and ICso on PKC was 31.4 11M. Its structure was postulated as lasalocid A sodium salt by physico-chemical properties and UV, IR. MS, IH-NMR.

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THE EFFECT OF THE GENISTEIN ON THE PROLIFERATION OF HT1080 AND EXPRESSION OF MEMBRANE TYPE 1-MATRIX METALLOPROTEINASE (MT1-MMP) mRNA (Genistein이 사람 섬유육종 세포주 증식 및 Membrane Type 1-Matrix Metalloproteinase (MT1-MMP) mRNA 발현에 미치는 영향)

  • Kang, Jin-Han;Myoung, Hoon;Kim, Myung-Jin
    • Journal of the Korean Association of Oral and Maxillofacial Surgeons
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    • v.27 no.4
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    • pp.314-320
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    • 2001
  • Matrix metalloproteinases have long been viewed as ideal candidates for proteinases that enables tumor cells to permeated basement membrane defenses and invade surrounding tissue. There is growing evidence that the MMPs have an expanded role, as they are important for the creation and maintenance of a microenvironment that facilitates growth and angiogenesis of tumors at primary and metastatic sites. MT-MMPs are not secreted but instead remaining attached to cell surfaces. Although not all of the MT-MMPs are fully characterized, MT-MMPs have important role in localizing and activating secreted MMPs. The MMP genes are transcriptionally responsive to a wide variety of oncogene, growth factors, cytokine, and hormones. Currently, a number of MMP inhibitors are being developed and some have reached clinical trials as anti-metastatic or anti-cancer therapies. MT1-MMP is involved in the activation of proMMP-2. MT1-MMP is significant not only as a tumor marker but as a new target for chemotherapy against cancer. The purpose of this study was to evaluate the effects of protein kinase C inhibitor(genistein) on the proliferation of HT1080 and expression of MT1-MMP mRNA. Human fibrosarcoma cell line HT1080 was cultured and divided 2 groups. The experimental group was treated with $100{\mu}M$ genistein and incubated 12h, 24h for $[3^H]-thymidine$ uptake assay and northern hybridization individually. And the control group was treated with same amount of PBS for the above procedures. $[3^H]-thymidine$ incorporation was measured with ${\beta}$ ray detector. And RT-PCR and northern blotting for MT1-MMP mRNA was performed. The results were as follows 1. $[3^H]-thymidine$ uptake was reduced in experimental group with statistical significance. 2. MT1-MMP mRNA expression was significantly reduced in experimental group. These results showed that protein kinase C inhibitor (genistein) inhibited proliferation of HT1080 and almost completely blocked transcription of MT1-MMP mRNA. So, it is possible to use the protein kinase inhibitor (genistein) as anti-metastatic and anti-proliferative agent.

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Effects of muscarinic receptor stimulation on the thyrotropin-induced thyroxine release in the guinea pig thyroid (기니픽 갑상선에서 Thyrotropin에 의한 thyroxine 유리에 대한 muscarinic 수용체 자극효과)

  • Kim, Hong-hyun;Kim, Jin-shang
    • Korean Journal of Veterinary Research
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    • v.39 no.1
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    • pp.55-61
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    • 1999
  • The present experiments were performed to examine the effects of acetylcholine (ACh) and carbachol (CC) on thyroxine ($T_4$) release and any possible relation between inhibition of $T_4$ release and signaling pathway in guinea pig thyroids. The thyroids were incubated in the medium containing the test agents, samples of the medium were assayed for $T_4$ by EIA kits. ACh and CC inhibited the TSH-stimulated $T_4$ release. These inhibition were reversed by atropine, but not by d-tubocurarine. The inhibitory effects of ACh on $T_4$ release were prevented by $M_{1^-}$ and $M_{3^-}$muscarinic antagonists and its inhibition was also slightly reversed by $M_{2^-}$ and $M_{4^-}$muscarinic antagonists. R59022, like ACh and CC, also inhibited the TSH-stimulated $T_4$ release. This inhibition was reversed by protein kinase C inhibitor and $Ca^{2+}$ channel blocker. The present study suggests that cholinergic inhibition of $T_4$ release from thyroids can be induced mainly by activation of the $M_{1^-}$ or $M_{3^-}$ receptors and that it is mediated through the muscarinic receptorstimulated protein kinase C activation.

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Role of Calcium Influx in mediating the TRH-induced c-fos Gene Expression (갑상선자극 분비 호르몬에 의해 유도되는 c-fos 유전자 발현에서 Ca2+의 역할에 관한 연구)

  • Seung Kirl Ahn;Don
    • The Korean Journal of Zoology
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    • v.36 no.4
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    • pp.487-495
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    • 1993
  • TRH (Thvrotropin-Releasing Hormone) known to regulate the transcription of the TSH (Thyroid-Stimulating Hormones gene in pituitary cells, but little is understood about the mechanism(sl involved. re present study was attempted to elucidate the role of Ca2+ movement through the voltage-gated channels in the regulation of TSH gene transcription. The c-fos is one of immediate early genes and used as model system for the investigation of signaling pathwavs involved in various stimuli. The changes of c-fos mRNA levels were determined after treatment of various agents using Northern and slot hybridization analysis. The c-fos mRNA was rapidly and transiently induced by TRH (about 3-fold) in GH3 cells and this induction was repressed by calcium chelating agent (EGTA), calcium channel blocker (verapamil) anti protein kinase C inhibitor (aminoacridine). The abilities of forskolin (adenvlate cvclase activators, PMA (protein kinase C activator), and A23187 (calcium ionophore) to affect c-ios gene transcription, either alone or in combination with TRH were tested in the same cells. All of them significantly increased the level of c-fos mRUA. However, no additive relationship was observed in all combined treatments except forskolin. These results suggest that TRH action on the c-fos gene activation is mediated by calcium influx as well as through protein kinase C.

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The Involvement of Protein Kinase C and Tyrosine Kinase in Vanadate-induced Contraction

  • Sim, Sang-Soo;Kim, Chang-Jong
    • Archives of Pharmacal Research
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    • v.21 no.3
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    • pp.315-319
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    • 1998
  • Gastric smooth muscle of cats was used to investigate the involvement of protein kinase in vanadate-induced contraction. Vanadate caused a contraction of cat gastric smooth muscle in a dose-dependent manner. Vanadate-induced contraction was totally inhibited by 2 mM EGTA and 1.5 mM $LACI_3$ and significantly inhibited by $10\mu$M verapamil and $1\mu$M nifedipine, suggesting that vanadate-induced contraction is dependent on the extracellular $Ca^{2+}$ concentration, and the influx of extracellular $Ca^{2+}$ was mediated through voltage-dependent $Ca^{2+}$ channel. Both protein kinase C inhibitor and tyrosine kinase inhibitor significantly inhibited the vanadate-induced contraction and the combined inhibitory effect of two protein kinase inhibitors was greater than that of each one. But calmodulin antagonists did not have any influence on the vanadate-induced contraction. On the other hand, both forskolin ($1\mu$M) and sodium nitroprusside ($1\mu$M) significantly inhibited vanadate-induced contraction. Therefore, these results suggest that both protein kinase C and tyrosino kinase are involved in the vanadate-induced contraction which required the influx of extracellular $Ca^{2+}$ in cat gastric smooth muscle, and that the contractile mechanism of vanadate may be different from that of agonist binding to its specific receptor.

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Interaction between Cholecystokinin and Secretin in Isolated Rat Pancreatic Acini

  • Yoon, Shin-Hee;Hahn, Sang-June;Sim, Sang-Soo;Rhie, Duck-Joo;Song, In-Young;Baek, Hye-Jung;Kim, Myung-Suk;Jo, Yang-Hyeok
    • The Korean Journal of Physiology
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    • v.29 no.2
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    • pp.243-250
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    • 1995
  • A possible potentiation between cholecystokinin (CCK) and secretin in amylase secretion from isolated rat pancreatic acini was investigated. Combined treatment of acini with secretin and CCK at low concentrations, which are known to be physiological, resulted in enzyme secretion larger than the arithmetic sum of their separate effects. Such a potentiating effect also occurred between secretin and A23187 (Ca ionophore), between forskolin (adenylate cyclase activator) and CCK, and between forskolin and A23187. Staurosporin (protein kinase C inhibitor) and W7 (calmodulin antagonist) inhibited markedly the potentiated amylase release induced by the agonists, but KT5720 (protein kinase A inhibitor) did not affect the potentiated amylase release. Therefore, we concluded that the action of CCK in a physiological concentration is potentiated by secretin in a physiological concentration range and vice versa, and that the intracellular mechanism necessary for the potentiation is associated with $Ca^{2+}$. However, it is uncertain what mechanisms are involved in potentiation of amylase release after CAMP and $Ca^{2+}$.

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The Role of Adenosine Receptor on Norepinephrine Release from Ischemic-Induced Rat Hippocampus (허혈이 유발된 흰쥐 해마에서 Norepinephrine 유리에 미치는 Adenosine 수용체의 역할)

  • Chung, Jong-Hoon;Choi, Bong-Kyu
    • The Korean Journal of Pharmacology
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    • v.32 no.2
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    • pp.139-150
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    • 1996
  • The effects of adenosine analogues on the electrically-evoked norepinephrine(NE) release and the influence of ischemia on the effects were studied in the rat hippocampus. Slices from the rat hippocampus were equilibrated with $0.1{\mu}M$ $[^3H]-norepinephrine$ and the release of the labelled product, $[^3H]-NE$, was evoked by electrical stimulation(3 Hz, 2 ms, 5 $VCm^{-1}$ and rectangular pulses for 90 sec), and the influence of various agents on the evoked tritium-outflow was investigated. Ischemia(15min with 95% $N_2$ +5% $CO_2$) increased both the basal and evoked NE release. These increases were abolished by addition of glucose into the superfused medium, and they were significantly inhibited either by $0.3\;{\mu}M$ tetrodotoxin pretreatment or by removing $Ca^{++}$ in the medium. MK-801$(1{sim}10\;{\mu}M)$, a specific NMDA receptor antagonist, and glibenclamide $(1\;{\mu}M)$, a $K^+-channel$ inhibitor, neither alter the evoked NE release nor affected the Ischemia-Induced increases in NE release. However, polymyxin B(0.03 mg), a specific protein kinase C inhibitor, inhibited the effect of ischemia on the evoked NE release. Adenosine and $N^6-cyclopentyladenosine$ decreased the NE release in a dose-dependent manner in ischemic condition, though the magnitude of inhibition was far less than those in normal (normoxic) condition. Also the treatment with $5{\mu}M$ DPCPX, a potent $A_1-adenosine$ receptor antagonist did not affect the ischemia-effect. These results suggest that the evoked-NE release is potentiated by ischemia, and this process being most probably mediated by protein kinase C, and that the decrease of NE release mediated through $A_1-adenosine$ receptor is significantly inhibited in ischemic state.

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