• Title/Summary/Keyword: AG490

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AG490, a Jak2-specific Inhibitor, Induces Osteoclast Survival by Activating the Akt and ERK Signaling Pathways

  • Kwak, Han Bok;Sun, Hyun Min;Ha, Hyunil;Lee, Jong Ho;Kim, Ha Neui;Lee, Zang Hee
    • Molecules and Cells
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    • v.26 no.5
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    • pp.436-442
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    • 2008
  • Osteoclasts are multinucleated cells with the unique ability to resorb bone. Elevated activity of these cells under pathologic conditions leads to the progression of bone erosion that occurs in osteoporosis, periodontal disease, and rheumatoid arthritis. Thus, the regulation of osteoclast apoptosis is important for bone homeostasis. In this study, we examined the effects of the Janus tyrosine kinase 2 specific inhibitor AG490 on osteoclast apoptosis. We found that AG490 greatly inhibited osteoclast apoptosis. AG490 stimulated the phosphorylation of Akt and ERK. Adenovirus-mediated expression of dominant negative (DN)-Akt and DN-Ras in osteoclasts inhibited the survival of osteoclasts despite the presence of AG490. Cytochrome c release during osteoclast apoptosis was inhibited by AG490 treatment, but this effect was inhibited in the presence of LY294002 or U0126. AG490 suppressed the pro-apoptotic proteins Bad and Bim, which was inhibited in osteoclasts infected with DN-Akt and DN-Ras adenovirus. In addition, constitutively active MEK and myristoylated-Akt adenovirus suppressed the cleavage of pro-caspase-9 and -3 and inhibited osteoclast apoptosis induced by etoposide. Taken together, our results suggest that AG490 inhibited cytochrome c release into the cytosol at least partly by inhibiting the pro-apoptotic proteins Bad and Bim, which in turn suppressed caspase-9 and -3 activation, thereby inhibiting osteoclast apoptosis.

Janus Kinase 2 Inhibitor AG490 Inhibits the STAT3 Signaling Pathway by Suppressing Protein Translation of gp130

  • Seo, In-Ae;Lee, Hyun-Kyoung;Shin, Yoon-Kyung;Lee, Sang-Hwa;Seo, Su-Yeong;Park, Ji-Wook;Park, Hwan-Tae
    • The Korean Journal of Physiology and Pharmacology
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    • v.13 no.2
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    • pp.131-138
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    • 2009
  • The binding of interleukin-6 (IL-6) cytokine family ligands to the gp130 receptor complex activates the Janus kinase (JAK)/ signal transducer and activator of transcription 3 (STAT3) signal transduction pathway, where STA T3 plays an important role in cell survival and tumorigenesis. Constitutive activation of STAT3 has been frequently observed in many cancer tissues, and thus, blocking of the gp130 signaling pathway, at the JAK level, might be a useful therapeutic approach for the suppression of STAT3 activity, as anticancer therapy. AG490 is a tyrphostin tyrosine kinase inhibitor that has been extensively used for inhibiting JAK2 in vitro and in vivo. In this study, we demonstrate a novel mechanism associated with AG490 that inhibits the JAK/STAT3 pathway. AG490 induced downregulation of gp130, a common receptor for the IL-6 cytokine family compounds, but not JAK2 or STAT3, within three hours of exposure. The downregulation of gp130 was not caused by enhanced degradation of gp130 or by inhibition of mRNA transcription. It most likely occurred by translation inhibition of gp130 in association with phosphorylation of the eukaryotic initiation factor-2 a. The inhibition of protein synthesis of gp130 by AG490 led to immediate loss of mature gp130 in cell membranes, due to its short half-life, thereby resulting in reduction in the STAT3 response to IL-6. Taken together, these results suggest that AG490 blocks the STAT3 activation pathway via a novel pathway.

Microstructure and Properties of ITO and ITO/Ag/ITO Multilayer Thin Films Prepared by D.C. Magnetron Sputtering (D.C. 마그네트론 스퍼터링법으로 제조한 ITO 및 ITO/Ag/ITO 박막의 미세조직과 투명 전극 특성)

  • Choi, Yong-Lak;Kim, Seon-Hwa
    • Korean Journal of Materials Research
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    • v.16 no.8
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    • pp.490-496
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    • 2006
  • ITO monolayer and ITO/Ag/ITO multilayer thin films are prepared by D.C. magnetron sputtering method. Ag layer was inserted for applying ITO to a flexible substrate at low temperature. Carrier concentration and carrier mobility of ITO and ITO/Ag/ITO thin films were measured, the transmittance of them also was done. The amorphous phase was confirmed to be combined in addition to (400) and (440) peaks from XRD result of ITO thin film. As the substrate temperature increased, the preferred orientation of (400) appeared. From the result of application of Ag layer at room temperature, the growth of columnar structure was inhibited, and the amorphous phase formed mostly. The ITO/Ag/ITO thin film represented the transmittance of above 80% when the thickness of Ag layer was 50 ${\AA}$, and the concentration of carrier increased up to above 10 times than that of ITO thin film. Finally, since very low resistance of 3.9${\Omega}/{\square}$ was observed, the effective application of low temperature process is expected to be possible for ITO thin film.

Fabrication of Low Temperature Cofired Ceramic (LTCC) Chip Couplers for High Frequencies ; II. Effect of Sintering Process on Ag Diffusion (고주파용 저온 동시소성 세라믹(LTCC)칩 커플러 제조: II. Ag 이온 확산에 대한 소결공정의 영향)

  • 이선우;김경훈;심광보;구기덕
    • Journal of the Korean Ceramic Society
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    • v.36 no.5
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    • pp.490-496
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    • 1999
  • The sintering behavior of LTCC (low temperature cofired ceramics) chip couplers was investigated in relation with Ag diffusion at the interface of glass ceramic substrate-Ag electrode. Sintering temperature was in the range of 825$^{\circ}C$-975$^{\circ}C$. The commercial green sheet and silver electrode were used. Below 875$^{\circ}C$ the diffusion of the Ag ion into the substrate and the penetration of glassy phases into the electrode occurred due to an increase of fluidity. Thus the lectrode line was severely deformed and damaged. At 975$^{\circ}C$ the transformation of crystalline phases into glassy phases and the melting of the Ag electrode resulted in the diffusion of the considerable amount of Ag ions.

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The Effect of Magnolol on UVB-induced Inflammation Damage Control via the Nrf2-SOCS3-Jak2-STAT3 Pathway in Human Dermal Fibroblasts (마그놀롤의 HDF세포에서 Nrf2-SOCS3-Jak2-STAT3에 의한 UVB 유래 염증데미지 조절)

  • Nam, Young sun;Ji, Juree
    • Journal of Life Science
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    • v.30 no.10
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    • pp.867-876
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    • 2020
  • This study investigated the repair of UVB-induced cell damage by magnolol. We performed a drug-repurposing screen, and, in the STAT3 reporter gene assay, magnolol was identified as a suppressor of STAT3 that improves the cell viability of HDF cells. HDF cells treated with IL-6, UVB, and IFNγ showed the highest expression of Jak2 and phosphorylated STAT3 (p-STAT3), and magnolol was able to decrease the expression of Jak2 and p-STAT3 in UVB-induced cells. Moreover, UVB-damaged cell growth increased significantly in correlation with both reactivation and with magnolol in a dose-dependent manner. Compared with AG490 (a Jak2 inhibitor) treatment of UVB-treated HDF cells, cell proliferation increased significantly. We confirmed that AG490 and magnolol reduced TNF-α concentrations, and Western blotting (protein level) showed decreases in Jak2 and p-STAT3 expression in only the magnolol-treated cells. The expression of Jak2, p-STAT3, and SOCS3 also increased only after treatment with magnolol. Cells were treated with magnolol and ML385 (an NRF2 inhibitor), and these secondary metabolites reduced cell proliferation and NRF2 expression. The amount of MMP9 was also increased by cotreatment with magnolol and ML385. Collectively, these results demonstrate the potential of magnolol for repairing cells after UVB-induced damage by regulating the expression of NRF2, SOCS3, Jak2, and STAT3.

The characteristics of holographic diffraction efficiency depend on thickness of Ag in AsGeSeS/Ag thin film (AsGeSeS/Ag 박막에서 Ag의 두께에 따른 홀로그래픽 회절 효율 특성)

  • Lee, Jung-Tae;Lee, Ki-Nam;Yeo, Cheol-Ho;Lee, Yeong-Jong;Chung, Hong-Bay
    • Proceedings of the Korean Institute of Electrical and Electronic Material Engineers Conference
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    • 2003.11a
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    • pp.490-493
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    • 2003
  • We have carried out two-beam interference experiment to form holographic grating on amorphous $As_{40}Ge_{10}Se_{15}S_{35}/Ag$ double-layer. In this study holographic grating formed using He-Ne laser(632.8nm) under non-polarization state and p-polarization state and we confirm that the diffraction efficiency depend on thickness of Ag. The diffraction efficiency was obtained by first order intensity. We got the maximum diffraction efficiency that thickness of Ag was $600{\AA}$. The maximum diffraction efficiency was 13.5% in (P:P) polarization state.

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Ag-Loaded LaSrCoFeO3 Perovskite Nano-Fibrous Web for Effective Soot Oxidation (Ag 담지된 LaSrCoFeO3 섬유상 perovskite 촉매의 탄소 입자상 물질의 산화반응)

  • Lee, Chanmin;Jeon, Yukwon;Hwang, Ho Jung;Ji, Yunseong;Kwon, Ohchan;Jeon, Ok Sung;Shul, Yong-Gun
    • Korean Chemical Engineering Research
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    • v.57 no.4
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    • pp.584-588
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    • 2019
  • The catalytic combustion of particulate matter (PM) is one of the key technologies to meet emission standards of diesel engine system. Therefore, we herein suggest Ag loaded $La_{0.6}Sr_{0.4}Co_{0.2}Fe_{0.8}O_3$ perovskite web catalyst. They were produced by the electrospinning method. FE-SEM, EDS mapping, XRD, XPS were studied to investigate the crystal and morphological structures of loaded Ag particles and $La_{0.6}Sr_{0.4}Co_{0.2}Fe_{0.8}O_3$ perovskite web catalyst. Following the catalytic soot oxidation, we found that the Ag loaded $La_{0.6}Sr_{0.4}Co_{0.2}Fe_{0.8}O_3$ perovskiteweb catalyst showed the higher catalytic activities (e.g., $T_{50}=490^{\circ}C$) than the only $La_{0.6}Sr_{0.4}Co_{0.2}Fe_{0.8}O_3$ perovskite web catalyst (e.g., $T_{50}=586^{\circ}C$). Thus, this finding suggests that Ag loaded $La_{0.6}Sr_{0.4}Co_{0.2}Fe_{0.8}O_3$ perovskite web catalyst can be a promising candidate for enhancing the soot oxidation.

Novel Enhanced Flexibility of ZnO Nanowires Based Nanogenerators Using Transparent Flexible Top Electrode

  • Gang, Mul-Gyeol;Ha, In-Ho;Kim, Seong-Hyeon;Jo, Jin-U;Ju, Byeong-Gwon;Lee, Cheol-Seung
    • Proceedings of the Korean Vacuum Society Conference
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    • 2014.02a
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    • pp.490.1-490.1
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    • 2014
  • The ZnO nanowire (NW)-based nanogenerators (NGs) can have rectifying current and potential generated by the coupled piezoelectric and semiconducting properties of ZnO by variety of external stimulation such as pushing, bending and stretching. So, ZnO NGs needed to enhance durability for stable properties of NGs. The durability of the metal electrodes used in the typical ZnO nanogenerators(NGs) is unstable for both electrical and mechanical stability. Indium tin oxide (ITO) is used as transparent flexible electrode but because of high cost and limited supply of indium, the fragility and lack of flexibility of ITO layers, alternatives are being sought. It is expected that carbon nanotube and Ag nanowire conductive coatings could be a prospective replacement. In this work, we demonstrated transparent flexible ZnO NGs by using CNT/Ag nanowire hybrid electrode, in which electrical and mechanical stability of top electrode has been improved. We grew vertical type ZnO NW by hydrothermal method and ZnO NW was coated with hybrid silicone coating solution as capping layer to enhance adhesion and durability of ZNW. We coated the CNT/Ag nanowire hybrid electrode by using bar coating system on a capping layer. Power generation of the ZnO NG is measured by using a picoammeter, a oscilloscope and confirmed surface condition with FE-SEM. As a results, the NGs using the CNT/Ag NW hybrid electrode show 75% transparency at wavelength 550 nm and small change of the resistance of the electrode after bending test. It will be discussed the effect of the improved flexibility of top electrode on power generation enhancement of ZnO NGs.

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The Role of Janus Kinase in Superoxide-mediated Proliferation of Diabetic Vascular Smooth Muscle Cells

  • Lee, Ji-Young;Park, Ji-Young;Kim, Chi-Dae
    • The Korean Journal of Physiology and Pharmacology
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    • v.11 no.1
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    • pp.31-36
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    • 2007
  • To elucidate a potential molecular link between diabetes and atherosclerosis, we investigated the role of Janus tyrosine kinase(JAK) for NAD(P)H oxidase-derived superoxide generation in the enhanced proliferative capacity of vascular smooth muscle cells(VSMC) of Otsuka Long-Evans Tokushima Fatty(OLETF) rat, an animal model of type 2 diabetes. An enhanced proliferative response to 10% fetal bovine serum(FBS) and superoxide generation with an increased NAD(P)H oxidase activity were observed in diabetic(OLETF) VSMC. Both the enhanced proliferation and superoxide generation in diabetic VSMC were significantly attenuated by AG490, JAK2 inhibitor, and PP2, Src kinase inhibitor. Tyrosine phosphorylation of proteins in diabetic VSMC, especially JAK2, was increased compared to control VSMC. Furthermore, the enhanced NAD(P)H oxidase activity in diabetic VSMC was significantly attenuated by AG490 in a dose-dependent manner. Together, these results indicate that the signal pathway which leads to diabetes-associated activation of Src kinase/JAK is critically involved in the diabetic VSMC proliferation through NAD(P)H oxidase activation and superoxide generation.