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Yhun Yhang, Sheen,Minjung, Cho,Wan-Seob, Cho,Mina, Choi,Sueng Jun, Kim,Beam Seak, Han,Sheen Hee, Kim,Hyoung Oak, Kim,Ja Young, Jeong 이화여자대학교 약학연구소 2010 藥學硏究論文集 Vol.- No.20
Many approaches for the application of nano-sized particles to the human body as nanotechnology have been recently developed. The size of nanoparticles is related to their useful character and also plays a key role in toxicity. Since this surface area can interact with biological components of cells, nanoparticles can be more reactive in than larger particles. In the present study, a fluorescence dye-labeled 50, 100 and 200 nm-sized silica particle suspension was intravenously injected into mice to identify the toxicity, tissue distribution and excretion of silica nanoparticles in vivo. Incidence and severity of inflammatory response was transiently increased with injection of 200 and 100 nm silica nanoparticles within 12h. But there was no significant response related to injection of 50 nm particles. The silica particles of 50, 100 and 200 nm were cleared via urine and bile. The 50 nm silica anoparticles cleared to urine and bile than 100 nm and particles of 200 nm existed at lower concentration than other two smaller particles in urine and feces. Silica nanoparticles were trapped by macrophages in the spleen and liver and remained there until 4 weeks after the single injection.
EW-7195, a novel inhibitor of ALKS kinase inhibits EMT and breast cancer metastasis to lung
Yhun Yhong, Sheen,Chul-Yong, Park,Jee-Yeon, Son,Cheng Hua, Jin,Jeong-Suk, Nam,Dae-Kee, Kim 梨花女子大學校 藥學硏究所 2012 藥學硏究論文集 Vol.- No.22
Recently, researchers are actively pursuing efforts to develop potent and selective ALK5 (TβRI) kinase inhibitors for clinical development. In this study, the authors examined a novel small molecule inhibitor of ALK5, 3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzonitrile (EW-7195) to determine if it has potential for cancer treatment. The inhibitory effects of EW-7195 on TGF-β-induced Smad signaling and epithelial-to-mesenchymal transition (EMT) were investigated in mammary epithelial cells using luciferase reporter assays, immunoblotting, confocal microscopy and wound healing assays. In addition, the suppressive effects of EW-7195 on mammary cancer metastasis to lung were examined using a Balb/c xenograft and MMTV/cNeu transgenic mice model system. The novel ALK5 inhibitor, EW-7195, inhibited the TGF-β(1)-stimulated transcriptional activations of p3TP-Lux and pCAGA(12)-Luc. In addition, EW-7195 decreased phosphorylated Smad2 levels and the nuclear translocation of Smad2 increased by TGF-β(1). In addition, EW-7195 inhibited TGF-β(1)-induced EMT and wound healing of NMuMG cells. Furthermore, in xenografted Balb/c and MMTV/cNeu mice, EW-7195 inhibited metastasis to lung from breast tumours. The novel ALK5 inhibitor, EW-7195, efficiently inhibited TGF-β(1)-induced Smad signaling, EMT and breast tumour metastasis to the lung in vivo, demonstrating that EW-7195 has therapeutic potential for the breast cancer metastasis to the lung.
HDAC inhibitors regulate CYP3A4 gene expression in Hepatic cells
Yhun, Yhong Sheen...et al. 이화여자대학교 약학연구소 2003 藥學硏究論文集 Vol.- No.13
Cytochrome P450 3A4 (CYP3A4) is the most abundant CYPs in human liver, comprising approximately 30% of the total liver CYPs contents and is involved in the metabolism of more than 60% of currently used therapeutic drugs. The expression of CYP3A4 is induced by a variety of structurally unrelated xenobiotics including the antibiotic rifampicin and endogenous hormones, and might be mediated through steroid and xenobiotic receptor (SXR) system. The molecular mechanisms underlying regulation of CYP3A4 gene expression have not been understood. In order to gain the insight of the molecular mechanism of CYP3A4 gene expression, study has been undertaken to investigate if the histone deacetylation is involved in the regulation of CYP3A4 gene expression by proximal promoter or not. Also SXR was investigated to see if they were involved in the regulation of CYP3A4 proximal promoter activity. HepG2 or Hepa-I cells were transfected with a plasmid containing ∼1kb of the CYP3A4 proximal promoter region (863 to +64 bp) cloned in front of a reporter gene, luciferase, in the presence or absence of SXR or hERa. Transfected cells were treated with CYP3A4 inducers such as rifampicin, PCN and RU 486, or with estradiol, in order to examine the regulation of CYP3A4 gene expression in the presence or absence of trichostatin A (TSA). In HepG2 cells, CYP3A4 inducers and estradiol increased significantly the luciferase activity by CYP3A4 proximal promoter, only when TSA was co-treated after SXR cotransfection. In the case of Hepa-I cells, CYP3A4 inducers and estradiol increased modestly the luciferase activity when TSA was co-treated, but this incresment was not enhanced by SXR cotransfection in contrast to HepG2 cells. Taken together, these results indicated that the inhibition of histone deacetylation was required to SXR-mediated increase in CYP3A4 proximal promoter region when rifampicin, or PCN was treated. Further a transactivation by SXR may demand other species-specific transcription factors.
Cinvited Review : Targeting the Transforming Growth Factor-β Signaling in Cancer Therapy
( Yhun Yhong Sheen ),( Min Jin Kim ),( Sang A Park ),( So Yeon Park ),( Jeong Seok Nam ) 한국응용약물학회 2013 Biomolecules & Therapeutics(구 응용약물학회지) Vol.21 No.5
TGF-β pathway is being extensively evaluated as a potential therapeutic target. The transforming growth factor-β (TGF-β) signaling pathway has the dual role in both tumor suppression and tumor promotion. To design cancer therapeutics successfully, it is important to understand TGF-β related functional contexts. This review discusses the molecular mechanism of the TGF-β pathway and describes the different ways of tumor suppression and promotion by TGF-β. In the last part of the review, the data on targeting TGF-β pathway for cancer treatment is assessed. The TGF-β inhibitors in pre-clinical studies, and Phase I and II clinical trials are updated.