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Park, Sun-Hee,Choi, Min-Jeong,Song, In-Kyung,Choi, Soon-Youn,Nam, Ju-Ock,Kim, Chan-Duck,Lee, Byung-Heon,Park, Rang-Woon,Park, Kwon Moo,Kim, Yong-Jin,Kim, In-San,Kwon, Tae-Hwan,Kim, Yong-Lim American Society of Nephrology 2007 Journal of the American Society of Nephrology Vol.18 No.5
<P>The inhibitory effects of recombinant human erythropoietin (rhEPO) were examined against (1) the progression of renal fibrosis in mice with complete unilateral ureteral obstruction and (2) the TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) in MDCK cells. Unilateral ureteral obstruction was induced in BALB/c mice and rhEPO (100 or 1000 U/kg, intraperitoneally, every other day) or vehicle was administered from day 3 to day 14. Immunoblotting and immunohistochemistry revealed increased expressions of TGF-beta1, alpha-smooth muscle actin (alpha-SMA), and fibronectin and decreased expression of E-cadherin in the obstructed kidneys. In contrast, rhEPO treatment significantly attenuated the upregulation of TGF-beta1 and alpha-SMA and the downregulation of E-cadherin. MDCK cells were treated with TGF-beta1 (5 ng/ml) for 48 h to induce EMT, and the cells were then co-treated with TGF-beta1 and rhEPO for another 48 h. Increased expressions of alpha-SMA and vimentin and decreased expressions of zona occludens-1 and E-cadherin were observed after TGF-beta1 treatment, and these changes were markedly attenuated by rhEPO co-treatment. TGF-beta1 increased phosphorylated Smad-2 expression in MDCK cells, which was decreased by rhEPO co-treatment. In conclusion, rhEPO treatment inhibits the progression of renal fibrosis in obstructed kidney and attenuates the TGF-beta1-induced EMT. It is suggested that the renoprotective effects of rhEPO could be mediated, at least partly, by inhibition of TGF-beta1-induced EMT.</P>
Caspase 9 promoter polymorphisms and risk of primary lung cancer
Park, Jae Yong,Park, Jung Min,Jang, Jin Sung,Choi, Jin Eun,Kim, Kyung Mee,Cha, Sung Ick,Kim, Chang Ho,Kang, Young Mo,Lee, Won Kee,Kam, Sin,Park, Rang Woon,Kim, In San,Lee, Jae-Tae,Jung, Tae Hoon IRL Press 2006 Human molecular genetics Vol.15 No.12
<P>Caspase-9 (CASP-9) is an initiator CASP in the apoptosome-driven apoptosis pathway and plays an important role in the development and progression of cancer. Polymorphisms in the promoter region of the <I>CASP-9</I> gene may influence the promoter activity of this gene, thereby modulating susceptibility to lung cancer. To test this hypothesis, we examined the association of four polymorphisms [−1263A>G, −905T>G, −712C>T and −293_−275delCGTGAGGTCAGTGCGGGGA (−293del)] in the <I>CASP-9</I> promoter with the risk of lung cancer in a Korean population. The <I>CASP-9</I> genotypes were determined in 432 lung cancer patients and 432 healthy controls that were frequency-matched for age and gender. The −1263 GG genotype was associated with a significantly decreased risk of lung cancer compared with the −1263 AA genotype or combined −1263 AA+AG genotype [adjusted odds ratio (OR)=0.64, 95% confidence interval (95% CI)=0.42–0.98, <I>P</I>=0.04 and adjusted OR=0.67, 95% CI=0.46–0.97, <I>P</I>=0.01, respectively]. For the −712C>T polymorphism, individuals with at least one −712T allele were at a significantly increased risk of lung cancer compared with those harboring the −712 CC genotype (adjusted OR=1.42, 95% CI=1.06–1.89, <I>P</I>=0.02). Consistent with the results of genotype analyses, the −1263G/−712C (G-C) haplotype was associated with a significantly decreased risk of lung cancer [adjusted OR=0.59, 95% CI=0.47–0.75, <I>P</I> and Bonferroni corrected <I>P</I> (<I>P</I><SUB>c</SUB>)<0.001]. Moreover, the risk of lung cancer decreased in a dose-dependent manner as the number of the G-C haplotypes increased (adjusted OR=0.60, 95% CI=0.45–0.81, <I>P</I>=0.0007 and <I>P</I><SUB>c</SUB>=0.0014 for the G-C heterozygotes and adjusted OR=0.34, 95% CI=0.17–0.68, <I>P</I>=0.0023 and <I>P</I><SUB>c</SUB>=0.0046 for the G-C homozygotes; <I>P</I><SUB>trend</SUB><0.001). The promoter assay revealed the G-C haplotype to have a significantly higher promoter activity than the −1263G/−712T and −1263A/−712C haplotypes. These results suggest that <I>CASP-9</I> promoter polymorphisms affect <I>CASP-9</I> expression and contribute to genetic susceptibility to lung cancer.</P>
Heparin–deoxycholic acid chemical conjugate as an anticancer drug carrier and its antitumor activity
Park, Kyeongsoon,Lee, Gee Young,Kim, Yoo-Shin,Yu, Mikyung,Park, Rang-Woon,Kim, In-San,Kim, Sang Yoon,Byun, Youngro Elsevier 2006 Journal of controlled release Vol.114 No.3
<P><B>Abstract</B></P><P>A chemically modified heparin–DOCA (HD) conjugate was developed as a drug carrier for cancer therapy. HD conjugate was found to have markedly low anticoagulant activity and to form self-assembled nanoparticles in aqueous condition. We observed that HD conjugate prevented squamous cell carcinoma (SCC) and human umbilical vascular endothelial cell (HUVEC) proliferation during BrdU incorporation assays. Here, we prepared doxorubicin-loaded heparin nanoparticles by entrapping doxorubicin into the amphiphilic HD conjugate by physical interaction and characterized the properties of these nanoparticles using Dynamic Light Scattering (DLS) and Atomic Force Microscope (AFM). In this study, doxorubicin-loaded heparin nanoparticles were designed to improve the antitumor effects of nano-sized particles (range of 180 to 210?nm) at high drug-loading efficiencies in the range 64% to 96%. These doxorubicin-loaded heparin nanoparticles displayed sustained drug release patterns. It was confirmed in vivo toxicity studies that HD conjugate did not induce unexpected side effects and that DHN 20 was safer than free DOX. An in vivo study showed that HD conjugate, doxorubicin and DHN 20 (one of doxorubicin-loaded heparin nanoparticles) induced tumor volume reductions of 43%, 56% and 74%, respectively, relative to the saline treated control. These results suggest that the drug-entrapped with heparin nanoparticles might provide a novel therapy for SCC.</P>
MEGF10 functions as a receptor for the uptake of amyloid-β
Singh, Thoudam Debraj,Park, Seung-Yoon,Bae, Jae-sung,Yun, Youngeun,Bae, Yong-Chul,Park, Rang-Woon,Kim, In-San Elsevier 2010 FEBS letters Vol.584 No.18
<P><B>Abstract</B></P><P>MEGF10 is predominantly expressed in the brain and known to function as a phagocytic receptor. Here, we provide evidence that MEGF10 is involved in the uptake of amyloid-β peptide (Aβ42) in the brain. Overexpression of MEGF10 dramatically increased Aβ42 uptake in Hela cells. Knockdown of endogenous MEGF10 expression significantly decreased Aβ42 uptake in N2A neuroblastoma cells. MEGF10-mediated Aβ uptake is mostly dependent on lipid raft endocytosis pathway. Furthermore, site-directed mutagenesis revealed that the conserved cytoplasmic NPxY and YxxØ motifs are crucial for MEGF10-mediated uptake of Aβ42 peptide. Thus, the identification of the MEGF10 as a functional receptor that mediates the uptake of amyloid-β peptide will help elucidate the molecular mechanisms of amlyoid-β clearance in Alzheimer’s disease.</P><P><B>Structured summary</B></P><P>MINT-7993537: <I>ctxB</I> (uniprotkb:P01556) and <I>Abeta</I> (uniprotkb:P05067) <I>colocalize</I> (MI:0403) by <I>fluorescence microscopy</I> (MI:0416)</P>
Min, Kyung Hyun,Park, Kyeongsoon,Kim, Yoo-Shin,Bae, Sang Mun,Lee, Seulki,Jo, Hyung Gon,Park, Rang-Woon,Kim, In-San,Jeong, Seo Young,Kim, Kwangmeyung,Kwon, Ick Chan Elsevier Science Publishers 2008 Journal of controlled release Vol.127 No.3
<P><B>Abstract</B></P><P>To prepare a water-insoluble camptothecin (CPT) delivery carrier, hydrophobically modified glycol chitosan (HGC) nanoparticles were constructed by chemical conjugation of hydrophobic 5β-cholanic acid moieties to the hydrophilic glycol chitosan backbone. Insoluble anticancer drug, CPT, was easily encapsulated into HGC nanoparticles by a dialysis method and the drug loading efficiency was above 80%. CPT-encapsulated HGC (CPT-HGC) nanoparticles formed nano-sized self-aggregates in aqueous media (280–330?nm in diameter) and showed sustained release of CPT for 1?week. Also, HGC nanoparticles effectively protected the active lactone ring of CPT from the hydrolysis under physiological condition, due to the encapsulation of CPT into the hydrophobic cores in the HGC nanoparticles. The CPT-HGC nanoparticles exhibited significant antitumor effects and high tumor targeting ability towards MDA-MB231 human breast cancer xenografts subcutaneously implanted in nude mice. Tumor growth was significantly inhibited after i.v. injection of CPT-HGC nanoparticles at doses of 10?mg/kg and 30?mg/kg, compared to free CPT at dose of 30?mg/kg. The significant antitumor efficacy of CPT-HGC nanoparticles was attributed to the ability of the nanoparticles to show both prolonged blood circulation and high accumulation in tumors, as confirmed by near infrared (NIR) fluorescence imaging systems. Thus, the delivery of CPT to tumor tissues at a high concentration, with the assistance of HGC nanoparticles, exerted a potent therapeutic effect. These results reveal the promising potential of HGC nanoparticles-encapsulated CPT as a stable and effective drug delivery system in cancer therapy.</P>