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Koung Li Kim,Ho-Kyew Choi,Sung-Oh Huh 한국실험동물학회 2005 Laboratory Animal Research Vol.21 No.4
Brain Factor-1 (BF-1) is winged-helix transcription factor with restricted expression pattern in the telencephalic neuroepithelium of the neural tube and in olfactory neuroepithelium. It was previously observed that the targeted disruption of the BF-1 gene by homologous recombination leads to hypoplasia of the cerebral hemispheres and defects in eye development. Here, we further examined BF-1 gene expression in olfactory system including the olfactory bulb, vomeronasal organ and in nasal epithelial regions in BF-1 heterozygote and homozygote mouse embryos. We were able to find strong expression of BF-1 gene in the vomeronasal organ and moderate expression in olfactory epithelia of BF-1 heterozygote mice. In BF-1 knock-out mice, however, we observed the failure of the vomeronasal organ formation. In addition, we found a significant loss of the nasal epithelial cells and abnormal morphogenesis of nasal labrynth in mice with targeted expression of BF-1 gene. Together, these results suggest a potential role of BF-1 gene in the morphogenesis of olfactory structures.
Lee, Jung Eun,Kim, Koung Li,Kim, Danbi,Yeo, Yeongju,Han, Hyounkoo,Kim, Myung Goo,Kim, Sun Hwa,Kim, Hyuncheol,Jeong, Ji Hoon,Suh, Wonhee DOVE MEDICAL PRESS 2017 INTERNATIONAL JOURNAL OF NANOMEDICINE Vol.12 No.-
<P>Pathological angiogenesis is one of the major symptoms of severe ocular diseases, including corneal neovascularization. The blockade of vascular endothelial growth factor (VEGF) action has been recognized as an efficient strategy for treating corneal neovascularization. In this study, we aimed to investigate whether nanoparticle-based delivery of apatinib, a novel and selective inhibitor of VEGF receptor 2, inhibits VEGF-mediated angiogenesis and suppresses experimental corneal neovascularization. Water-insoluble apatinib was encapsulated in nanoparticles composed of human serum albumin (HSA)-conjugated polyethylene glycol (PEG). In vitro angiogenesis assays showed that apatinib-loaded HSA-PEG (Apa-HSA-PEG) nanoparticles potently inhibited VEGF-induced tube formation, scratch wounding migration, and proliferation of human endothelial cells. In a rat model of alkali burn injury-induced corneal neovascularization, a subconjunctival injection of Apa-HSA-PEG nanoparticles induced a significant decrease in neovascularization compared to that observed with an injection of free apatinib solution or phosphate-buffered saline. An in vivo distribution study using HSA-PEG nanoparticles loaded with fluorescent hydrophobic model drugs revealed the presence of a substantial number of nanoparticles in the corneal stroma within 24 h after injection. These in vitro and in vivo results demonstrate that apatinib-loaded nanoparticles may be promising for the prevention and treatment of corneal neovascularization-related ocular disorders.</P>
( Won Hee Suh ),( Koung Li Kim ),( Chan Mi Choi ) 한국응용약물학회 2014 Biomolecules & Therapeutics(구 응용약물학회지) Vol.22 No.2
Marfan syndrome (MFS) is a dominantly inherited connective tissue disorder caused by mutations in the gene encoding fibrillin-1(FBN1) and is characterized by aortic dilatation and dissection, which is the primary cause of death in untreated MFS patients. However, disease progression-associated changes in gene expression in the aortic lesions of MFS patients remained unknown. Using a mouse model of MFS, FBN1 hypomorphic mouse (mgR/mgR), we characterized the aortic gene expression profiles duringthe progression of the MFS. Homozygous mgR mice exhibited MFS-like phenotypic features, such as fragmentation of elasticfibers throughout the vessel wall and were graded into mgR1-4 based on the pathological severity in aortic walls. Comparativegene expression profiling of WT and four mgR mice using microarrays revealed that the changes in the transcriptome were a directreflection of the severity of aortic pathological features. Gene ontology analysis showed that genes related to oxidation/reduction,myofibril assembly, cytoskeleton organization, and cell adhesion were differentially expressed in the mgR mice. Further analysisof differentially expressed genes identified several candidate genes whose known roles were suggestive of their involvement inthe progressive destruction of aorta during MFS. This study is the first genome-wide analysis of the aortic gene expression profilesassociated with the progression of MFS. Our findings provide valuable information regarding the molecular pathogenesis duringMFS progression and contribute to the development of new biomarkers as well as improved therapeutic strategies.
( Jeong-ho Park ),( Min-seob Kim ),( Seokran Ham ),( Eon Sub Park ),( Koung Li Kim ),( Wonhee Suh ) 한국응용약물학회 2020 Biomolecules & Therapeutics(구 응용약물학회지) Vol.28 No.1
Marfan syndrome (MFS), a connective tissue disorder caused by mutations in the fibrillin-1 (Fbn1) gene, has vascular manifestations including aortic aneurysm, dissection, and rupture. Its vascular pathogenesis is assumed to be attributed to increased transforming growth factor β (TGFβ) signaling and blockade of excessive TGFβ signaling has been thought to prevent dissection and aneurysm formation. Here, we investigated whether galunisertib, a potent small-molecule inhibitor of TGFβ receptor I (TβRI), attenuates aneurysmal disease in a murine model of MFS (Fbn1<sup>C1039G/+</sup>) and compared the impact of galuninsertib on the MFSrelated vascular pathogenesis with that of losartan, a prophylactic agent routinely used for patients with MFS. Fbn1<sup>C1039G/+</sup> mice were administered galunisertib or losartan for 8 weeks, and their ascending aortas were assessed for histopathological changes and phosphorylation of Smad2 and extracellular signal-regulated kinase 1/2 (Erk1/2). Mice treated with galunisertib or losartan barely exhibited phosphorylated Smad2, suggesting that both drugs effectively blocked overactivated canonical TGFβ signaling in Fbn1<sup>C1039G/+</sup> mice. However, galunisertib treatment did not attenuate disrupted medial wall architecture and only partially decreased Erk1/2 phosphorylation, whereas losartan significantly inhibited MFS-associated aortopathy and markedly decreased Erk1/2 phosphorylation in Fbn1C1039G/+ mice. These data unexpectedly revealed that galunisertib, a TβRI inhibitor, showed no benefits in aneurysmal disease in MFS mice although it completely blocked Smad2 phosphorylation. The significant losartaninduced inhibition of both aortic vascular pathogenesis and Smad2 phosphorylation implied that canonical TGFβ signaling might not prominently drive aneurysmal diseases in MFS mice.
Lee, Young-Sam,Jang, Hyung-Suk,Kim, Jeong-Min,Lee, Jung-Sun,Lee, Jae-Young,Li Kim, Koung,Shin, In-Soon,Suh, Wonhee,Choi, Jin-Ho,Jeon, Eun-Seok,Byun, Jonghoe,Kim, Duk-Kyung Elsevier 2005 Molecular therapy Vol.12 No.2
<P><B>Abstract</B></P><P>To test the hypothesis that overexpression of early growth response factor-1 (Egr-1) contributes to the revascularization of ischemic limbs, a constitutively active form of Egr-1 (Egr-1*) was made and evaluated <I>in vitro</I> and <I>in vivo.</I> Analyses of the transduced myocytes revealed significant upregulation of bFGF, PDGF-A, PDGF-B, IGF-II, and TGF-β1. A coculture assay of the paracrine effects indicated that Ad-Egr-1* promoted proliferation and migration of endothelial cells. When Ad-Egr-1* was injected into the tibialis anterior muscle of mice, followed by explant culture in growth factor-reduced Matrigel, many capillary-like structures were observed in the Egr-1* group compared with minimal sprouting from the LacZ group, suggesting an angiogenic potential of Egr-1*. Next we evaluated Ad-Egr-1* in a murine model of hindlimb ischemia. Compared with slow revascularization in the control PBS or LacZ group, a rapid increase in tissue perfusion was observed in the Egr-1* group and the difference in flux ratio was statistically significant at day 7. In the injected muscle, expression of Egr-1*, upregulation of its target genes, and increased number of vessels staining positive for smooth muscle α-actin were observed. These results suggest that Egr-1 plays an important role in vascular recovery after occlusion and could be a potential target for therapeutic angiogenesis.</P>
Jang, Hyung-Suk,Nam, Hye Yeong,Kim, Jeong-Min,Hahm, Dong-Hoon,Nam, So Hee,Kim, Koung Li,Joo, Jae-Ryang,Suh, Wonhee,Park, Jong-Sang,Kim, Duk Kyung,Gwon, Hyeon-Cheol Wiley Subscription Services, Inc., A Wiley Company 2009 CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Vol.74 No.6
<B>Objective:</B><P>To evaluate the efficacy of the curcumin-coating stent (CCS) on the inhibition of restenosis in a rabbit iliac artery stent model.</P><B>Results:</B><P>Curcumin, pigment naturally acquired from the rhizome of the plant curcuma longa, is known to have antiproliferative, antimigratory, and anti-inflammatory effects. However, it is still unclear that curcumin can inhibit neointimal proliferation of the injured vessel.</P><B>Methods:</B><P>Dose-dependent inhibition of cell growth was observed over a dose range from 10 nM to 10 μM. CCS was prepared by a dip-coating method (high-dose: HD, low-dose: LD). The release profile of the HD CCS showed that drug release persisted until day 21. Scanning electron microscopy of the CCS showed an intact surface of the stent even after expansion. To test the efficacy of CCS in vivo, LD CCS, HD CCS, and bare metal stents (BMS) were implanted in random order in one iliac artery (N = 30 arteries) of male New Zealand White rabbits (N = 15).</P><B>Results:</B><P>After 28 days, the LD and HD CCS groups had a 43% and 55% reduction in the neointimal area, compared with the BMS group (BMS 3.3 ± 1.0 mm<SUP>2</SUP>, LD 1.9 ± 0.8 mm<SUP>2</SUP>, and HD 0.9 ± 0.5 mm<SUP>2</SUP>, P < 0.05). There appeared to be no cytotoxicity related to curcumin at the indicated doses.</P><B>Conclusions:</B><P>Curcumin, a natural compound in the human diet, seems to be a safe and effective candidate drug for use in a drug-eluting stent for the prevention of stent restenosis following angioplasty. © 2009 Wiley-Liss, Inc.</P>
( Yeongju Yeo ),( Hayoung Jeong ),( Minju Kim ),( Yanghee Choi ),( Koung Li Kim ),( Wonhee Suh ) 생화학분자생물학회 2022 BMB Reports Vol.55 No.11
Pulmonary arterial hypertension (PAH) is a progressive and devastating disease whose pathogenesis is associated with a phenotypic switch of pulmonary arterial vascular smooth muscle cells (PASMCs). Bone morphogenetic protein (BMP) signaling and potassium two pore domain channel subfamily K member 3 (KCNK3) play crucial roles in PAH pathogenesis. However, the relationship between BMP signaling and KCNK3 expression in the PASMC phenotypic switching process has not been studied. In this study, we explored the effect of BMPs on KCNK3 expression and the role of KCNK3 in the BMP-mediated PASMC phenotypic switch. Expression levels of BMP receptor 2 (BMPR2) and KCNK3 were downregulated in PASMCs of rats with PAH compared to those in normal controls, implying a possible association between BMP/BMPR2 signaling and KCNK3 expression in the pulmonary vasculature. Treatment with BMP2, BMP4, and BMP7 significantly increased KCNK3 expression in primary human PASMCs (HPASMCs). BMPR2 knockdown and treatment with Smad1/5 signaling inhibitor substantially abrogated the BMP-induced increase in KCNK3 expression, suggesting that KCNK3 expression in HPASMCs is regulated by the canonical BMP-BMPR2-Smad1/5 signaling pathway. Furthermore, KCNK3 knockdown and treatment with a KCNK3 channel blocker completely blocked BMP-mediated anti-proliferation and expression of contractile marker genes in HPAMSCs, suggesting that the expression and functional activity of KCNK3 are required for BMP-mediated acquisition of the quiescent PASMC phenotype. Overall, our findings show a crosstalk between BMP signaling and KCNK3 in regulating the PASMC phenotype, wherein BMPs upregulate KCNK3 expression and KCNK3 then mediates BMP-induced phenotypic switching of PASMCs. Our results indicate that the dysfunction and/or downregulation of BMPR2 and KCNK3 observed in PAH work together to induce aberrant changes in the PASMC phenotype, providing insights into the complex molecular pathogenesis of PAH. [BMB Reports 2022; 55(11): 565-570]