Evidence of carrier‐mediated transport in the penetration of donepezil into the rat brain

Kim, Mi&#x2010,Hwa,Maeng, Han&#x2010,Joo,Yu, Kyung&#x2010,Ha,Lee, Kyeong&#x2010,Ryoon,Tsuruo, Takashi,Kim, Dae‐,Duk,Shim, Chang&#x2010,Koo,Chung, Suk&#x2010,Jae Wiley Subscription Services, Inc., A Wiley Company 2010 Journal of Pharmaceutical Sciences Vol.99 No.3

<P><B>Abstract</B></P><P>The objective of this study was to characterize the mechanism that controls the transport of donepezil into the brain. The apparent brain uptake clearance (CL<SUB>app,br</SUB>) was decreased as a function of the dose of donepezil, suggesting an involvement of a saturable transport process via transporter(s) in the penetration across the blood–brain barrier (BBB). Consistent with <I>in vivo</I> results, the uptake of substrates for organic cation transporters was significantly reduced by donepezil in both MBEC4 cells (i.e., a model for BBB) and HEK 293 cells expressing the transporters found in the brain, indicative of the involvement of organic cation transporters in the transport of the drug. Furthermore, donepezil transport was enhanced (<I>p</I> < 0.01) in HEK 293 cells expressing rOCNT1, rOCTN2, or rCHT1. The CL<SUB>app,br</SUB> was reduced up to 52.8% of the control in rats that had been pretreated with choline, while the CL<SUB>app,br</SUB> was unaffected with pretreatments with organic cations other than choline, suggesting that choline and donepezil share a common transport mechanism in the penetration across the BBB <I>in vivo</I>. Taken together, these observations suggest that the transport of donepezil across the BBB is mediated by organic cation transporters such as choline transport system(s). © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1548–1566, 2010</P>

A liver‐specific gene expression panel predicts the differentiation status of <i>in vitro</i> hepatocyte models

Kim, Dae‐,Soo,Ryu, Jea&#x2010,Woon,Son, Mi&#x2010,Young,Oh, Jung&#x2010,Hwa,Chung, Kyung&#x2010,Sook,Lee, Sugi,Lee, Jeong&#x2010,Ju,Ahn, Jun&#x2010,Ho,Min, Ju&#x2010,Sik,Ahn, Jiwon,Kang, Hyun Mi John Wiley and Sons Inc. 2017 Hepatology Vol.66 No.5

<P>Alternative cell sources, such as three‐dimensional organoids and induced pluripotent stem cell–derived cells, might provide a potentially effective approach for both drug development applications and clinical transplantation. For example, the development of cell sources for liver cell–based therapy has been increasingly needed, and liver transplantation is performed for the treatment for patients with severe end‐stage liver disease. Differentiated liver cells and three‐dimensional organoids are expected to provide new cell sources for tissue models and revolutionary clinical therapies. However, conventional experimental methods confirming the expression levels of liver‐specific lineage markers cannot provide complete information regarding the differentiation status or degree of similarity between liver and differentiated cell sources. Therefore, in this study, to overcome several issues associated with the assessment of differentiated liver cells and organoids, we developed a liver‐specific gene expression panel (LiGEP) algorithm that presents the degree of liver similarity as a “percentage.” We demonstrated that the percentage calculated using the LiGEP algorithm was correlated with the developmental stages of <I>in vivo</I> liver tissues in mice, suggesting that LiGEP can correctly predict developmental stages. Moreover, three‐dimensional cultured HepaRG cells and human pluripotent stem cell–derived hepatocyte‐like cells showed liver similarity scores of 59.14% and 32%, respectively, although general liver‐specific markers were detected. <I>Conclusion</I>: Our study describes a quantitative and predictive model for differentiated samples, particularly liver‐specific cells or organoids; and this model can be further expanded to various tissue‐specific organoids; our LiGEP can provide useful information and insights regarding the differentiation status of <I>in vitro</I> liver models. (H<SMALL>EPATOLOGY</SMALL> 2017;66:1662–1674).</P>

Large‐Deformation Behavior of Honeycomb‐Structured Polymer Sheets as a Function of Polar Angle

Jin, Kwang&#x2010,Yong,Kim, Dae‐,Yoon,Kim, So&#x2010,Eun,Kuo, Shiao&#x2010,Wei,Lee, Joong Hee,Lyu, Min&#x2010,Young,Hwang, Seok&#x2010,Ho,Gent, Alan N.,Nah, Changwoon,Jeong, Kwang&#x2010,Un WILEY‐VCH Verlag 2011 Macromolecular chemistry and physics Vol.212 No.9

<P><B>Abstract</B></P><P>To construct the structure/property relationships of patterned polymer architectures depending on symmetry, the large‐deformation behavior of 2D HSPS with respect to the polar angle was studied. Holes aligned along the HSPS apex were more effective in decreasing tensile force and reducing stress concentration than those located along the plane. On varying the polar angle from 0 to 30°, the tensile force fluctuated up and down like an undamped negative sinusoidal wave with a wavelength of 15°. Additionally, molecular orientations of HSPS were monitored in situ. By comparing experimental measurements with computer simulations, it was concluded that the tensile force depends on the number of holes as well as the orientation of the axes of the honeycomb structure. </P>

Serum arylhydrocarbon receptor transactivating activity is elevated in type 2 diabetic patients with diabetic nephropathy

Kim, Jin Taek,Kim, Sang Soo,Jun, Dae Won,Hwang, Young Hwan,Park, Wook&#x2010,Ha,Pak, Youngmi Kim,Lee, Hong Kyu Wiley-Blackwell 2013 Journal of diabetes investigation Vol.4 No.5

<P><B>Abstract</B></P><P><B>Aims/Introduction</B></P><P>Evidence is emerging that exposure to persistent organic pollutants (POPs) is a risk factor for obesity‐related diseases and for diabetes mellitus (DM). We found that POPs could be measured by a cell‐based arylhydrocarbon receptor (AhR)‐dependent reporter assay. We tested if serum AhR transactivating (AHRT) activities are a risk factor for diabetic nephropathy in people with type 2 diabetes.</P><P><B>Materials and Methods</B></P><P>We enrolled diabetic patients with normoalbuminuria (<I>n </I>= 36), microalbuminuria (<I>n </I>= 29), macroalbuminuria (<I>n </I>= 8) and end‐stage renal disease (<I>n </I>= 31). Sera were tested for their AHRT activities, which were standardized by an AhR ligand, 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) and expressed as TCDD equivalents (TCDDeq pmol/L).</P><P><B>Results</B></P><P>Mean serum AHRT activities were higher in patients with microalbuminuria (40.1 ± 7.1 pmol/L), macroalbuminuria (37.4 ± 5.5 pmol/L) and end‐stage renal disease (59.1 ± 20.0 pmol/L) than in subjects with normoalbuminuria (12.7 ± 5.4 pmol/L; <I>P </I>< 0.05 for all comparisons). Serum AhR ligands showed a correlation with estimated glomerular filtration rate (eGFR;<I> r </I>= −0.663, <I>P </I>< 0.001), serum creatinine level (<I>r </I>= 0.635, <I>P </I>< 0.001), systolic blood pressure (<I>r </I>= 0.223, <I>P </I>= 0.026), glycated hemoglobim (<I>r </I>= 0.339, <I>P </I>< 0.001) and diabetic duration (<I>r </I>= 0.394, <I>P </I>< 0.001). In a multiple regression analysis, diabetic nephropathy was found to be an independent risk factor for higher AHRT activity after controlling for the confounding factors.</P><P><B>Conclusions</B></P><P>The present findings suggest serum AHRT activity, thus serum AhR ligands, is a risk factor for diabetic nephropathy. Further studies are required to clarify if an accumulation of POPs in the body is causally related to diabetic nephropathy.</P>

Down‐regulation of <i>GIGANTEA</i> ‐ <i>like</i> genes increases plant growth and salt stress tolerance in poplar

Ke, Qingbo,Kim, Ho Soo,Wang, Zhi,Ji, Chang Yoon,Jeong, Jae Cheol,Lee, Haeng&#x2010,Soon,Choi, Young&#x2010,Im,Xu, Bingcheng,Deng, Xiping,Yun, Dae‐,Jin,Kwak, Sang&#x2010,Soo John Wiley and Sons Inc. 2017 Plant biotechnology journal Vol.15 No.3

<P><B>Summary</B></P><P>The flowering time regulator GIGANTEA (GI) connects networks involved in developmental stage transitions and environmental stress responses in <I>Arabidopsis</I>. However, little is known about the role of GI in growth, development and responses to environmental challenges in the perennial plant poplar. Here, we identified and functionally characterized three <I>GI‐like</I> genes (<I>PagGIa</I>,<I> PagGIb</I> and <I>PagGIc)</I> from poplar (<I>Populus alba × Populus glandulosa</I>). <I>PagGIs</I> are predominantly nuclear localized and their transcripts are rhythmically expressed, with a peak around zeitgeber time 12 under long‐day conditions. Overexpressing <I>PagGIs</I> in wild‐type (WT) <I>Arabidopsis</I> induced early flowering and salt sensitivity, while overexpressing <I>PagGIs</I> in the <I>gi‐2</I> mutant completely or partially rescued its delayed flowering and enhanced salt tolerance phenotypes. Furthermore, the PagGIs‐PagSOS2 complexes inhibited PagSOS2‐regulated phosphorylation of PagSOS1 in the absence of stress, whereas these inhibitions were eliminated due to the degradation of PagGIs under salt stress. Down‐regulation of <I>PagGIs</I> by RNA interference led to vigorous growth, higher biomass and enhanced salt stress tolerance in transgenic poplar plants. Taken together, these results indicate that several functions of <I>Arabidopsis GI</I> are conserved in its poplar orthologues, and they lay the foundation for developing new approaches to producing salt‐tolerant trees for sustainable development on marginal lands worldwide.</P>

Pyridoxal‐5′‐phosphate phosphatase/chronophin induces astroglial apoptosis via actin‐depolymerizing factor/cofilin system in the rat brain following status epilepticus

Kim, Ji&#x2010,Eun,Ryu, Hea Jin,Kim, Min&#x2010,Ju,Kim, Dae‐,Won,Kwon, Oh&#x2010,Shin,Choi, Soo Young,Kang, Tae&#x2010,Cheon Wiley Subscription Services, Inc., A Wiley Company 2010 Glia Vol.58 No.16

<P><B>Abstract</B></P><P>Actin‐depolymerizing factor (ADF)/cofilin is a small cytoskeletal protein that is a stimulus‐responsive mediator of actin dynamics. ADF/cofilin also translocates into mitochondria and nuclei in response to apoptotic stimuli for cytochrome c release. These ADF/cofilin translocations are negatively regulated by phosphorylation. Recently, it has been reported that pyridoxal‐5′‐phosphate (PLP) phosphatase/chronophin (PLPP/CIN) regulates phosphorylation of ADF/cofilin levels. Therefore, we investigated whether PLPP/CIN contributes to apoptosis‐like events via modulation of ADF/cofilin phosphorylation following status epilepticus (SE). In the present study, apoptosis‐like astroglial damages were detected in the dentate gyrus after SE. Upregulation of ADF/cofilin and PLPP/CIN expression in the cytoplasm and nucleus were accompanied by apoptosis‐like events. PLPP/CIN level showed a direct proportionality to nuclear translocation of ADF/cofilin. Moreover, nuclear accumulation of apoptosis‐inducing factor was simultaneously observed with that of ADF/cofilin. Tat‐PLPP/CIN pretreatment accelerated astroglial apoptosis‐like degeneration following SE, although Tat‐PLPP/CIN transduction alone could not induce apoptosis or necrosis in astrocytes. Therefore, our findings suggest that nuclear accumulation of ADF/cofilin itself may not induce apoptogenic events, but may play a synergic role in apoptosis‐like astroglial loss following SE. © 2010 Wiley‐Liss, Inc.</P>

Piezoelectric properties of (Na _0.5 K _0.5 )(Nb _1‐_x S b _x )O ₃ ‐SrTiO ₃ ceramics with tetragonal‐pseudocubic PPB structure

Kim, Dae‐,Hyeon,Lee, Tae&#x2010,Gon,Cho, Sung&#x2010,Hoon,Lee, Ku&#x2010,Tak,Lee, Tae&#x2010,Ho,Hong, Youn&#x2010,Woo,Hong, Chang&#x2010,Hyo,Kim, Jeong&#x2010,Seog,Nahm, Sahn Wiley (Blackwell Publishing) 2018 JOURNAL OF THE AMERICAN CERAMIC SOCIETY - Vol.101 No.9

<P>CuO-added 0.96(Na0.5K0.5)(Nb1-xSbx)O-3-0.04SrTiO(3) ceramics sintered at the low temperature of 960 degrees C for 10hours showed dense microstructures and high relative densities. The specimens with 0.0 x0.04 had orthorhombic-tetragonal polymorphic phase boundary (PPB) structure. Tetragonal-pseudocubic PPB structure was observed in specimens with 0.05 x0.07, while the specimen with x=0.08 has a pseudocubic structure. The structural variation in the specimens is explained by the decreases in the orthorhombic-tetragonal transition temperature and Curie temperature with the addition of Sb5+ ions. The specimens with 0.05 x0.07, which have tetragonal-pseudocubic PPB structure, had large electric field-induced strains of 0.14%-0.016%. Moreover, these specimens also showed increased d(33) values between 280 pC/N and 358 pC/N. In particular, the specimen with x=0.055 showed particularly enhanced piezoelectric properties: d(33) of 358 pC/N, k(p) of 0.45, and the electric field-induced strain of 0.16% at 4.5kV/mm.</P>

Stretching‐Induced Growth of PEDOT‐Rich Cores: A New Mechanism for Strain‐Dependent Resistivity Change in PEDOT:PSS Films

Lee, Yoo&#x2010,Yong,Lee, Ji&#x2010,Hoon,Cho, Ju&#x2010,Young,Kim, Na&#x2010,Rae,Nam, Dae‐,Hyun,Choi, In&#x2010,Suk,Nam, Ki Tae,Joo, Young&#x2010,Chang WILEY‐VCH Verlag 2013 Advanced functional materials Vol.23 No.32

<P><B>Abstract</B></P><P>It remains a fundamental challenge in the development of stretchable electronics to understand how mechanical strain changes the electrical properties of materials. Although the piezoresistive behavior of poly(3,4‐ethylene‐ dioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) has been observed, its intrinsic origin is not yet fully understood because there are many extrinsic contributing factors and an experimental platform with which to assess such behavior has not been established. Here, systematic analysis shows that the matching Poisson's ratio and elastic modulus between PEDOT:PSS films and their underlying substrates is important in decoupling the factors that affect the material's piezoresistivity, allowing for tunable resistivity. Based on such a fundamental understanding, the conductivity of PEDOT:PSS can be controlled to be invariant and decrease as a function of applied tensile stress. Furthermore, a linear response of the resistivity with respect to mechanical strains of up to 60%, which has never before been realized, is shown. The irreversible conductivity enhancement is primarily caused by the coalescence‐induced growth of conductive PEDOT‐rich cores.</P>

Polymer‐Stabilized Chromonic Liquid‐Crystalline Polarizer

Park, Seul&#x2010,Ki,Kim, So&#x2010,Eun,Kim, Dae‐,Yoon,Kang, Shin&#x2010,Woong,Shin, Seunghan,Kuo, Shiao&#x2010,Wei,Hwang, Seok&#x2010,Ho,Lee, Seung Hee,Lee, Myong&#x2010,Hoon,Jeong, Kwang&#x201 WILEY‐VCH Verlag 2011 Advanced functional materials Vol.21 No.11

<P><B>Abstract</B></P><P>Robust coatable polarizer is fabricated by the self‐assembly of lyotropic chromonic liquid crystals and subsequent photo‐polymerizing processes. Their molecular packing structures and optical behaviors are investigated by the combined techniques of microscopy, scattering and spectroscopy. To stabilize the oriented Sunset Yellow FCF (H‐SY) films and to minimize the possible defects generated during and after the coating, acrylic acid (AA) is added to the H‐SY/H<SUB>2</SUB>O solution and photo‐polymerized. Utilizing cross‐polarized optical microscopy, phase behaviors of the H‐SY/H<SUB>2</SUB>O/AA solution are monitored by varying the compositions and temperatures of the solution. Based on the experimental results of two‐dimensional wide angle X‐ray diffraction and selected area electron diffraction, the H‐SY crystalline unit cell is determined to be a monoclinic structure with the dimensions of <I>a</I> = 1.70 nm, <I>b</I> = 1.78 nm, <I>c</I> = 0.68 nm, <I>α</I> = <I>β</I> = 90.0° and <I>γ</I> = 84.5°. The molecular arrangements in the oriented H‐SY films were further confirmed by polarized Fourier‐transform infrared spectroscopy. The polymer‐stabilized H‐SY films show good mechanical and chemical stabilities with a high polarizability. Additionally, patterned polarizers are fabricated by applying a photo‐mask during the photo‐polymerization of AA, which may open new doors for practical applications in electro‐optic devices.</P>

Clinical trial: Inhibitory effect of revaprazan on gastric acid secretion in healthy male subjects

Kim, Hyung&#x2010,Keun,Park, Soo&#x2010,Heon,Cheung, Dae‐,Young,Cho, Young&#x2010,Seok,Kim, Jin&#x2010,Il,Kim, Sung&#x2010,Soo,Chae, Hiun&#x2010,Suk,Kim, Jae&#x2010,Kwang,Chung, In&#x2010,Sik Blackwell Publishing Asia 2010 Journal of gastroenterology and hepatology Vol.25 No.10

<P><B>Abstract</B></P><P><B>Background and Aim: </B> Revaprazan is a novel acid pump antagonist. The aim of this study was to investigate the inhibitory effect of revaprazan on gastric acid secretion in healthy male subjects.</P><P><B>Methods: </B> In a double‐blind, three‐way cross‐over study, 30 healthy male volunteers were randomized to 100, 150 or 200 mg of oral revaprazan daily for 7 days. Serum gastrin concentration was measured, and 24‐h intragastric pH was recorded at baseline and on days 1 and 7 of each administration period. Serial blood samples were processed for pharmacokinetics.</P><P><B>Results: </B> Median intragastric pH over 24 h and mean percentage time that pH was > 4 increased in a dose‐dependent manner and were significantly higher on days 1 and 7 compared with baseline in all groups (<I>P</I> < 0.05). The antisecretory effect of revaprazan was rapid and nearly maximal on day 1 in all groups. Serum gastrin levels were rapidly normalized by 100 and 150 mg/day of revaprazan on days 1 and 7, but were significantly higher in the 200 mg/day revaprazan group. The pharmacokinetic effect was rapidly absorbed and eliminated on days 1 and 7 in all groups.</P><P><B>Conclusions: </B> Revaprazan rapidly and effectively inhibits gastric acid secretion in healthy male subjects. Therefore, revaprazan can be used as an effective drug for acid‐related disease.</P>