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Four-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of TS-DP2, a Novel Human Granulocyte Colony Stimulating Factor in Rats

  • Lee, JooBuom;Lee, Kyungsun;Choe, Keunbum;Jung, Hyunseob;Cho, Hyunseok;Choi, Kiseok;Kim, Taegon;Kim, Seojin;Lee, Hyeong-Seok;Cha, Mi-Jin;Song, Si-Whan;Lee, Chul Kyu;Chun, Gie-Taek
    • Toxicological Research
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    • v.31 no.4
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    • pp.371-392
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    • 2015
  • TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of $1000{\mu}g/kg/day$. Rats received TS-DP2 intravenously at doses of 250, 500, and $1000{\mu}g/kg/day$ once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 $500{\mu}g/kg/day$ and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was $250{\mu}g/kg/day$, and no observed adverse effect level (NOAEL) in females was $250{\mu}g/kg/day$ in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures ($AUC_{0-24h}$ and $C_0$) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats.

ZNF424, a novel human KRAB/C2H2 zinc finger protein, suppresses NFAT and p21 pathway

  • Wang, Yuequn;Zhou, Junnei;Ye, Xiangli;Wan, Yongqi;Li, Youngqing;Mo, Xiaoyan;Yuan, Wuzhou;Yan, Yan;Luo, Na;Wang, Zequn;Fan, Xiongwei;Deng, Yun;Wu, Xiushan
    • BMB Reports
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    • v.43 no.3
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    • pp.212-218
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    • 2010
  • Zinc finger-containing transcription factors are the largest single family of transcriptional regulators in mammals, which play an essential role in cell differentiation, cell proliferation, apoptosis, and neoplastic transformation. Here we have cloned a novel KRAB-related zinc finger gene, ZNF424, encoding a protein of 555aa. ZNF424 gene consisted of 4 exons and 3 introns, and mapped to chromosome 19p13.3. ZNF424 gene was ubiquitously expressed in human embryo tissues by Northern blot analysis. ZNF424 is conserved across species in evolution. Using a GFP-labeled ZNF424 protein, we demonstrate that ZNF424 localizes mostly in the nucleus. Transcriptional activity assays shows ZNF424 suppresses transcriptional activity of L8G5-luciferase. Overexpression of ZNF424 in HEK-293 cells inhibited the transcriptional activity of NFAT and p21, which may be silenced by siRNA. The results suggest that ZNF424 protein may act as a transcriptional repressor that suppresses NFAT and p21 pathway to mediate cellular functions.

Dielectric Properties of (Ba0.7Sr0.3-3x/2Lax)(Ti0.9Zr0.1)O3 Ceramics with La3+ Substitution for Sr2+-Site ((Ba0.7Sr0.3-3x/2Lax)(Ti0.9Zr0.1)O3 세라믹의 Sr2+-자리에 대한 La3+ 치환에 따른 유전 특성)

  • Si Hyun Kim;Ju Hye Kim;Eung Soo Kim
    • Korean Journal of Materials Research
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    • v.33 no.11
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    • pp.465-474
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    • 2023
  • The effects of La3+ substitution for Sr2+-site on the crystal structure and the dielectric properties of (Ba0.7Sr0.3-3x/2Lax) (Ti0.9Zr0.1)O3 (BSLTZ) (0.005 ≤ x ≤ 0.02) ceramics were investigated. The structural characteristics of the BSLTZ ceramics were quantitatively evaluated using the Rietveld refinement method from X-ray diffraction (XRD) data. For the specimens sintered at 1,550 ℃ for 6 h, a single phase with a perovskite structure and homogeneous microstructure were observed for the entire range of compositions. With increasing La3+ substitution (x), the unit cell volume decreased because the ionic size of La3+ (1.36 Å) ions is smaller than that of Sr2+ (1.44 Å) ions. With increasing La3+ substitution (x), the tetragonal phase fraction increased due to the A-site cation size mismatch effect. Dielectric constant (εr) increased with the La3+ substitution (x) due to the increase in tetragonality (c/a) and the average B-site bond valence of the ABO3 perovskite. The BSLTZ ceramics showed a higher dielectric loss due to the smaller grain size than that of (Ba0.7Sr0.3)(Ti0.9Zr0.1)O3 ceramics. BSLTZ (x = 0.02) ceramics met the X7R specification proposed by the Electronic Industries Association (EIA).

Distribution Characteristic of Exploitable Macrobenthic Invertebrates of Beach Sediments in the Southern Coastal Water of Jeju Island (제주남부해역 사질대 유용생물 분포특성)

  • Ko, Jun-Cheol;Ko, Hyuck-Joon;Kim, Bo-Yeon;Cha, Hyung-Kee;Chang, Dae-Su
    • The Korean Journal of Malacology
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    • v.28 no.3
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    • pp.197-213
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    • 2012
  • This study was performed to know the community structure of macrobenthos and environmental factors at each 16 stations in the subtidal sandy bottoms of the southern coastal water of Jeju Island from July to November, 2011. Mean temperature and mean salinity were $20.2-22.7^{\circ}C$, 33.7-34.9 psu which shows stable water messes. Chlorophyll a concentrations of phytoplankton ranged from 0.71 to 1.71 mg/L (1.11 mg/L), showing higher July than September and November with a blooming in summer. The mean concentration values (the ranges in parentheses) of nitrate, phosphate, and silicate are 0.029-0.206 mg/L (0.101 mg/L), 0.001-0.027 mg/L (0.007 mg/L), 0.024-0.682 mg/L (0.454 mg/L), respectively. However, the values higher coastal zone due to influxes from the land. A total of 37 species was identified. of these mollusca comprised 29 secies (78.4%); Echinodermata 5 (13.5%); Arthropoda 3 (8.1%). density and biomass were estimated to be 550 ind./$m^2$ and 20,951.8 gwwt/$m^2$, respectively. Mollusca were the most dominant faunal group in terms of abundance (481 ind./$m^2$) and number of species as well, whereas bivalves were predominant in biomass (16,647.6 gwwt/$m^2$). The dominant species were Vasticardium burchardi, Oblimopa japonica, Mactar achatina, Bornatemishistrioiw akawai, Paphia vernicosa, Amusium japonicum, Glycymeris albolineata, Astriclypeus manni in 15-30 m. The seasonal variation appeared as distinct, Mollusca of individual and biomass. When summer was make a slow increase, after the highest decrease in autumn. The abundance of macrobenthic invertebrates showed significant correlation with environmental factors (Chlorophyll a, DIN, $SiO_2$, Fine sand, Very fine sand) in almost all sampling depths. The biodiversity, evenness richness index were appeared 1.56-2.50 (H'), 0.49-0.80 (E'), 4.12-4.67 (R) in each stations. The dominace index were appeared Highest in November and lowest in September.

Creation of an Environmental Forest as an Ecological Restoration

  • Lee, Chang-Seok;You, Young-Han
    • The Korean Journal of Ecology
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    • v.24 no.2
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    • pp.101-109
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    • 2001
  • We created an environmental forest on the basis of ecological design around the incineration plant of Jindo Engineering and Construction Co., Ltd., which is located in Jeongwang-dong, Siheung-si, Kyunggi-do. To get ecological information of this site, physico-chemical properties of soil on salt marsh, which is located close to the syudy site and of forest soil transported from other sites for ecological restoration were analyzed. Texture of salt marsh and transported soils were loam and sandy loam, respectively. pH, organic matter, T-N, available P, and exchangeable K and Na contents of salt marsh and transported forest soils were 6.7 and 5.4, 4.1 and 0.4%, 1.0 and 0.3mg/g, 46.7 and 6.8ppm, 521 and 207ppm, and 3.8 and 0.5mg/g, respectively. Introduced plants were selected among the dominant species of forests and the species composing the potential natural vegetation around the present study site. Those plants were selected again by considering the tolerances to air pollution and to salt, and their availability. Selected trees were Pinus thunbergii, Sophora japonica, Celtis sinensis, Quercus aliena, Q. serrata, Q. dentata, and Q. acutissima. Selected sub-trees were Albizzia julibrissin, Koelreuteria poniculata, and Styrax japonica and shrubs were Rhododendron yedoense var. poukhanense, R. mucronulatum, Callicarpa japonica, Euonymus alatus, E. japonica, and R. schlippenbachii. On the other hand, introduction of herbs was not considered except for Liriope platyphylla, which was ornamentally planted in one site. Planting bed of mound type was adopted to provide the fine drainage system. Mound was designed to furnish litter, A, B, and C layers simuating the profile of forest soil. Slope of mound was mulched by rice straw of 2cm in thickness to prevent for sliding of litter and soil in cases of strong wind or heavy rain. Height of mound was designed to secure more than 1 m by combining A and B layers. Narrow zones, in which mound with stable slope degree cannot be prepared, was designed to equip the standard soil depth with the introduction of stone for supporting. On the other hand, plants with shallow root system were arranged in some zones, in which satisfactory soil depth cannot be ensured. Plants were arranged in the order of tree, sub-tree, and shrub from center to edge on the mound to make a mature forest of a dome shape in the future. Dispersion of plants was designed to be random pattern rather than clumped one. Problems on creation of the environmental forest by such ecological design were found to be management or inspection by non-specialized project operators and inspecting officers, and regulations for construction without ecological background. Alternative plans to solve such problems were suggested.

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Neuroprotective Mechanism of Acupuncture at GB34 for Dopaminergic Neurons in the Striatum of a Parkinson's Disease Mouse Model (파킨슨병 동물 모델을 이용한 양릉천(GB34)의 선조체 내 도파민성신경세포 보호 기전 연구)

  • Jeon, Hyongjun;Yoo, Tae-Won;Kim, Dongsoo;Kwon, Sunoh;Kim, Seungtae
    • Korean Journal of Acupuncture
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    • v.32 no.3
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    • pp.108-115
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    • 2015
  • Objectives : Acupuncture is frequently used as an alternative therapy for Parkinson's disease(PD) in Korea. Using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson's disease mouse model, the present study investigated a possible role of acupuncture stimulation at GB34 in suppressing dopaminergic neuronal death and regulating the phosphorylation of protein kinase B(Akt) in substantia nigra(SN) and striatum(ST). Methods : Eight-week-old male C57BL/6 mice were administered intraperitoneally with 30 mg/kg of MPTP at 24-h intervals for 5 days. Acupuncture stimulation at GB34 or SI3 was performed once a day for 12 days consecutively from the first MPTP injection. After the last acupuncture stimulation, pole test was performed to assess the effect of the acupuncture stimulations. Dopaminergic neuronal survival in the SN and the ST, dopamine transporter( DAT) and caspase-3 expression in the ST were evaluated by immunohistochemistry. The phosphorylations of Akt in the SN and the ST were measured by Western blotting. Results : MPTP administration caused behavioral impairment and dopaminergic neuronal death in the SN and the ST. It also decreased DAT expression and increased caspase-3 expression in the ST. Acupuncture stimulation at GB34 alleviated these MPTP-induced impairments. Moreover, MPTP suppressed Akt phosphorylation in the SN and the ST, whereas acupuncture stimulation at GB34 alleviated the phosphorylation in the SN. Conclusions : These results indicate that acupuncture stimulation at GB34 can inhibit MPTP-induced dopaminergic neuronal death and alleviate the Akt phosphorylation in the SN, suggesting a possible role for acupuncture in the treatment of PD.

A Scientific Analysis of Dancheong Pigments at Yaksajeon Hall in Gwallyoungsa Temple (창녕 관룡사 약사전 단청안료의 과학적 분석)

  • Han, Min-su;Kim, Jin-hyoung;Lee, Jang-jon
    • Korean Journal of Heritage: History & Science
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    • v.47 no.1
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    • pp.18-31
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    • 2014
  • This study aims at identifying of characteristics and types of the pigments used for Dancheong(surface decorative and protective pigments) of Yaksajeon Hall in Gwallyoungsa Temple using a Micro-XRF, XRD, SEM-EDS and thereafter, comparing it with the pigments of the wall painting in the same building and with Dancheong pigments of Daeungjeon Hall. The results can be briefly summarized as two points. First, different types of pigments for red, green and white colours had been applied based on different parts of the building and more than two different pigments had been mixed to produce various colours in so me parts. Second, scientific analysis has confirmed that raw minerals for each colour groups are: Cinnabar, minium and Hematite for red; white clay and oyster shell white($Al_2O_3{\cdot}SiO_2{\cdot}4H_2O$) for white; Atacamite and Celadonite for green; carbon(C) for black; Yellow Ocher for yellow; and Lazulite for blue. Comparative analysis of such result with that of the wall paintings and of Dancheong of Daeungjeon Hall has revealed that similar minerals had been used in overall except that several different pigments had been added or removed for making green, white and yellow colour groups in some parts. In conclusion, the result has displayed that painters had used different ways of producing pigments by a type of painting or a building within the same period or for the buildings in the same buddhist temple compound.

Characteristics of Ocean Environmental Factors and Community Structure of Macrobenthos around Munseom, Jeju Island, Korea (제주도 문섬 주변해역 해양환경특성 및 저서무척추동물의 군집구조)

  • Ko, Joon-Chul;Koo, Jun-Ho;Yang, Moon-Ho
    • The Korean Journal of Malacology
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    • v.24 no.3
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    • pp.215-228
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    • 2008
  • This study was performed to find out the community structure of macrobenthos and the environmental factors around Munseom coastal water in Jeju Island from June to December, 2007. Mean temperature and mean salinity were $19.6^{\circ}C$ and 34.03 psu, indicating stable water masses. Concentrations of DO, COD and SS were as low as those in the standard sea-water-quality classes I. Chlorophyll a concentrations ranged from 0.40 to 1.09 mg/L (mean, 0.69 mg/L), and higher concentration was observed in December rather than in June due to a blooming in winter. The mean concentration (their ranges are in parentheses) of nitrate, phosphate, and silicate were 0.15 mg/L (0.073-0.264 mg/L), 0.01 mg/L (0.004-0.011 mg/L) and 0.23 mg/L (0.039-0.464 mg/L), respectively. The values were higher near the Munseom due to influxes from the land. Of the 112 species that were identified, 40 species (36.0%) were Mollusca; 33 (28.8%) were Cnidaria; 13 (11.7%) were Porifera; 8 (7.2%) were Arthropoda and 17 species (15.3%) were others including Echinodermata. Density and biomass were estimated to be 4,340 individual/$m^2$ and $53,107.8\;gwwt/m^2$ respectively. Anthozoa was the most dominant group in abundance ($2,132\;ind./m^2$) as well as in the number of species, whereas Cnidaria was predominant in biomass ($37,630.9\;gwwt/m^2$). The dominant species were Dendronephthya gigantea, Scleronephthya gracillimum, Anthoplexaura dimorpha, Dendronephthya castanea, Thecocarpus niger, Dendronephthya spinulosa, Dendronephthya putteri, and Acabaria bicolor in the depth of 10-30 m. The seasonal variations of the number of individual and biomass of Cnidaria and Mollusca were observed. There was a slow increment in June, a decrement in October, and a drastic increasing in December. The biodiversity, evenness and richness index in surveyed stations were 2.715-3.413 (H'), 0.758-0.851(E'), and 5.202-8.720 (R) respectively. The dominance index was the highest in station M2 and the lowest in station M1.

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Synthesis of Ultrasound Contrast Agent: Characteristics and Size Distribution Analysis (초음파 조영제의 합성 및 합성된 초음파 조영제의 특성 분석)

  • Lee, Hak Jong;Yoon, Tae Jong;Yoon, Young Il
    • Ultrasonography
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    • v.32 no.1
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    • pp.59-65
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    • 2013
  • Purpose: The purpose of this study is to establish the methodology regarding synthesis of ultrasound contrast agent imaging, and to evaluate the characteristics of the synthesized ultrasound contrast agents, including size or degradation interval and image quality. Materials and Methods: The ultrasound contrast agent, composed of liposome and SF6, was synthesized from the mixture solution of $21{\mu}mol$ DPPC (1, 2-Dihexadecanoyl-sn-glycero-3-phosphocholine, $C_{40}H_{80}NO_8P$), $9{\mu}mol$ cholesterol, $1.9{\mu}mol$ of DCP (Dihexadecylphosphate, $[CH_3(CH_2)_{15}O]_2P(O)OH$), and chloroform. After evaporation in a warm water bath and drying during a period of 12-24 hours, the contrast agent was synthesized by the sonication process by addition of buffer and SF6 gas. The size of the contrast agent was controlled by use of either extruder or sonication methods. After synthesis of contrast agents, analysis of the size distribution of the bubbles was performed using dynamic light scattering measurement methods. The degradation curve was also evaluated by changes in the number of contrast agents via light microscopy immediate, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, and 84 hours after synthesis. For evaluation of the role as an US contrast agent, the echogenicity of the synthesized microbubble was compared with commercially available microbubbles (SonoVue, Bracco, Milan, Italy) using a clinical ultrasound machine and phantom. Results: The contrast agents were synthesized successfully using an evaporation-drying-sonication method. The majority of bubbles showed a mean size of 154.2 nanometers, and they showed marked degradation 24 hours after synthesis. ANOVA test revealed a significant difference among SonoVue, synthesized contrast agent, and saline (p < 0.001). Although no significant difference was observed between SonoVue and the synthesized contrast agent, difference in echogenicity was observed between synthesized contrast agent and saline (p < 0.01). Conclusion: We could synthesize ultrasound contrast agents using an evaporation-drying-sonication method. On the basis of these results, many prospective types of research, such as anticancer drug delivery, gene delivery, including siRNA or microRNA, targeted molecular imaging, and targeted therapy can be performed.

A Comparative Study of Production of [68Ga]PSMA-11 with or without Cassette Type Modules (비 카세트 방식과 카세트 방식을 이용한 [68Ga]PSMA-11의 자동 합성 방법 비교)

  • Hyun-Sik, Park;Byeong-Min, Jo;Hyun-Ho, An;Hong-Jin, Lee;Jin-Hyeong, Lee;Gyeong-Jae, Lee;Byung-Chul, Lee;Won-Woo, Lee
    • The Korean Journal of Nuclear Medicine Technology
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    • v.26 no.2
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    • pp.15-19
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    • 2022
  • Purpose [68Ga]PSMA-11 is needed the high reproducibility, excellent radiochemical yield and purity. In term of radiation safety, the radiation exposure of operator for its production also should be considered. In this work, we performed a comparative study for the fully automated synthesis of [68Ga]PSMA-11 between non-cassette type and cassette type. Materials and Methods Two different type of modules (TRACERlab FX N pro for non-cassette type and BIKBox for cassette type) were used for the automated production of [68Ga]PSMA-11. According to the previously identified elution profile, Only 2.5 ml with high radioactivity was used for the reaction. After adjusting the pH of the reaction solution with HEPES buffer solution, the precursor was added and reacted with at 95 ℃ for 15 minutes. The reaction mixture was separated and purified using a C18 light cartridge. The product was eluted with 50% EtOH/saline solution and diluted with saline. It was completed by sterilizing filter. In the non-cassette type, the aforementioned process must be prepared directly. However, in the cassette method, synthesis was possible simply by installing a kit that was already completed. Results Both total [68Ga]PSMA-11 production time were 25±3(non-cassette type) and 23±3 minutes(cassette type). The radiochemical yield of the non-cassette type(65.5±5.7%) was higher than that of the cassette type(61.6±4.8%) after sterilization filter. The non-cassette type took about 120 minutes of preparation time before synthesis due to washing of synthesizer and reagent preparation. However, since the cassette type does not require washing and reagent preparation, it took about 20 minutes to prepare before synthesis. Both type of synthesizer had a radiochemical high purity(>99%). Conclusion The non-cassette type production of [68Ga]PSMA-11 showed higher radiochemical yield and lower cost than the cassette type. However, The cassette type has an advantage in terms of preparation time, convenience, and equipment maintenance.