Farnesyl transferase 억제제인 YH3938 및 YH3945에 의한 Ras 발암원성 억제

Myung-Ju Oh(오명주),Nong Yeon Kim(김농연),Su-Eun Lim(임수은),Young-Hwa Chung(정영화),Byung H Jhun(전병학) 한국생명과학회 2010 생명과학회지 Vol.20 No.2

Ras 유전자는 30%의 인간암에서 변이가 발견되며 세 종류의 isoform, H-Ras, K-Ras 및 N-Ras로 구성되어 있다. Ras 단백질의 CAAX motif에 farnesylation과 같은 번역 후 변형은 Ras의 활성에 필수 요소이다. 본 연구에서는 새로운 farnesyl transferase 억제제인 YH3938과 YH3945의 발암원성 H-Ras, K-Ras 및 N-Ras의 작용에 대한 영향을 조사하였다. YH3938과 YH3945는 발암원성 H-Ras에 의해 형질전환된 Rat2 세포의 증식과 형태 변화를 억제하였으나 K-Ras에 대해서는 효과가 없었다. N-Ras에 대해서는 약한 영향이 있었다. H-Ras와 N-Ras에 의한 SRE promoter 활성화는 YH3938과 YH3945에 의해 억제되었으나, K-Ras에는 영향이 없었다. Ras 단백질의 bandshift 분석을 통해 YH3938은 H-Ras와 N-Ras의 번역 후 변환을 억제하였으나, K-Ras에는 영향이 없었다. YH3945는 H-Ras의 변환에만 영향이 있었다. 결론적으로 YH3938과 YH3945는 H-Ras의 farnesylation을 억제하여 그 발암원성을 억제하며, YH3938은 N-Ras 작용을 농도의존적으로 억제하며, K-ras에 대해서는 영향이 없음을 알 수 있었다. Ras genes are responsible for up to 30% of human tumor mutations and are composed of three isoforms: H-Ras, K-Ras and N-Ras. The post-translational modification of the CAAX motif of the Ras protein is essential in Ras actions. In the present study, we studied the effects of novel farnesyl transferase inhibitors (FTIs), YH3938 and YH3945, on the actions of oncogenic mutants of H-Ras, K-Ras and N-Ras. YH3938 and YH3945 completely reverted the proliferation and morphology of oncogenic H-Ras-transformed Rat2 cells, but not of oncogenic K-Ras-transformed Rat2 cells. Oncogenic N-Rastransformed Rat2 cells were slightly affected. Activation of SRE promoters by oncogenic H-Ras and N-Ras, but not by K-Ras, were inhibited by treatment with YH3938 and YH3945. Using bandshift analysis, YH3938 suppressed the processing of oncogenic H-Ras and N-Ras, but not that of oncogenic K-Ras protein. YH3945 only inhibited the processing of H-Ras. From these results, we conclude that YH3938 and YH3945 specifically inhibit actions of oncogenic H-Ras through inhibition of its farnesylation, that YH3938 also inhibits N-Ras activity in a dose-dependent manner, and that these drugs have no effect on oncogenic K-Ras activity.

H ₂ CS IN OUTFLOWS OF THE MASSIVE STAR-FORMING CORE DR21(OH)

Minh, Y. C.,Liu, S.-Y.,Chen, H.-R.,Su, Y.-N. IOP Publishing 2011 ASTROPHYSICAL JOURNAL LETTERS - Vol.737 No.1

<P>For the first time, using the Submillimeter Array, H2CS emission was observed to show a typical bipolar outflow morphology toward DR21(OH). The emission consisted of a strong concentration toward a hot molecular core (MM1a) and a symmetrically extended feature aligned roughly in the north-south direction. H2CS is one of the hot core species, and its extended emission is expected to result from the interaction between the outflow of MM1a and the dense ambient gas. We derive H2CS column densities of similar to 3 x 10(15) cm(-2) and similar to 1 x 10(15) cm(-2) toward MM1a and the centers of the extended emission, respectively. Its fractional abundance, f(H2CS) similar to 10(-9) relative to the total H-2 abundance, is comparable to those in other star-forming regions, suggesting that H2CS may be present in a region closer to the center than previously thought. Our results suggest that the observed H2CS emission arises via direct evaporation or sputtering of the solid H2CS on the grain surface, and H2CS may be one of the major sulfur-bearing species residing in the ice grain mantles in a solid form, at least in the case of DR21(OH).</P>

Ferromagnetism in ZnCoO due to Hydrogen-Mediated Co–H–Co Complexes: How to Avoid the Formation of Co Metal Clusters?

Kim, Su Jae,Cha, Su Young,Kim, Ji Young,Shin, Jong Moon,Cho, Yong Chan,Lee, Seunghun,Kim, Won-Kyung,Jeong, Se-Young,Yang, Y. S.,Cho, Chae Ryong,Choi, H. W.,Jung, Myung-Hwa,Jun, Byeong-Eog,Kwon, Ki-Yon American Chemical Society 2012 The Journal of Physical Chemistry Part C Vol.116 No.22

<P>There have been many studies of ferromagnetism in ZnCoO, and the results have been controversial. Secondary phases, such as Co oxides and Co metal clusters, in ZnCoO are easily produced during treatment, but the formation conditions are not well understood. We fabricated samples under hydrogen-injection conditions at different heat-treatment temperatures and examined the conditions by using synchrotron X-ray analysis under which Co<SUB>3</SUB>O<SUB>4</SUB> appeared or was transformed into Co metal. We investigated the transforming process of the ferromagnetic origin from intrinsic to extrinsic nature via intermediate region competition by Co–H–Co and Co metal cluster and suggest conditions that induce ferromagnetic spin ordering in ZnCoO due to Co–H–Co complexes through hydrogen mediation.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jpccck/2012/jpccck.2012.116.issue-22/jp300536w/production/images/medium/jp-2012-00536w_0010.gif'></P>

Anti-Helicobacter pylori activities of FEMY-R7 composed of fucoidan and evening primrose extract in mice and humans

Tae-Su Kim,Ehn-Kyoung Choi,Jihyun Kim,Kyungha Shin,Sung-Pyo Lee,Youngjin Choi,Joseph H. Jeon,Yun-Bae Kim 한국실험동물학회 2014 Laboratory Animal Research Vol.30 No.3

Helicobacter pylori-eliminating effects of FEMY-R7, composed of fucoidan and evening primrose extract, were investigated in mice and humans. Male C57BL/6 mice were infected with the bacteria by intragastric inoculation (1×10<SUP>9</SUP> CFU/mouse) 3 times at 2-day intervals, and simultaneously, orally treated twice a day with 10 or 100 mg/kg FEMY-R7 for 2 weeks. In Campylobcter-like organism-detection test, FEMY-R7 markedly reduced the urease-positive reactivity. In a clinical sudy, human subjects, confirmed to be infected with Helicobacter pylori, were orally administered twice a day with a capsule containing 150 mg FEMY-R7 for 8 weeks. FEMY-R7 significantly decreased both the Delta over baseline-value in urea breath test and the serum pepsinogens I and II levels. The results indicate that FEMY-R7 not only eliminates H. pylori from gastric mucosa of animals and humans, but also improves gastric function.

Biodistribution of <SUP>99m</SUP>Tc Labeled Integrin Antagonist

Beom-Su Jang,Seung-Hee Park,In Soo Shin,Jin-Soo Maeng,Chang H. Paik 한국독성학회 2013 Toxicological Research Vol.29 No.1

The selective targeting of an integrin αvβ3 receptor using radioligands may enable the assessment of angiogenesis and integrin αvβ3 receptor status in tumors. The aim of this research was to label a peptidomimetic integrin αvβ3 antagonist (PIA) with <SUP>99m</SUP>Tc(CO)3 and to test its receptor targeting properties in nude mice bearing receptor-positive tumors. PIA was reacted with tris-succinimidyl aminotriacetate (TSAT) (20 mM) as a PIA per TSAT. The product, PIA-aminodiacetic acid (ADA), was radiolabeled with [<SUP>99m</SUP>Tc(CO)3(H2O)3]<SUP>+1</SUP>, and purified sequentially on a Sep-Pak C-18 cartridge followed by a Sep-Pak QMA anion exchange cartridge. Using gradient C-18 reverse-phase HPLC, the radiochemical purity of <SUP>99m</SUP>Tc(CO)3-ADA-PIA (retention time, 10.5 min) was confirmed to be > 95%. Biodistribution analysis was performed in nude mice (n = 5 per time point) bearing receptor-positive M21 human melanoma xenografts. The mice were administered <SUP>99m</SUP>Tc(CO)3-ADA-PIA intravenously. The animals were euthanized at 0.33, 1, and 2 hr after injection for the biodistribution study. A separate group of mice were also co-injected with 200 μg of PIA and euthanized at 1 hr to quantify tumor uptake. <SUP>99m</SUP>Tc(CO)3-ADA-PIA was stable in phosphate buffer for 21 hr, but at 3 and 6 hr, 7.9 and 11.5% of the radioactivity was lost as histidine, respectively. In tumor bearing mice, <SUP>99m</SUP>Tc(CO)3-ADA-PIA accumulated rapidly in a receptor-positive tumor with a peak uptake at 20 min, and rapid clearance from blood occurring primarily through the hepatobiliary system. At 20 min, the tumor-toblood ratio was 1.8. At 1 hr, the tumor uptake was 0.47% injected dose (ID)/g, but decreased to 0.12% ID/g when co-injected with an excess amount of PIA, indicating that accumulation was receptor mediated. These results demonstrate successful <SUP>99m</SUP>Tc labeling of a peptidomimetic integrin antagonist that accumulated in a tumor via receptor-specific binding. However, tumor uptake was very low because of low blood concentrations that likely resulted from rapid uptake of the agent into the hepatobiliary system. This study suggests that for <SUP>99m</SUP>Tc(CO)3-ADA-PIA to be useful as a tumor detection agent, it will be necessary to improve receptor binding affinity and increase the hydrophilicity of the product to minimize rapid hepatobiliary uptake.

Biodistribution of ^99mTc Labeled Integrin Antagonist

Jang, Beom-Su,Park, Seung-Hee,Shin, In Soo,Maeng, Jin-Soo,Paik, Chang H. Korean Society of ToxicologyKorea Environmental Mu 2013 Toxicological Research Vol.29 No.1

The selective targeting of an integrin ${\alpha}_v{\beta}_3$ receptor using radioligands may enable the assessment of angiogenesis and integrin ${\alpha}_v{\beta}_3$ receptor status in tumors. The aim of this research was to label a peptidomimetic integrin ${\alpha}_v{\beta}_3$ antagonist (PIA) with $^{99m}Tc(CO)_3$ and to test its receptor targeting properties in nude mice bearing receptor-positive tumors. PIA was reacted with tris-succinimidyl aminotriacetate (TSAT) (20 mM) as a PIA per TSAT. The product, PIA-aminodiacetic acid (ADA), was radiolabeled with $[^{99m}Tc(CO)_3(H_2O)_3]^{+1}$, and purified sequentially on a Sep-Pak C-18 cartridge followed by a Sep-Pak QMA anion exchange cartridge. Using gradient C-18 reverse-phase HPLC, the radiochemical purity of $^{99m}Tc(CO)_3$-ADA-PIA (retention time, 10.5 min) was confirmed to be > 95%. Biodistribution analysis was performed in nude mice (n = 5 per time point) bearing receptor-positive M21 human melanoma xenografts. The mice were administered $^{99m}Tc(CO)_3$-ADA-PIA intravenously. The animals were euthanized at 0.33, 1, and 2 hr after injection for the biodistribution study. A separate group of mice were also co-injected with 200 ${\mu}g$ of PIA and euthanized at 1 hr to quantify tumor uptake. $^{99m}Tc(CO)_3$-ADA-PIA was stable in phosphate buffer for 21 hr, but at 3 and 6 hr, 7.9 and 11.5% of the radioactivity was lost as histidine, respectively. In tumor bearing mice, $^{99m}Tc(CO)_3$-ADA-PIA accumulated rapidly in a receptor-positive tumor with a peak uptake at 20 min, and rapid clearance from blood occurring primarily through the hepatobiliary system. At 20 min, the tumor-to-blood ratio was 1.8. At 1 hr, the tumor uptake was 0.47% injected dose (ID)/g, but decreased to 0.12% ID/g when co-injected with an excess amount of PIA, indicating that accumulation was receptor mediated. These results demonstrate successful $^{99m}TC$ labeling of a peptidomimetic integrin antagonist that accumulated in a tumor via receptor-specific binding. However, tumor uptake was very low because of low blood concentrations that likely resulted from rapid uptake of the agent into the hepatobiliary system. This study suggests that for $^{99m}Tc(CO)_3$-ADA-PIA to be useful as a tumor detection agent, it will be necessary to improve receptor binding affinity and increase the hydrophilicity of the product to minimize rapid hepatobiliary uptake.

[ $Bi_2Sr_2CaCu_2O{8+\delta}$ ] Intrinsic Josephson Junctions in a Parallel Magnetic Field

Lee, J.H.,Chong, Yon-Uk,Lee, Su-Youn,Khim, Z.G. The Korean Superconductivity Society 2000 Progress in superconductivity Vol.1 No.2

We have investigated the Josephson vortex dynamics in $Bi_2Sr_2CaCu_2O{8+\delta}$ intrinsic Josephson junctions subjected to a magnetic field parallel to $CuO_2$ planes. We investigated mesas with $40\times40{\mu}m^2$ in size and containing 6 and 20. intrinsic junctions. The zero field I-V characteristics exhibited a typical hysteretic, multi-branched nature of the intrinsic Josephson effect. At high magnetic fields (H>1.5 T), I-V characteristics showed flux flow steps. The Swihart velocity obtained from this observation was about $4.2\times10^5$ m/s, which was the lowest mode electromagnetic wave velocity of N coupled stack. The experimental I-V curves fitted well into the simple model of Cherenkov radiation including Ohmic and non-linear dissipation terms. This suggests that the dissipation mechanism of Josephson vortex be due to both Cherenkov radiation and quasiparticle tunneling current.

Polarity affects the antioxidant and antimicrobial activities of jellyfish (Acromitus hardenbergi) extracts

Khong, Nicholas M.H.,Foo, Su Chern,Yau, Sook Kun,Chan, Kim Wei,Yusoff, Fatimah Md. The Korean Society of Fisheries and Aquatic Scienc 2022 Fisheries and Aquatic Sciences Vol.25 No.4

Jellyfish is an emerging aquaculture species, farmed for Oriental cuisines and nutraceutical ingredients. This study aimed to examine antioxidative and antimicrobial potentials of various fractions of the jellyfish, Acromitus hardenbergi. The bell and oral arms of the jellyfish were sequentially extracted with petroleum ether (PE), dichloromethane (DCM), chloroform (CHCl₃), methanol (MeOH), and water (H₂O) to extract its bioactive in an increasing polarity gradient. Test fractions were assayed for antiradical activities using electron spin resonance spectrometry, β-carotene-linoleate model and Folin-Ciocalteu assay; and antimicrobial activity against 2 Gram-negative bacteria, 4 Gram-positive bacteria and 2 fungal species using the disc diffusion assay. All fractions were also subjected to Fourier Transform Infrared (FTIR) analysis to identify types of functional groups present. It was found that the hydrophilic extracts (H₂O fractions) possessed the most effective radical scavenging activity (p < 0.05) while the lipophilic extracts (PE fractions) the most active antimicrobial activity, especially against Gram-positive bacteria (p < 0.05). Total oxidation substrates content was found to be highest in the PE fractions of jellyfish bell and oral arms (p < 0.05). FTIR data showed that the H₂O and MeOH fractions contains similar functional groups including -OH, -C=O, -N-H and -S=O groups, while the PE, DCM, and CHCl₃ fractions, the -CH₃, -COOH groups. This study showed that A. hardenbergi contains antioxidants and antimicrobials, thereby supporting the traditional claim of the jellyfish as an anti-aging and health-promoting functional food. Bioassay-guided fractionation approach serves as a critical milestone for the strategic screening, purification, and elucidation of therapeutically significant actives from jellyfish.

Genetically engineered fibroblasts with antigen-presenting capability:Efficient induction of an antigen-specific cytotoxic T-lymphocyte response and protection against tumor development in vivo

Kim, Tae S .,Chung, Su W .,Kim, Seung H .,Kang, Bok Y .,Hwang, Seung Y .,Lee, Jae W . 전남대학교 약품개발연구소 2000 약품개발연구지 Vol.9 No.1

BLK mouse fibroblasts (H-2^b) were genetically engineered to express costimulatory B7.1 and interleukin-2 (BLK/IL2/B7.1). The BLK/IL2/B7.1 cells were then pulsed with an ovalbumin (OVA) epitope as a model antigen (Ag) (BLK/IL2/B7.1/OVA), and tested for the induction of OVA-specific cytotoxic T lymphocytes (CTLs) in C57BL/6 mice (H-2^b). The genetically engineered fibroblasts lacking one or two of three factors (interleukin-2, B7.1, and OVA) were constructed and used as controls. Immunization with the BLK/IL2/B7.1/OVA cells induced strong cytotoxic activities against OVA-expressing EL4 (EG7) tumor cells, but not against other H-2^b tumor cells, such as EL4, C1498 and B16F1 cells. The magnitude of the cytotoxic response in mice with the BLK/IL2/B7.1/OVA cells was significantly higher than the response in mice immunized with any other cell constructs. CD8^+ T cells with OVA-specific cytotoxic activities were predominant in mice immunized with the BLK/IL2/B7.1/OVA cells. Furthermore, immunization with the BLK/IL2/B7.1/OVA cells significantly prolonged the survival of mice, compared with any other cell constructs, when the mice were challenged with EG7 tumor cells at 2 weeks postimmunization. Induction of antitumoral CTL immunity by the BLK/IL2/B7.1/OVA cells was independent of host Ag-presenting cells and of CD4^+ T-cell and natural killer 1.1^+ cell help. These results suggest that fibroblasts can be genetically modified to efficient Ag-presenting cells for the induction of an Ag-specific CTL response.

Perturbative studies of toroidal momentum transport in KSTAR H-mode and the effect of ion temperature perturbation

Yang, S.M.,Na, Yong-Su,Na, D.H.,Park, J.-K.,Shi, Y.J.,Ko, W.H.,Lee, S.G.,Hahm, T.S. International Atomic Energy Agency 2018 Nuclear fusion Vol.58 No.6

<P>Perturbative experiments have been carried out using tangential neutral beam injection (NBI) and non-resonant magnetic perturbation (NRMP) to analyze the momentum transport properties in KSTAR H-modes. Diffusive and non-diffusive terms of momentum transport are evaluated from the transient analysis. Although the operating conditions and methodologies applied in the two cases are similar, the momentum transport properties obtained show clear differences. The estimated momentum diffusivity and pinch obtained in the NBI modulation experiments is larger than that in the NRMP modulation experiments. We found that this discrepancy could be a result of uncertainties in the assumption for the analysis. By introducing time varying momentum transport coefficients depending on the temperature gradient, the linearized equation shows that if the temperature perturbation exists, the evolution of toroidal rotation perturbation could be faster than the transport rate of mean quantity, since the evolution of toroidal rotation perturbation is related to <img ALIGN='MIDDLE' ALT='' SRC='http://ej.iop.org/images/0029-5515/58/6/066008/nfaab90eieqn001.gif'/>, a momentum diffusivity from perturbative analysis. This could explain the estimated higher momentum diffusivity using time independent transport coefficients in NBI experiments with higher ion temperature perturbation compared to that in NRMP modulation experiments. The differences in the momentum transport coefficient with NRMP and NBI are much reduced by considering time varying momentum transport coefficients in the time dependent transport simulation.</P>