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Yun, Jung-A,Kim, Joohwan,Baek, Yi-Yong,Park, Wonjin,Park, Minsik,Kim, Suji,Kim, Taesam,Choi, Seunghwan,Jeoung, Dooil,Lee, Hansoo,Won, Moo-Ho,Kim, Ji-Yoon,Ha, Kwon-Soo,Kwon, Young-Guen,Kim, Young-Myeon American Society for Pharmacology and Experimental 2019 Molecular pharmacology Vol.96 No.6
<P>The tetrapeptide Arg-Leu-Tyr-Glu (RLYE), a vascular endothelial growth factor (VEGF) receptor-2 antagonist, has been used previously either alone or in combination with chemotherapeutic drugs for treating colorectal cancer in a mouse model. We analyzed the half-life of the peptide and found that because of degradation by aminopeptidases B and N, it had a short half-life of 1.2 hours in the serum. Therefore, to increase the stability and potency of the peptide, we designed the modified peptide, N-terminally acetylated RLYE (Ac-RLYE), which had a strongly stabilized half-life of 8.8 hours in serum compared with the original parent peptide. The IC<SUB>50</SUB> value of Ac-RLYE for VEGF-A-induced endothelial cell migration decreased to approximately 37.1 pM from 89.1 pM for the parent peptide. Using a mouse xenograft tumor model, we demonstrated that Ac-RLYE was more potent than RLYE in inhibiting tumor angiogenesis and growth, improving vascular integrity and normalization through enhanced endothelial cell junctions and pericyte coverage of the tumor vasculature, and impeding the infiltration of macrophages into tumor and their polarization to the M2 phenotype. Furthermore, combined treatment of Ac-RLYE and irinotecan exhibited synergistic effects on M1-like macrophage activation and apoptosis and growth inhibition of tumor cells. These findings provide evidence that the N-terminal acetylation augments the therapeutic effect of RLYE in solid tumors via inhibition of tumor angiogenesis, improvement of tumor vessel integrity and normalization, and enhancement of the livery and efficacy of the coadministered chemotherapeutic drugs.</P><P><B>SIGNIFICANCE STATEMENT</B></P><P>The results of this study demonstrate that the N-terminal acetylation of the tetrapeptide RLYE (Ac-RLYE), a novel vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor, significantly improves its serum stability, antiangiogenic activity, and vascular normalizing potency, resulting in enhanced therapeutic effect on solid tumors. Furthermore, the combined treatment of Ac-RLYE with the chemotherapeutic drug, irinotecan, synergistically enhanced its antitumor efficacy by improving the perfusion and delivery of the drug into the tumors and stimulating the conversion of the tumor-associated macrophages to an immunostimulatory M1-like antitumor phenotype.</P>
( Wonjin Park ),( Yi-yong Baek ),( Joohwan Kim ),( Dong Hyun Jo ),( Seunghwan Choi ),( Jin Hyoung Kim ),( Taesam Kim ),( Suji Kim ),( Minsik Park ),( Ji Yoon Kim ),( Moo-ho Won ),( Kwon-soo Ha ),( Jeo 한국응용약물학회 2019 Biomolecules & Therapeutics(구 응용약물학회지) Vol.27 No.5
Vascular endothelial growth factor (VEGF) plays a pivotal role in pathologic ocular neovascularization and vascular leakage via activation of VEGF receptor 2 (VEGFR2). This study was undertaken to evaluate the therapeutic mechanisms and effects of the tetrapeptide Arg-Leu-Tyr-Glu (RLYE), a VEGFR2 inhibitor, in the development of vascular permeability and choroidal neovascularization (CNV). In cultured human retinal microvascular endothelial cells (HRMECs), treatment with RLYE blocked VEGF-Ainduced phosphorylation of VEGFR2, Akt, ERK, and endothelial nitric oxide synthase (eNOS), leading to suppression of VEGFA- mediated hyper-production of NO. Treatment with RLYE also inhibited VEGF-A-stimulated angiogenic processes (migration, proliferation, and tube formation) and the hyperpermeability of HRMECs, in addition to attenuating VEGF-A-induced angiogenesis and vascular permeability in mice. The anti-vascular permeability activity of RLYE was correlated with enhanced stability and positioning of the junction proteins VE-cadherin, β-catenin, claudin-5, and ZO-1, critical components of the cortical actin ring structure and retinal endothelial barrier, at the boundary between HRMECs stimulated with VEGF-A. Furthermore, intravitreally injected RLYE bound to retinal microvascular endothelium and inhibited laser-induced CNV in mice. These findings suggest that RLYE has potential as a therapeutic drug for the treatment of CNV by preventing VEGFR2-mediated vascular leakage and angiogenesis.
Energy Transfer Fluorescence Quenching of $Pr^{3+}$ in LaOCI
Kim, Taesam,Ha, Younggu 한국분석과학회 1995 분석과학 Vol.8 No.2
두 가지 활성제를 분포시킨 LaOCl:Pr, Tb와 LaOCl:Pr, Eu계에서 에너지 전달을 관찰하였다. 레이저에 의한 들뜨기와 형광 스펙트럼의 관찰로부터 활성제 이온들 사이에 독특한 에너지 전달 과정이 있음을 발견하였다. $Tb^{3+}$에서 흡수한 에너지는 $Pr^{3+}$로 직접 전달되었다. 들뜬 $Pr^{3+}$의 에너지가 아래 준위인 $^1D_2$로 단계적으로 풀리는 현상이 $Eu^{3+}$에 의해 야기되었다. 비슷한 조건을 가진 $Tb^{3+}$는 $Eu^{3+}$처럼 촘촘한 $^7F_J$ 바닥 준위를 가지고 있으나 단계적 풀림에 효과적이지 못하였다. 이 결과는 에너지 전달에 있어서 이온의 양자 상태가 에너지 전달에 절대적인 조건이 되지 못하며 에너지 전달은 활성제가 가까이 있을 경우 그 준위들 사이에 경쟁적임을 보여 주었다. The energy transfer is observed in double-activator-doped LaOCl:Pr, Tb and LaOCl:Pr, Eu system. From laser excitation and fluorescence spectra, a peculiar process for energy transfer between the activators is found. The energy absorbed by $Tb^{3+}$ is directly transferred to $Pr^{3+}$ ion. A cascade relaxation of an excited $Pr^{3+}$ level to lower level, $^1D_2$ is induced by $Eu^{3+}$, $Tb^{3+}$, which has $^7F_J$ ground levels like $Eu^{3+}$ ion, does not affect the cascade relaxation. The result represents that the quantum state of ion is not absolute condition for the energy transfer and that the energy transfer is competitive between levels of activator when the activator ions are closely located.
ENERGY TRANSFER PROCESS BETWEEN $Ce^{3+}$ AND $Tb^{3+}$ IN LaOCl HOST
Kim, Taesam,Sung, Hakje,Kim, Kunhan,Ha, Younggu,Chang, Joowhan,Song, Sunho 한국분석과학회 1993 분석과학 Vol.6 No.3
LaOCl 입자 물질에서 $Ce^{3+}$와 $Tb^{3+}$ 사이의 에너지 전달 과정을 연구하였다. $Ce^{3+}$에서 흡수된 에너지는 강한 형광 방출 준위가 있는 $Tb^{3+}$으로 에너지가 전달되었다. 에너지가 전달되는 확률은 활성제 이온의 농도 혹은 거리에 크게 의존하였다. 농도가 낮을 때는 $Tb^{3+}$으로 전달된 에너지가 $^5D_3$ 준위에서 방출되었다. 그러나 높은 농도에서는 다시 $Ce^{3+}$으로 에너지는 이동하고(역전달) 더 낮은 $Ce^{3+}$ 혹은 $Tb^{3+}$의 준위로부터 방출되었다. 역전달 현상은 $Ce^{3+}$ 이온의 농도를 변화시키는 실험을 통하여 확인하였다. 이와 같이 $Ce^{3+}$이 관여하면 매개하지 않은 경우보다 이완이 잘 일어났다. Energy transfer process between $Tb^{3+}$ and $Ce^{3+}$ has been studied in LaOCl host. The energy absorbed by $Ce^{3+}$ transfers to $Tb^{3+}$ which has levels emitting strong fluorescence. The probability of energy transfer depends strongly on the concentration or the distance of activator ions. While the energy transferred on $Tb^{3+}$ emits from $^5D_3$ level at low concentration of $Ce^{3+}$, the energy goes back to $Ce^{3+}$(Back Transfer) and then emits from low levels of $Ce^{3+}$ and $Tb^{3+}$ at the high concentration. The Back Transfer process has been identified by the experiment with varying the concentration of the activator, $Ce^{3+}$. The relaxation is more effective if $Ce^{3+}$ intermediates than if not.
REDD‐1 aggravates endotoxin‐induced inflammation <i>VIA</i> atypical NF‐κB activation
Lee, Dong‐,Keon,Kim, Ji‐,Hee,Kim, Joohwan,Choi, Seunghwan,Park, MinSik,Park, Wonjin,Kim, Suji,Lee, Kyu‐,Sun,Kim, Taesam,Jung, Jiwon,Choi, Yoon Kyung,Ha, Kwon‐,Soo,Won, Moo Federation of American Society for Experimental Bi 2018 The FASEB Journal Vol.32 No.8