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Hoang, Van-Hai,Tran, Phuong-Thao,Cui, Minghua,Ngo, Van T. H.,Ann, Jihyae,Park, Jongmi,Lee, Jiyoun,Choi, Kwanghyun,Cho, Hanyang,Kim, Hee,Ha, Hee-Jin,Hong, Hyun-Seok,Choi, Sun,Kim, Young-Ho,Lee, Jeewoo American Chemical Society 2017 Journal of medicinal chemistry Vol.60 No.6
<P>Glutaminyl cyclase (QC) has been implicated in the formation of toxic amyloid plaques by generating the N-terminal pyroglutamate of beta-amyloid peptides (pGlu-A beta) and thus may participate in the pathogenesis of Alzheimer's disease (AD). We designed a library of glutamyl cyclase (QC) inhibitors based on the proposed binding mode of the preferred substrate, A beta 3E-42. An in vitro structure-activity relationship study identified several excellent QC inhibitors demonstrating 5- to 40-fold increases in potency compared to a known QC inhibitor. When tested in mouse models of AD, compound 212 significantly reduced the brain concentrations of pyroform A beta and total A beta and restored cognitive functions. This potent A beta-lowering effect was achieved by incorporating an additional binding region into our previously established pharmacophoric model, resulting in strong-interactions with the carboxylate group of Glu327 in the QC binding site. Our study offers useful insights in designing novel QC inhibitors as a potential treatment option for AD.</P>
Hoang, Van-Hai,Ngo, Van T. H.,Cui, Minghua,Manh, Nguyen Van,Tran, Phuong-Thao,Ann, Jihyae,Ha, Hee-Jin,Kim, Hee,Choi, Kwanghyun,Kim, Young-Ho,Chang, Hyerim,Macalino, Stephani Joy Y.,Lee, Jiyoun,Choi, S American Chemical Society 2019 Journal of medicinal chemistry Vol.62 No.17
<P>Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disease whose pathogenesis cannot be defined by one single element but consists of various factors; thus, there is a call for alternative approaches to tackle the multifaceted aspects of AD. Among the potential alternative targets, we aim to focus on glutaminyl cyclase (QC), which reduces the toxic pyroform of β-amyloid in the brains of AD patients. On the basis of a putative active conformation of the prototype inhibitor <B>1</B>, a series of N-substituted thiourea, urea, and α-substituted amide derivatives were developed. The structure-activity relationship analyses indicated that conformationally restrained inhibitors demonstrated much improved QC inhibition in vitro compared to nonrestricted analogues, and several selected compounds demonstrated desirable therapeutic activity in an AD mouse model. The conformational analysis of a representative inhibitor indicated that the inhibitor appeared to maintain the Z-E conformation at the active site, as it is critical for its potent activity.</P> [FIG OMISSION]</BR>
Ngo, Van T.H.,Hoang, Van-Hai,Tran, Phuong-Thao,Van Manh, Nguyen,Ann, Jihyae,Kim, Eunhye,Cui, Minghua,Choi, Sun,Lee, Jiyoun,Kim, Hee,Ha, Hee-Jin,Choi, Kwanghyun,Kim, Young-Ho,Lee, Jeewoo Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.12
<P><B>Abstract</B></P> <P>Glutamyl cyclase (QC) is a promising therapeutic target because of its involvement in the pathogenesis of Alzheimer’s disease. In this study, we developed novel QC inhibitors that contain 3-aminoalkyloxy-4-methoxyphenyl and 4-aminoalkyloxyphenyl groups to replace the previously developed pharmacophore. Several potent inhibitors were identified, showing IC<SUB>50</SUB> values in a low nanomolar range, and were further studied for <I>in vitro</I> toxicity and <I>in vivo</I> activity. Among these, inhibitors <B>51</B> and <B>53</B> displayed the most potent Aβ<SUB>N3pE−40</SUB>-lowering effects in <I>in vivo</I> acute model with reasonable BBB penetration, without showing cytotoxicity and <I>h</I>ERG inhibition. The molecular modeling analysis of <B>53</B> indicated that the salt bridge interaction and the hydrogen bonding in the active site provided a high potency. Given the potent activity and favorable BBB penetration with low cytotoxicity, we believe that compound <B>53</B> may serve as a potential candidate for anti-Alzheimer’s agents.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Xp-tree : Xpath 로케이션 스텝의 효율화를 위한 새로운 공간기반의 인덱싱 기법
Nguyen Van Trang(Nguyen Van Trang),황정희(Jeong Hee Hwang),류근호(Keun Ho Ryu) 한국정보과학회 2004 한국정보과학회 학술발표논문집 Vol.31 No.1B
Nowadays, with the rapid emergence of XML as a standard for data exchange over the Internet had led to considerable interest in the problem of data management requirements such as the need to store and query XML documents in which the location path languages Xpath is of particular important for XML application since it is a core component of many XML processing standards such as XSLT or XQuery. This paper gives a brief overview about method and design by applying a new spatial-based indexing method namely Xp-tree that used for supporting Xpath. Spatial indexing technique has been proved its capacity on searching in large databases. Based on accelerating a node using planar as combined with the numbering schema, we devise efficiently derivative algorithms, which are simple, but useful. Besides that, it also allows to trace all its relative nodes of context node in a manner supporting queries natural to the types especially Xpath queries with predicates.
Ngo, Van T.H.,Hoang, Van-Hai,Tran, Phuong-Thao,Ann, Jihyae,Cui, Minghua,Park, Gyungseo,Choi, Sun,Lee, Jiyoun,Kim, Hee,Ha, Hee-Jin,Choi, Kwanghyun,Kim, Young-Ho,Lee, Jeewoo Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.5
<P><B>Abstract</B></P> <P>Pyroglutamate-modified amyloid β peptides (pGlu-Aβ) are highly neurotoxic and promote the formation of amyloid plaques. The pGlu-Aβ peptides are generated by glutaminyl cyclase (QC), and recent clinical studies indicate that QC represents an alternative therapeutic target to treat Alzheimer’s disease (AD). We have previously developed a series of QC inhibitors with an extended pharmacophoric scaffold, termed the Arg-mimetic D-region. In the present study, we focused on the structure activity relationship (SAR) of analogues with modifications in the D-region and evaluated their biological activity. Most compounds in this series exhibited potent activity in vitro, and our SAR analysis and the molecular docking studies identified compound <B>202</B> as a potential candidate because it forms an additional hydrophobic interaction in the <I>h</I>QC active site. Overall, our study provides valuable insights into the Arg-mimetic pharmacophore that will guide the design of novel QC inhibitors as potential treatments for AD.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
( Van Anh Vo ),( Jae Won Lee ),( Ji Eun Chang ),( Ji Young Kim ),( Nam Ho Kim ),( Hee Jae Lee ),( Sung Soo Kim ),( Wan Joo Chun ),( Yong Soo Kwon ) 한국응용약물학회 2012 Biomolecules & Therapeutics(구 응용약물학회지) Vol.20 No.6
Avicularin, quercetin-3-a-L-arabinofuranoside, has been reported to possess diverse pharmacological properties such as anti-in-flammatory and anti-infectious effects. However, the underlying mechanism by which avicularin exerts its anti-inflammatory activity has not been clearly demonstrated. This study aimed to elucidate the anti-inflammatory mechanism of avicularin in lipopolysac-charide (LPS)-stimulated RAW 264.7 macrophage cells. Avicularin significantly inhibited LPS-induced excessive production of pro-inflammatory mediators such as nitric oxide (NO) and PGE2 and the protein levels of iNOS and COX-2, which are responsible for the production of NO and PGE2, respectively. Avicularin also suppressed LPS-induced overproduction of pro-inflammatory cytokine IL-1b. Furthermore, avicularin significantly suppressed LPS-induced degradation of IκB, which retains NF-κB in the cytoplasm, consequently inhibiting the transcription of pro-inflammatory genes by NF-κB in the nucleus. To understand the un-derlying signaling mechanism of anti-inflammatory activity of avicularin, involvement of multiple kinases was examined. Avicularin significantly attenuated LPS-induced activation of ERK signaling pathway in a concentration-dependent manner. Taken together, the present study clearly demonstrates that avicularin exhibits anti-inflammatory activity through the suppression of ERK signaling pathway in LPS-stimulated RAW 264.7 macrophage cells.
Van-Tung Phan,Hong-Hee Lee,Tae-Won Chun 전력전자학회 2010 JOURNAL OF POWER ELECTRONICS Vol.10 No.6
This paper presents an effective rotor current controller for variable-speed stand-alone doubly fed induction generator (DFIG) systems feeding an unbalanced three-phase load. The proposed current controller is developed based on proportional plus two resonant regulators, which are tuned at the positive and negative slip frequencies and implemented in the rotor reference frame without decomposing the positive and negative sequence components of the measured rotor current. In addition, the behavior of the proposed controller is examined in terms of control performance and stability with respect to rotor speed variations, i.e., slip frequency variations. Simulations and experimental results are shown to validate the robustness and effectiveness of the proposed control method.
Van, Mien,Kang, Hee-Jun Professional Engineering Publishing Ltd 2015 Proceedings of the Institution of Mechanical Engin Vol. No.
<P>This paper investigates a robust fault-tolerant control scheme for uncertain robot manipulators. The proposed scheme is designed via active fault-tolerant control method by combining a fault estimation scheme with a novel robust adaptive quasi-continuous second-order sliding mode (AQC2S) controller, so as to accommodate not only system failures but also uncertainties. First, a neural network based fault estimation is designed to online approximate the unknown uncertainties and faults. The estimated uncertainty and fault information are then used to compensate in advance for the effects of uncertainties in fault-free operation and both uncertainties and faults in fault operation. To eliminate the neural network compensation error, QC2S with adaptation gain, named as adaptive QC2S (AQC2S), is proposed. By integrating the advantages of the neural network observer and the AQC2S controller, the integrated scheme has a good capability to accommodate both the uncertainties and faults with chattering-free, higher position tracking accuracy, and no requirement of prior knowledge of the fault information. The stability and convergence of the proposed fault-tolerant control system is proved theoretically. Simulation results for a PUMA560 robot demonstrate the effectiveness of the proposed algorithm.</P>
van der Put, Robert M. F.,Kim, Tae Hee,Guerreiro, Catherine,Thouron, Franç,oise,Hoogerhout, Peter,Sansonetti, Philippe J.,Westdijk, Janny,Stork, Michiel,Phalipon, Armelle,Mulard, Laurence A. American Chemical Society 2016 Bioconjugate chemistry Vol.27 No.4
<P>Conjugation chemistry is among the most important parameters governing the efficacy of glycoconjugate vaccines. High robustness is required to ensure high yields and batch to batch reproducibility. Herein, we have established a robust bioconjugation protocol based on the thiol-maleimide addition. Major variables were determined and acceptable margins were investigated for a synthetic pentadecasaccharide-tetanus toxoid conjugate, which is a promising vaccine candidate against Shigella flexneri serotype 2a infection. The optimized process is applicable to any thiol-equipped hapten and provides an efficient control of the hapten:carrier ratio. Moreover, comparison of four S. flexneri 2a glycoconjugates only differing, by their pentadecasaccharide:tetanus toxoid ratio confirmed preliminary findings indicating that hapten loading is critical for immunogenicity with an optimal ratio here in the range of 17 +/- 5. In addition, the powerful influence of alum on the immunogenicity of a Shigella synthetic carbohydrate-based conjugate vaccine candidate is demonstrated for the first time, with a strong anti-S. flexneri 2a antibody response sustained for more than one year.</P>