Discovery of Isoquinolinoquinazolinones as a Novel Class of Potent PPARγ Antagonists with Anti-adipogenic Effects

( Yifeng Jin ),( Younho Han ),( Daulat Bikram Khadka ),( Chao Zhao ),( Kwang Youl Lee ),( Won-jea Cho ) 전남대학교 약품개발연구소 2016 약품개발연구지 Vol.25 No.-

Conformational change in helix 12 can alter ligand-in duced PPARγ activity; based on this reason, isoquinolinoquinazolinones, structural homologs of berberine, were designed and synthesized as PPARγ antagonists. Computational docking and mutational study indicated that isoquinolinoquinazolinones form hydrogen bonds with the Cys285 and Arg288 residues of PPARγ. Furthermore, SPR results demonstrated strong binding affinity of isoquinolinoquinazolinones towards PPARγ. Additionally, biological assays showed that this new series of PPARγ antagonists more strongly inhibit adipocyte differentiation and PPARγ2-induced transcriptional activity than GW9662.

羌族民歌“劳动歌”的分类研究

金藝風(Jin Yifeng) 아시아민족조형학회 2010 아시아민족조형학보 Vol.8 No.1

“Labour Songs” are a kind of the earliest produced language arts, and are origins of all folk songs. In the current research achievements in music of folk songs of Qiang Nationality, there are vague and unreasonable definitions in the word senses of “Labour Songs” and in the contents of category involved. To analyze and summarize the classifications of “Labour Songs” is of benefit to unearthing, sorting out, protecting, developing and researching the folk songs of Qiang Nationality.

Berberine bioisostere Q8 compound stimulates osteoblast differentiation and function <i>in vitro</i>

Han, Younho,Jin, Yifeng,Lee, Sung Ho,Khadka, Daulat Bikram,Cho, Won-Jea,Lee, Kwang Youl ACADEMIC PRESS 2017 PHARMACOLOGICAL RESEARCH Vol.119 No.-

<P><B>Abstract</B></P> <P>The Q8 compound is a unique derivative of berberine. The present study investigated the functional role of Q8 to evaluate its potential for use in bone regeneration, especially in osteoblast differentiation. The safe concentration of Q8 increased BMP4-induced alkaline phosphatase (ALP) activity, and induced RNA expression of ALP, bone sialoprotein (BSP), and osteocalcin (OC). The activities of ALP-, BSP- and OC-luciferase reporters were also increased by Q8. During osteoblast differentiation, Q8 stabilized the Runx2 and Osterix protein abundance by blocking the ubiquitin-proteasome pathway, which in turn promoted Runx2 and Osterix induced transcriptional activity and subsequently increased the osteoblast differentiation. Meanwhile, depletion of Runx2 and Osterix markedly abolished the bone anabolic effect of Q8 on osteoblast differentiation. To evaluate the signal transduction pathway involved in the Q8-mediated regulation of Runx2 and Osterix, we examined the reporter assay using various kinase inhibitors. Treatment with a protein kinase A (PKA) inhibitor, H89 inhibited the Q8-mediated regulation of Runx2 and Osterix. Based on these findings, this study demonstrates that Q8 promotes the osteoblast differentiation by stabilization of Runx2/Osterix through the increased activation of PKA signaling. The enhancement of osteoblast function by Q8 may contribute to the prevention for osteoporosis.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Dynamic fracture catastrophe model of concrete beam under static load

Zhonggou Chen,Chuanqing Fu,Yifeng Ling,Xianyu Jin 사단법인 한국계산역학회 2020 Computers and Concrete, An International Journal Vol.25 No.6

An experimental system on three point bending notched beams was established to study the fracture process of concrete. In this system, the acoustic emission (AE) was used to build the cumulative generation order (AGO) and dynamically track the process of microcrack evolution in concrete. A grey-cusp catastrophe model was built based on AE parameters. The results show that the concrete beams have significant catastrophe characteristic. The developed grey-cusp catastrophe model, based on AGO, can well describe the catastrophe characteristic of concrete fracture process. This study also provides a theoretical and technical support for the application of AE in concrete fracture prediction.

Geometry and Mechanical Behaviour of Radially Retractable Roof Structures During the Movement Process

Jianguo Cai,Yuhang Zhou,Yifeng Zhu,Yixiang Xu,Jin Zhang 한국강구조학회 2016 International Journal of Steel Structures Vol.16 No.3

In this paper, the kinematic characteristic of the radially retractable roof structure was firstly discussed and the motion boundary of the system was also studied. The results show that the diameter of the outer boundary of the system increases firstly and then decreases when the roof is open. Moreover, the numerical study of the structural behavior of the retractable roof with radial foldable bars and circumferential foldable bars was carried out, respectively. It can be found the latter one has a better structural behavior. Then the mechanical behaivor of the system during the motion was also investigated. Finally, a loop linkage based on a special scissor-like element was proposed to support the retractable roof.

Tanshinone IIA suppresses FcεRI-mediated mast cell signaling and anaphylaxis by activation of the Sirt1/LKB1/AMPK pathway

Li, Xian,Park, Soon Jin,Jin, Fansi,Deng, Yifeng,Yang, Ju Hye,Chang, Jae-Hoon,Kim, Dong-Young,Kim, Jung-Ae,Lee, Youn Ju,Murakami, Makoto,Son, Kun Ho,Chang, Hyeun Wook Pergamon Press 2018 Biochemical pharmacology Vol.152 No.-

<P><B>Abstract</B></P> <P>AMP-activated protein kinase (AMPK) and its upstream mediators liver kinase B1 (LKB1) and sirtuin 1 (Sirt1) are generally known as key regulators of metabolism. We have recently reported that the AMPK pathway negatively regulates mast cell activation and anaphylaxis. Tanshinone IIA (Tan IIA), an active component of <I>Salvia miltiorrhiza</I> extract that is currently used for the treatment of cardiovascular and cerebrovascular diseases, shows anti-diabetic activity and improves insulin resistance in <I>db/db</I> mice through activation of AMPK. The aim of this study was to evaluate the anti-allergic activity of Tan IIA <I>in vivo</I> and to investigate the underlying mechanism <I>in vitro</I> in the context of AMPK signaling. The anti-allergic effect of Tan IIA was evaluated using mouse bone marrow-derived mast cells (BMMCs) from <I>AMPKα2</I> <SUP>−/−</SUP> or <I>Sirt1</I> <SUP>−/−</SUP> mice, or BMMCs transfected with siRNAs specific for AMPKα2, LKB1, or Sirt1. <I>AMPKα2</I> <SUP>−/−</SUP> and <I>Sirt1</I> <SUP>−/−</SUP> mice were used to confirm the anti-allergic effect of Tan IIA in anaphylaxis <I>in vivo</I>. Tan IIA dose-dependently inhibited FcεRI-mediated degranulation and production of eicosanoids and cytokines in BMMCs. These inhibitory effects were diminished by siRNA-mediated knockdown or genetic deletion of AMPKα2 or Sirt1. Moreover, Tan IIA inhibited a mast cell-mediated local passive anaphylactic reaction in wild-type mice, but not in <I>AMPKα2</I> <SUP>−/−</SUP> or <I>Sirt1</I> <SUP>−/−</SUP> mice. In conclusion, Tan IIA suppresses FcεRI-mediated mast cell activation and anaphylaxis through activation of the inhibitory Sirt1-LKB1-AMPK pathway. Thus, Tan IIA may be useful as a new therapeutic agent for mast cell-mediated allergic diseases.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Morphology-selective synthesis of mesoporous SBA-15 particles over micrometer, submicrometer and nanometer scales

Lee, Hyung Ik,Kim, Jin Hoe,Stucky, Galen D.,Shi, Yifeng,Pak, Chanho,Kim, Ji Man Royal Society of Chemistry 2010 Journal of materials chemistry Vol.20 No.39

<P>Mesoporous silica structures are of increasing importance as supports for enzymes and molecular organometallic catalysts. For high-surface-area, porous 3-d catalytic supports, the relationship between the exterior particle morphology and the 3-d mesopore structure is of particular significance. This paper describes the designed synthesis of selected morphologies of mesoporous SBA-15, which can be chosen from micrometer sized spheres to hundreds or tens of nanometers sized monodispersed particles such as platelets, hexagonal columns, rice-shapes, rods with tunable aspect ratios, and donuts. These are directly synthesized <I>via</I> control of the fundamental synthesis factors, including initial temperature, stirring rate and micelle packing parameter, rather than by the use of additives that have been generally utilized for specific morphologies in previous reports. The relationship between these basic synthesis parameters and morphologies provides insights into the formation of mesostructured materials.The SBA materials with various morphologies are expected to be useful in applications that require anisotropic or path-length-controlled diffusion.</P> <P>Graphic Abstract</P><P>Control of fundamental synthesis factors such as initial temperature, stirring rate, and micelle-packing parameter enables morphological control of mesoporous SBA-15 silica over wide size range and improves its potential applications. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c0jm00820f'> </P>

Design, synthesis, and biological evaluation of 1,3-diarylisoquinolines as novel topoisomerase I catalytic inhibitors

Khadka, Daulat Bikram,Park, Seojeong,Jin, Yifeng,Han, Jinhe,Kwon, Youngjoo,Cho, Won-Jea Elsevier 2018 European journal of medicinal chemistry Vol.143 No.-

<P><B>Abstract</B></P> <P>With a goal of identifying potent topoisomerase (topo) inhibitor, the C4-aromatic ring of the anticancer agent, 3,4-diarylisoquinolone, was strategically shifted to design 1,3-diarylisoquinoline. Twenty-two target compounds were synthesized in three simple and efficient steps. The 1,3-diarylisoquinolines exhibited potent anti-proliferative effects on cancer cells but few compounds spared non-cancerous cells. Inhibition of topo I/IIα-mediated DNA relaxation by several derivatives was greater than that by camptothecin (CPT)/etoposide even at low concentration (20 μM). In addition, these compounds had little or no effect on polymerization of tubulin. A series of biological evaluations performed with the most potent derivative <B>4cc</B> revealed that the compound is a non-intercalative topo I catalytic inhibitor interacting with free topo I. Collectively, the potent cytotoxic effect on cancer cells including the drug resistance ones, absence of lethal effect on normal cells, and different mechanism of action than topo I poisons suggest that the 1,3-diarylisoquinolines might be a promising class of anticancer agents worthy of further pursuit.</P> <P><B>Highlights</B></P> <P> <UL> <LI> 1,3-Diarylisoquinoline was designed based on structure of 3,4-diarylisoquinoline. </LI> <LI> 1,3-Diarylisoquinolines were cytotoxic against cancer cells. </LI> <LI> Several derivatives inhibited topo I/IIα activity even at low concentration. </LI> <LI> 1,3-Diarylisoquinolines had weak or no antitubulin activity. </LI> <LI> 1,3-Diarylisoquinoline <B>4 cc</B> is a non-intercalative topo I catalytic inhibitor. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Efficient delivery of nuclease proteins for genome editing in human stem cells and primary cells

Liu, Jia,Gaj, Thomas,Yang, Yifeng,Wang, Nan,Shui, Sailan,Kim, Sojung,Kanchiswamy, Chidananda Nagamangala,Kim, Jin-Soo,Barbas III, Carlos F Nature Publishing Group 2015 NATURE PROTOCOLS -ELECTRONIC EDITION- Vol.10 No.11

Targeted nucleases, including zinc-finger nucleases (ZFNs), transcription activator-like (TAL) effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9), have provided researchers with the ability to manipulate nearly any genomic sequence in human cells and model organisms. However, realizing the full potential of these genome-modifying technologies requires their safe and efficient delivery into relevant cell types. Unlike methods that rely on expression from nucleic acids, the direct delivery of nuclease proteins to cells provides rapid action and fast turnover, leading to fewer off-target effects while maintaining high rates of targeted modification. These features make nuclease protein delivery particularly well suited for precision genome engineering. Here we describe procedures for implementing protein-based genome editing in human embryonic stem cells and primary cells. Protocols for the expression, purification and delivery of ZFN proteins, which are intrinsically cell-permeable; TALEN proteins, which can be internalized via conjugation with cell-penetrating peptide moieties; and Cas9 ribonucleoprotein, whose nucleofection into cells facilitates rapid induction of multiplexed modifications, are described, along with procedures for evaluating nuclease protein activity. Once they are constructed, nuclease proteins can be expressed and purified within 6 d, and they can be used to induce genomic modifications in human cells within 2 d.

Design and synthesis of novel androgen receptor antagonists via molecular modeling

( Chao Zhao ),( You Hee Choi ),( Daulat Bikram Khadka ),( Yifeng Jin ),( Kwang-youl Lee ),( Won-jea Cho ) 전남대학교 약품개발연구소 2016 약품개발연구지 Vol.25 No.-

Several androgen receptor (AR) antagonists are clinically prescribed to treat prostate cancer. Unfortunately, many patients become resistant to the existing AR antagonists. To overcome this, a novel AR antagonist candidate called DIMN was discovered by our research group in 2013. In order to develop compounds with improved potency, we designed novel DIMN derivatives based on a docking study and substituted carbons with heteroatom moieties. Encouraging in vitro results for compounds 1b, 1c, 1e, 3c, and 4c proved that the new design was successful. Among the newly synthesized compounds. 1e exhib-ited the strongest inhibitory effect on LNCaP cell growth (IC-₅₀=0.35 μm) and also acted as a competitive AR antagonist with selectivity over the estrogen receptor (ER) and the glucocorticoid receptor (GR). A docking study of compound 1e fully supported these biological results. Compound 1e is considered to be a novel, potent and AR-specific antagonist for treating prostate cancer. Thus, our study successfully applied molecular modeling and bioisosteric replacement for hit optimization. The methods here provide a guide for future development of drug candidates through structure-based drug discovery and chemical Modifications. ⓒ 2015 Elsevier Ltd. All rights reserved.