A Combined Pharmacophore-Based Virtual Screening, Docking Study and Molecular Dynamics (MD) Simulation Approach to Identify Inhibitors with Novel Scaffolds for Myeloid cell leukemia (Mcl-1)

Guang-kai Bao,Lu Zhou,Tai-jin Wang,Lu-fen He,Tao Liu 대한화학회 2014 Bulletin of the Korean Chemical Society Vol.35 No.7

Chemical feature based quantitative pharmacophore models were generated using the HypoGen module implemented in DS2.5. The best hypothesis, Hypo1, which was characterized by the highest correlation coefficient (0.96), the highest cost difference (61.60) and the lowest RMSD (0.74), consisted of one hydrogen bond acceptor, one hydrogen bond donor, one hydrophobic and one ring aromatic. The reliability of Hypo1 was validated on the basis of cost analysis, test set, Fischer’s randomization method and GH test method. The validated Hypo1 was used as a 3D search query to identify novel inhibitors. The screened molecules were further refined by employing ADMET, docking studies and visual inspection. Three compounds with novel scaffolds were selected as the most promising candidates for the designing of Mcl-1 antagonists. Finally, a 10 ns molecular dynamics simulation was carried out on the complex of receptor and the retrieved ligand to demonstrate that the binding mode was stable during the MD simulation.

한국어 목적 범주에 대한 소고

노광위 ( Lu Guang-wei ) 인하대학교 한국학연구소 2018 한국학연구 Vol.0 No.51

목적 범주는 지향성, ‘목적-행위’ 또는 ‘행위-목적’의 의미관계, 비현실 등 세 가지 근본적인 의미특징을 가진다. 그리고 이 세 가지 의미특징을 의미기초로 목적 범주를 수립할 수 있다. 한편 이 세 가지 의미특징의 유무에 따라 한 문장이 목적 범주를 표현하는지 여부를 판단할 수 있다. 본고에서 판단한 결과 한국어 목적관계 연결어미나 연결구성에 의해 구성된 목적관계 접속문과 어떤 목적을 이루려고 한다는 뜻을 나타내는 동사 ‘위하-’에 의해 구성된 목적관계 단문이 목적 범주를 표현할 수 있는 것으로 나타났다. 그리하여 연결어미 혹은 연결구성 ‘-(으)러, -(으)려고, -고자, -기 위해/위해서, -느라고, -게, -도록’과 동사 ‘위하-’ 등은 한국어 목적 범주의 목적 표지로 볼 수 있다. The purpose category possesses three fundamental semantic features: intentionality, the semantic relationship of “Purpose-Action” or “Action-Purpose”, and irrealis. Moreover, these three semantic features can be used as the semantic foundation to establish the purpose category. In addition, whether a sentence possesses these three semantic features or not can be regarded as a criteria to tell this sentence reflects the purpose category or not. The findings of this research showed that the purpose conjunctive sentence which formed by linking Korean connective ending of purposive relationship or connective expression of purposive relationship has the function of reflecting the purpose category. Besides, the purpose conjunctive simple sentence, which is connected by verb “weile(for)” that expresses the meaning of a purpose, is also able to reflect the purpose category. Therefore, we can regard the connective ending or the connective expression as the purposive marker of the Korean purpose category, such as “-(eu)reo, -(eu)ryeogo,-goja,-gi uyhaj/uyhajseo,-neurago,-ge,-dorok” and the verb “uyha-”.

A Combined Pharmacophore-Based Virtual Screening, Docking Study and Molecular Dynamics (MD) Simulation Approach to Identify Inhibitors with Novel Scaffolds for Myeloid cell leukemia (Mcl-1)

Bao, Guang-Kai,Zhou, Lu,Wang, Tai-Jin,He, Lu-Fen,Liu, Tao Korean Chemical Society 2014 Bulletin of the Korean Chemical Society Vol.35 No.7

Chemical feature based quantitative pharmacophore models were generated using the HypoGen module implemented in DS2.5. The best hypothesis, Hypo1, which was characterized by the highest correlation coefficient (0.96), the highest cost difference (61.60) and the lowest RMSD (0.74), consisted of one hydrogen bond acceptor, one hydrogen bond donor, one hydrophobic and one ring aromatic. The reliability of Hypo1 was validated on the basis of cost analysis, test set, Fischer's randomization method and GH test method. The validated Hypo1 was used as a 3D search query to identify novel inhibitors. The screened molecules were further refined by employing ADMET, docking studies and visual inspection. Three compounds with novel scaffolds were selected as the most promising candidates for the designing of Mcl-1 antagonists. Finally, a 10 ns molecular dynamics simulation was carried out on the complex of receptor and the retrieved ligand to demonstrate that the binding mode was stable during the MD simulation.

p13 from group II baculoviruses is a killing-associated gene

( Nan Lu ),( En Qi Du ),( Yang Kun Liu ),( Hong Qiao ),( Lun Guang Yao ),( Zi Shu Pan ),( Song Ya Lu ),( Yi Peng Qi ) 생화학분자생물학회(구 한국생화학분자생물학회) 2012 BMB Reports Vol.45 No.12

p13 gene was first described in Leucania separata multinuclear polyhedrosis virus (Ls-p13) several years ago, but the function of P13 protein has not been experimentally investigated to date. In this article, we indicated that the expression of p13 from Heliothis armigera single nucleocapsid nucleopolyhedrovirus (Ha-p13) was regulated by both early and late promoter. Luciferase assay demonstrated that the activity of Ha-p13 promoter with hr4 enhancer was more than 100 times in heterologous Sf9 cells than that in nature host Hz-AM1 cells. Both Ls-P13 and Ha-P13 are transmembrane proteins. Confocal microscopic analysis showed that both mainly located in the cytoplasm membrane at 48 h. Results of RNA interference indicated that Ha-p13 was a killing-associated gene for host insects H. armigera. The AcMNPV acquired the mentioned killing activity and markedly accelerate the killing rate when expressing Ls-p13. In conclusion, p13 is a killing associated gene in both homologous and heterologous nucleopolyhedrovirus. [BMB Reports 2012; 45(12): 730-735]

Intravenous Tenecteplase for Acute Ischemic Stroke Within 4.5–24 Hours of Onset (ROSE-TNK): A Phase 2, Randomized, Multicenter Study

Wang Lu,Dai Ying-Jie,Cui Yu,Zhang Hong,Jiang Chang-Hao,Duan Ying-Jie,Zhao Yong,Feng Ye-Fang,Geng Shi-Mei,Zhang Zai-Hui,Lu Jiang,Zhang Ping,Zhao Li-Wei,Zhao Hang,Ma Yu-Tong,Song Cheng-Guang,Zhang Yi,Ch 대한뇌졸중학회 2023 Journal of stroke Vol.25 No.3

Background and Purpose Intravenous tenecteplase (TNK) efficacy has not been well demonstrated in acute ischemic stroke (AIS) beyond 4.5 hours after onset. This study aimed to determine the effect of intravenous TNK for AIS within 4.5 to 24 hours of onset. Methods In this pilot trial, eligible AIS patients with diffusion-weighted imaging (DWI)-fluid attenuated inversion recovery (FLAIR) mismatch were randomly allocated to intravenous TNK (0.25 mg/kg) or standard care within 4.5–24 hours of onset. The primary endpoint was excellent functional outcome at 90 days (modified Rankin Scale [mRS] score of 0–1). The primary safety endpoint was symptomatic intracranial hemorrhage (sICH). Results Of the randomly assigned 80 patients, the primary endpoint occurred in 52.5% (21/40) of TNK group and 50.0% (20/40) of control group, with no significant difference (unadjusted odds ratio, 1.11; 95% confidence interval 0.46–2.66; <i>P</i>=0.82). More early neurological improvement occurred in TNK group than in control group (11 vs. 3, <i>P</i>=0.03), but no significant differences were found in other secondary endpoints, such as mRS 0–2 at 90 days, shift analysis of mRS at 90 days, and change in National Institutes of Health Stroke Scale score at 24 hours and 7 days. There were no cases of sICH in this trial; however, asymptomatic intracranial hemorrhage occurred in 3 of the 40 patients (7.5%) in the TNK group. Conclusion This phase 2, randomized, multicenter study suggests that intravenous TNK within 4.5–24 hours of onset may be safe and feasible in AIS patients with a DWI-FLAIR mismatch.

목적 범주의 의미기초와 중국어 목적 범주의 문법 표현 형식에 대하여

노광위 ( Lu Guang-wei ) 한국중국언어학회 2018 중국언어연구 Vol.0 No.79

目的範疇具有“意向性”、“‘目的-行爲’或‘行爲-目的’的語義關係”、“非現實”等三個根本性的語義特徵。幷且,以這三項語義特徵爲語義基礎可以建立目的範疇。 另外,以是否具有這三項語義特徵爲判斷標準,可以判斷一個句子或格式是否體現目的範疇。本硏究的判斷結果顯示:漢語目的複句、目的緊縮複句、帶有關聯詞語的目的單句、目的連動句以及“V + PO”結構能勾體現目的範疇。 因此,我們可以把關聯詞“爲、爲了、爲著、以、以便、以期、以求、好、借以、用以、來、以免、以防、省得、免得”以及關聯短語“爲(了)……而……、爲(了)……起見、爲的是、是爲了”等看做漢語目的範疇的目的標記。 The purpose category possesses three fundamental semantic features: intentionality, the semantic relationship of “Purpose-Action” or “Action- Purpose”, and irrealis. Moreover, these three semantic features can be used as the semantic foundation to establish the purpose category. In addition, whether a sentence or a construction possesses these three semantic features or not can be regarded as a criteria to tell this sentence or construction reflects the purpose category or not. The findings of this research showed that the purpose conjunctive sentence and the purpose contraction conjunctive sentence, the purpose conjunctive simple sentence which is connected by connectives, the purpose conjunctive serial verb sentence and ‘V + PO’ construction have the function of reflecting the purpose category. Among these members of purpose category, the purpose conjunctive sentence is the most prototypical member, and rest of the members are marginal members. Therefore, we can regard the connective word such as “wei, weile, weizhe, yi, yibian, yiqi, yiqiu, hao, jieyi, yongyi, lai, yimian, yifang, shengde, miande” and the connective phrase such as “wei(le)……er……, wei(le)……qijian, weideshi, shiweile” as the purposive marker of the Chinese purpose category.

Structures, biomimetic synthesis, and anti-SARS-CoV-2 activity of two pairs of enantiomeric phenylpropanoid-conjugated protoberberine alkaloids from the rhizomes of Corydalis decumbens

Jing-Guang Lu,Yingwei Wang,Ming-Rong Yang,Cai-Yun Wang,Jieru Meng,Jiazheng Liu,Zifeng Yang,Kongsong Wu,Li-Ping Bai,Guo-Yuan Zhu,Zhi-Hong Jiang 대한약학회 2022 Archives of Pharmacal Research Vol.45 No.9

(±)-Decumicorine A ( 1 ) and (±)- epi -decumicorine A ( 2 ), two pairs of enantiomeric isoquinoline alkaloids featuring a novel phenylpropanoid-conjugated protoberberine skeleton, were isolated and purifi ed from the rhizomes of Corydalis decumbens . The separation of (±)- 1 and (±)- 2 was achieved by chiral HPLC to produce four optically pure enantiomers. The structures and absolute confi gurations of compounds (−)- 1 , (+)- 1 , (−)- 2 , and (+)- 2 were elucidated by spectroscopic analysis, ECD calculations, and X-ray crystallographic analyses. The two racemates were generated from a Diels-Alder [4 + 2] cycloaddition between jatrorrhizine and ferulic acid in the proposed biosynthetic pathways, which were fully verifi ed by a biomimetic synthesis. Moreover, compound (+)- 1 exhibited an antiviral entry eff ect on SARS-CoV-2 pseudovirus by blocking spike binding to the ACE2 receptor on HEK-293T-ACE2 h host cells.

Ginsenoside Rh2 reduces depression in offspring of mice with maternal toxoplasma infection during pregnancy by inhibiting microglial activation via the HMGB1/TLR4/NF-kB signaling pathway

Xiang Xu,Yu-Nan Lu,Jia-Hui Cheng,Hui-Wen Lan,Jing-Mei Lu,Guang-Nan Jin,Guang-Hua Xu,Cheng-Hua Jin,Juan Ma,Hu-Nan Piao,Xuejun Jin,Lian-Xun Piao 고려인삼학회 2022 Journal of Ginseng Research Vol.46 No.1

Background: Maternal Toxoplasma gondii (T. gondii) infection during pregnancy has been associated with various mental illnesses in the offspring. Ginsenoside Rh2 (GRh2) is a major bioactive compound obtained from ginseng that has an anti-T. gondii effect and attenuates microglial activation through toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-kB) signaling pathway. GRh2 also alleviated tumor-associated or lipopolysaccharide-induced depression. However, the effects and potential mechanisms of GRh2 on depression-like behavior in mouse offspring caused by maternal T. gondii infection during pregnancy have not been investigated. Methods: We examined GRh2 effects on the depression-like behavior in mouse offspring, caused by maternal T. gondii infection during pregnancy, by measuring depression-like behaviors and assaying parameters at the neuronal and molecular level. Results: We showed that GRh2 significantly improved behavioral measures: sucrose consumption, forced swim time and tail suspended immobility time of their offspring. These corresponded with increased tissue concentrations of 5-hydroxytryptamine and dopamine, and attenuated indoleamine 2,3-dioxygenase or enhanced tyrosine hydroxylase expression in the prefrontal cortex. GRh2 ameliorated neuronal damage in the prefrontal cortex. Molecular docking results revealed that GRh2 binds strongly to both TLR4 and high mobility group box 1 (HMGB1). Conclusion: This study demonstrated that GRh2 ameliorated the depression-like behavior in mouse offspring of maternal T. gondii infection during pregnancy by attenuating the excessive activation of microglia and neuroinflammation through the HMGB1/TLR4/NF-kB signaling pathway. It suggests that GRh2 could be considered a potential therapy in preventing and treating psychiatric disorders in the offspring mice of mothers with prenatal exposure to T. gondii infection.

Simultaneous treatment with sorafenib and glucose restriction inhibits hepatocellular carcinoma in vitro and in vivo by impairing SIAH1-mediated mitophagy

Zhou Jing,Feng Ji,Wu Yong,Dai Hui-Qi,Zhu Guang-Zhi,Chen Pan-Hong,Wang Li-Ming,Lu Guang,Liao Xi-Wen,Lu Pei-Zhi,Su Wen-Jing,Hooi Shing Chuan,Ye Xin-Pin,Shen Han-Ming,Peng Tao,Lu Guo-Dong 생화학분자생물학회 2022 Experimental and molecular medicine Vol.54 No.-

Transarterial chemoembolization (TACE) is the first-line treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). It is of high clinical significance to explore the synergistic effect of TACE with antiangiogenic inhibitors and the molecular mechanisms involved. This study determined that glucose, but not other analyzed nutrients, offered significant protection against cell death induced by sorafenib, as indicated by glucose deprivation sensitizing cells to sorafenib-induced cell death. Next, this synergistic effect was found to be specific to sorafenib, not to lenvatinib or the chemotherapeutic drugs cisplatin and doxorubicin. Mechanistically, sorafenib-induced mitophagy, as indicated by PINK1 accumulation, increased the phospho-poly-ubiquitination modification, accelerated mitochondrial membrane protein and mitochondrial DNA degradation, and increased the amount of mitochondrion-localized mKeima-Red engulfed by lysosomes. Among several E3 ubiquitin ligases tested, SIAH1 was found to be essential for inducing mitophagy; that is, SIAH1 silencing markedly repressed mitophagy and sensitized cells to sorafenib-induced death. Notably, the combined treatment of glucose restriction and sorafenib abolished ATP generation and mitophagy, which led to a high cell death rate. Oligomycin and antimycin, inhibitors of electron transport chain complexes, mimicked the synergistic effect of sorafenib with glucose restriction to promote cell death mediated via mitophagy inhibition. Finally, inhibition of the glucose transporter by canagliflozin (a clinically available drug used for type-II diabetes) effectively synergized with sorafenib to induce HCC cell death in vitro and to inhibit xenograft tumor growth in vivo. This study demonstrates that simultaneous treatment with sorafenib and glucose restriction is an effective approach to treat HCC, suggesting a promising combination strategy such as transarterial sorafenib-embolization (TASE) for the treatment of unresectable HCC.

Multiple down-regulated cytochrome P450 monooxygenase genes contributed to synergistic interaction between chlorpyrifos and imidacloprid against Nilaparvata lugens

Lu Xue,Guanghua Luo,Yang Sun,Shuijin Huang,De-Jin Xu,Guang-Chun Xu,Zhao-Jun Han,Zhong-Yan Gu,Ya-Nan Zhang 한국응용곤충학회 2020 Journal of Asia-Pacific Entomology Vol.23 No.1

Insecticide mixtures are an effective strategy in pest resistance management. The synergistic chlorpyrifos and imidacloprid mixture could significantly increase toxicity against rice pest, Nilaparvata lugens, despite their high levels of resistance. However, synergism mechanisms to explain this phenomenon remain unknown. Chlorpyrifos and imidacloprid at a 1:0.5 ratio showed significant synergism on N. lugens with a combination index value of 0.18 after topical exposure. We constructed a genetic database of the genes expressed in individual and synergistic chlorpyrifos and imidacloprid treatments of N. lugens using Illumina Hiseq™ X Ten, and 17 co-downregulated genes putatively involved in synergism were detected by comparative transcriptome analyses. Expression patterns of the 17 candidate synergistic genes matched with transcriptome sequencing data by quantitative real-time PCR analyses. Feeding of dsRNAs further reduced the expression levels of 10 of these candidate synergistic genes (from 1.68 to 4.13-fold). Nymphs fed with only dsRNAs of CYP4DE1, CYP6AY1v2, CYP353D1, and CYP439A1 experienced more high mortality rates (81.45–90.34%) to improve synergism between chlorpyrifos and imidacloprid. Multiple reductive expressed P450 genes were potentially associated with synergism of a mixture of chlorpyrifos and imidacloprid, as confirmed by comparative transcriptome analyses and RNAi assays. Our findings suggested that synergistic interactions between chlorpyrifos and imidacloprid might be controlled by P450s.