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学者姓名：赵丽娇
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Abstract ：
Chloroethylnitrosoureas (CENUs) are important chemotherapies applied in the treatment of cancer. They exert anticancer activity by inducing DNA interstrand cross-links (ICLs) via the formation of two O-6-alkylguanine intermediates, O-6-chloroethylguanine (O-6-ClEtG) and N1,O-6-ethanoguanine (N1,O-6-EtG). However, O-6-alkylguanine-DNA alkyltransferase (AGT), a DNA-repair enzyme, can restore the O-6-alkylguanine damages and thereby obstruct the formation of ICLs (dG-dC cross-link). In this study, the inhibitory mechanism of ICL formation was investigated to elucidate the drug resistance of CENUs mediated by AGT in detail. Based on the structures of the substrate-enzyme complexes obtained from docking and MD simulations, two ONIOM (QM/MM) models with different sizes of the QM region were constructed. The model with a larger QM region, which included the substrate (O-6-ClEtG or N1,O-6-EtG), a water molecule, and five residues (Tyr114, Cys145, His146, Lys165, and Glu172) in the active pocket of AGT, accurately described the repairing reaction and generated the results coinciding with the experimental outcomes. The repair process consists of two sequential steps: hydrogen transfer to form a thiolate anion on Cys145 and alkyl transfer from the O-6 site of guanine (the rate-limiting step). The repair of N1,O-6-EtG was more favorable than that of O-6-ClEtG from both kinetics and thermodynamics aspects. Moreover, the comparison of the repairing process with the formation of dG-dC cross-link and the inhibition of AGT by O-6-benzylguanine (O-6-BG) showed that the presence of AGT could effectively interrupt the formation of ICLs leading to drug resistance, and the inhibition of AGT by O-6-BG that was energetically more favorable than the repair of O-6-ClEtG could not prevent the repair of N1,O-6-EtG. Therefore, it is necessary to completely eliminate AGT activity before CENUs medication to enhance the chemotherapeutic effectiveness. This work provides reasonable explanations for the supposed mechanism of AGT-mediated drug resistance of CENUs and will assist in the development of novel CENU chemotherapies and their medication strategies.
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| GB/T 7714 | Wang, Jiaojiao , Ren, Ting , Sun, Guohui et al. Mechanism of AGT-Mediated Repair of dG-dC Cross-Links in the Drug Resistance to Chloroethylnitrosoureas: Molecular Docking, MD Simulation, and ONIOM (QM/MM) Investigation [J]. | JOURNAL OF CHEMICAL INFORMATION AND MODELING , 2024 , 64 (8) : 3411-3429 . |
| MLA | Wang, Jiaojiao et al. "Mechanism of AGT-Mediated Repair of dG-dC Cross-Links in the Drug Resistance to Chloroethylnitrosoureas: Molecular Docking, MD Simulation, and ONIOM (QM/MM) Investigation" . | JOURNAL OF CHEMICAL INFORMATION AND MODELING 64 . 8 (2024) : 3411-3429 . |
| APA | Wang, Jiaojiao , Ren, Ting , Sun, Guohui , Zhang, Na , Zhao, Lijiao , Zhong, Rugang . Mechanism of AGT-Mediated Repair of dG-dC Cross-Links in the Drug Resistance to Chloroethylnitrosoureas: Molecular Docking, MD Simulation, and ONIOM (QM/MM) Investigation . | JOURNAL OF CHEMICAL INFORMATION AND MODELING , 2024 , 64 (8) , 3411-3429 . |
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Abstract ：
目的 构建CK2天然产物类抑制剂的定量构效关系(quantitative structure-activity relationship,QSAR)模型,揭示影响该类抑制剂活性的结构因素,为新型CK2抑制剂的开发提供理论基础和实验依据.方法 基于文献报道的115个多骨架CK2天然产物类抑制剂,采用遗传算法(genetic algorithm,GA)联合多元线性回归(multiple linear regression,MLR)方法,建立了基于优选的Dragon描述符的QSAR模型,以留一法交叉验证系数Q2LOO以及相关系数R2作为模型内部验证的评价指标;通过Q2ext和R2ext评估模型的外部预测能力.结果 最优2D-QSAR模型由8个描述符组成,基于训练集内部验证的统计学参数为Q2Loo=0.7914、R2=0.8220;基于测试集外部验证的统计学参数为Q2ext=0.7921、R2ext=0.7998,表明该模型具有较高的可靠性和预测能力.结论 影响CK2天然产物类抑制剂活性的分子描述符包括IVDE、CATS2D_08_DA、nArX、IC1、Chi_D/Dt、SdssC、F08[C-O]以及C-006.本研究可为新型CK2抗癌抑制剂的发现提供实验指导.
Keyword ：
定量结构-活性关系 定量结构-活性关系 天然产物类抑制剂 天然产物类抑制剂 遗传算法 遗传算法 多元线性回归 多元线性回归 蛋白激酶CK2 蛋白激酶CK2
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| GB/T 7714 | 张雪文 , 张娜 , 李春华 et al. 蛋白激酶CK2天然产物类抑制剂的定量构效关系研究 [J]. | 北京生物医学工程 , 2023 , 42 (1) : 81-87 . |
| MLA | 张雪文 et al. "蛋白激酶CK2天然产物类抑制剂的定量构效关系研究" . | 北京生物医学工程 42 . 1 (2023) : 81-87 . |
| APA | 张雪文 , 张娜 , 李春华 , 孙国辉 , 赵丽娇 , 钟儒刚 . 蛋白激酶CK2天然产物类抑制剂的定量构效关系研究 . | 北京生物医学工程 , 2023 , 42 (1) , 81-87 . |
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Abstract ：
现代仪器分析是我校化学生物学、食品质量与安全和生物技术等专业的基础核心课，同时被列为化学生物学专业的 “课程思政”示范课，在“三全育人”的大格局下，现代仪器分析课程应发挥头雁效应，率先开展“课程思政”教 学改革。本文就作者自身教学实践，浅谈现代仪器分析的“课程思政”教学模式，旨在将知识传授、能力传授和价 值引领寓为一体，坚持立德树人，进一步将教学引向教育。
Keyword ：
教学模式 教学模式 现代仪器分析 现代仪器分析 课程思政 课程思政
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| GB/T 7714 | 孙国辉 , 刘昕 , 赵丽娇 et al. 现代仪器分析“课程思政”教学模式的初步探索 [J]. | 新教育时代电子杂志（教师版） , 2023 , (15) : 73-75 . |
| MLA | 孙国辉 et al. "现代仪器分析“课程思政”教学模式的初步探索" . | 新教育时代电子杂志（教师版） 15 (2023) : 73-75 . |
| APA | 孙国辉 , 刘昕 , 赵丽娇 , 钟儒刚 . 现代仪器分析“课程思政”教学模式的初步探索 . | 新教育时代电子杂志（教师版） , 2023 , (15) , 73-75 . |
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Abstract ：
Carmustine (BCNU), a vital type of chloroethylnitrosourea (CENU), inhibits tumor cells growth by inducing DNA damage at O(6 )position of guanine and eventually forming dG-dC interstrand cross-links (ICLs). However, the clinical application of BCNU is hindered to some extent by the absence of tumor selectivity, poor stability and O-6- alkylguanine-DNA alkyltransferase (AGT) mediated drug resistance. In recent years, tumor microenvironment has been widely utilized for advanced drug delivery. In the light of the features of tumor microenvironment, we constructed a multifunctional hypoxia/esterase-degradable nanomicelle with AGT inhibitory activity named HACB NPs for tumor-targeting BCNU delivery and tumor sensitization. HACB NPs was self-assembled from hyaluronic acid azobenzene AGT inhibitor conjugates, in which O6-BG analog acted as an AGT inhibitor, azobenzene acted as a hypoxia-responsive linker and carboxylate ester bond acted as both an esterase-sensitive switch and a connector with hyaluronic acid (HA). The obtained HACB NPs possessed good stability, favorable biosafety and hypoxia/ esterase-responsive drug-releasing ability. BCNU-loaded HACB/BCNU NPs exhibited superior cytotoxicity and apoptosis-inducing ability toward the human uterine cervix carcinoma HeLa cells compared with traditional combined medication of BCNU plus O-6-BG. In vivo studies further demonstrated that after a selective accumulation in the tumor site, the micelles could respond to hypoxic tumor tissue for rapid drug release to an effective therapeutic dosage. Thus, this multifunctional stimulus-responsive nanocarrier could be a new promising strategy to enhance the anticancer efficacy and reduce the side effects of BCNU and other CENUs.
Keyword ：
Carmustine Carmustine Stimulus-responsive nanocarrier Stimulus-responsive nanocarrier O-6-alkylguanine-DNA alkyltransferase O-6-alkylguanine-DNA alkyltransferase Drug delivery Drug delivery
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| GB/T 7714 | Li, Duo , Ren, Ting , Ge, Yunxuan et al. A multi-functional hypoxia/esterase dual stimulus responsive and hyaluronic acid-based nanomicelle for targeting delivery of chloroethylnitrosouea [J]. | JOURNAL OF NANOBIOTECHNOLOGY , 2023 , 21 (1) . |
| MLA | Li, Duo et al. "A multi-functional hypoxia/esterase dual stimulus responsive and hyaluronic acid-based nanomicelle for targeting delivery of chloroethylnitrosouea" . | JOURNAL OF NANOBIOTECHNOLOGY 21 . 1 (2023) . |
| APA | Li, Duo , Ren, Ting , Ge, Yunxuan , Wang, Xiaoli , Sun, Guohui , Zhang, Na et al. A multi-functional hypoxia/esterase dual stimulus responsive and hyaluronic acid-based nanomicelle for targeting delivery of chloroethylnitrosouea . | JOURNAL OF NANOBIOTECHNOLOGY , 2023 , 21 (1) . |
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Abstract ：
Carmustine (BCNU) is a typical chemotherapy used for treatment of cerebroma and other solid tumors, which exerts antitumor effect by inducing DNA damage at O6 position of guanine. However, the clinical application of BCNU was extremely limited due to the drug resistance mainly mediated by O6-alkylguanine-DNA alkyltransferase (AGT) and absence of tumor-targeting ability. To overcome these limitations, we developed a hypoxia-responsive nanomicelle with AGT inhibitory activity, which was successfully loaded with BCNU. In this nano-system, hyaluronic acid (HA) acts as an active tumor-targeting ligand to bind the overexpressing CD44 receptors on the surface of tumor cells. An azo bond selectively breaks in hypoxic tumor microenvironment to release O6-benzylguanine (BG) as AGT inhibitor and BCNU as DNA alkylating agent. The obtained HA-AZO-BG NPs with shell core structure had an average particle size of 176.98 & PLUSMN; 11.19 nm and exhibited good stability. Meanwhile, HA-AZO-BG NPs possessed a hypoxia-responsive drug release profile. After immobilizing BCNU into HA-AZO-BG NPs, the obtained HA-AZO-BG/BCNU NPs exhibited obvious hypoxia-selectivity and superior cytotoxicity in T98G, A549, MCF-7 and SMMC-7721 cells with IC50 at 189.0, 183.2, 90.1 and 100.1 & mu;m, respectively, under hypoxic condition. Near-infrared imaging in HeLa tumor xenograft models showed that HAAZO-BG/DiR NPs could effectively accumulate in tumor site at 4 h of post-injection, suggesting its good tumortargetability. In addition, in vivo anti-tumor efficacy and toxicity evaluation indicated that HA-AZO-BG/BCNU NPs was more effective and less harmful compared to the other groups. After treatment, the tumor weight of HA-AZO-BG/BCNU NPs group was 58.46 % and 63.33 % of the control group and BCNU group, respectively. Overall, HA-AZO-BG/BCNU NPs was expected to be a promising candidate for targeted delivery of BCNU and elimination of chemoresistance.
Keyword ：
Carmustine Carmustine O6-alkylguanine-DNA alkyltransferase O6-alkylguanine-DNA alkyltransferase Hypoxia-responsive functional nanocarrier Hypoxia-responsive functional nanocarrier
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| GB/T 7714 | Li, Duo , Wang, Xiaoli , Han, Kaishuo et al. Hypoxia and CD44 receptors dual-targeted nano-micelles with AGT-inhibitory activity for the targeting delivery of carmustine [J]. | INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES , 2023 , 246 . |
| MLA | Li, Duo et al. "Hypoxia and CD44 receptors dual-targeted nano-micelles with AGT-inhibitory activity for the targeting delivery of carmustine" . | INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES 246 (2023) . |
| APA | Li, Duo , Wang, Xiaoli , Han, Kaishuo , Sun, Yaqian , Ren, Ting , Sun, Guohui et al. Hypoxia and CD44 receptors dual-targeted nano-micelles with AGT-inhibitory activity for the targeting delivery of carmustine . | INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES , 2023 , 246 . |
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Abstract ：
Dual-specific tyrosine phosphorylation regulated kinase 1 (DYRK1A) has been regarded as a potential therapeutic target of neurodegenerative diseases, and considerable progress has been made in the discovery of DYRK1A inhibitors. Identification of pharmacophoric fragments provides valuable information for structure- and fragment-based design of potent and selective DYRK1A inhibitors. In this study, seven machine learning methods along with five molecular fingerprints were employed to develop qualitative classification models of DYRK1A inhibitors, which were evaluated by cross-validation, test set, and external validation set with four performance indicators of predictive classification accuracy (CA), the area under receiver operating characteristic (AUC), Matthews correlation coefficient (MCC), and balanced accuracy (BA). The PubChem fingerprint-support vector machine model (CA = 0.909, AUC = 0.933, MCC = 0.717, BA = 0.855) and PubChem fingerprint along with the artificial neural model (CA = 0.862, AUC = 0.911, MCC = 0.705, BA = 0.870) were considered as the optimal modes for training set and test set, respectively. A hybrid data balancing method SMOTETL, a combination of synthetic minority over-sampling technique (SMOTE) and Tomek link (TL) algorithms, was applied to explore the impact of balanced learning on the performance of models. Based on the frequency analysis and information gain, pharmacophoric fragments related to DYRK1A inhibition were also identified. All the results will provide theoretical supports and clues for the screening and design of novel DYRK1A inhibitors.
Keyword ：
heterocyclic inhibitors heterocyclic inhibitors DYRK1A DYRK1A classification models classification models pharmacophoric fragments pharmacophoric fragments
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| GB/T 7714 | Bi, Mengzhou , Guan, Zhen , Fan, Tengjiao et al. Identification of Pharmacophoric Fragments of DYRK1A Inhibitors Using Machine Learning Classification Models [J]. | MOLECULES , 2022 , 27 (6) . |
| MLA | Bi, Mengzhou et al. "Identification of Pharmacophoric Fragments of DYRK1A Inhibitors Using Machine Learning Classification Models" . | MOLECULES 27 . 6 (2022) . |
| APA | Bi, Mengzhou , Guan, Zhen , Fan, Tengjiao , Zhang, Na , Wang, Jianhua , Sun, Guohui et al. Identification of Pharmacophoric Fragments of DYRK1A Inhibitors Using Machine Learning Classification Models . | MOLECULES , 2022 , 27 (6) . |
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Abstract ：
稠环与非稠环芳烃(FNFAHs)的致癌性与人类的健康密切相关。用传统实验测试方法进行毒理学研究成本昂贵、耗时，且涉及伦理问题。因此，用于致癌性预测的定量构效关系(QSAR)等计算机替代方法受到了监管机构的广泛关注。根据严格的OECD指南，基于2D分子描述符采用遗传算法(GA)结合多元线性回归(MLR)方法建立了FNFAHs对雌性大鼠、雄性大鼠和大鼠的致癌性QSAR模型，所有模型均通过国际广泛接受的内部和外部验证指标，并进行应用域(AD)分析。同时，机理解释确定了结构信息(描述符)和致癌性之间的详细关系。此外，还首次应用所建立的模型预测了没有实验值的真实外部集化合物的致癌效力。就监管目的而言，所...
Keyword ：
稠环与非稠环芳烃 稠环与非稠环芳烃 替代方法 替代方法 致癌性 致癌性 定量构效关系 定量构效关系 风险评估 风险评估
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| GB/T 7714 | 李非凡 , 范腾蛟 , 孙国辉 et al. 稠环与非稠环芳烃对大鼠致癌性的定量构效关系研究 [J]. | 化学试剂 , 2022 , 44 (07) : 990-1000 . |
| MLA | 李非凡 et al. "稠环与非稠环芳烃对大鼠致癌性的定量构效关系研究" . | 化学试剂 44 . 07 (2022) : 990-1000 . |
| APA | 李非凡 , 范腾蛟 , 孙国辉 , 赵丽娇 , 钟儒刚 . 稠环与非稠环芳烃对大鼠致癌性的定量构效关系研究 . | 化学试剂 , 2022 , 44 (07) , 990-1000 . |
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Abstract ：
目的 探究肌醇缺乏环境下骨形成蛋白（bone morphogenetic proteins,BMP）/果蝇与秀丽隐杆线虫蛋白同源物（homologues of the drosophila protein, mothers against decapentaplegic and the caenorhabditis elegans protein,Smad）1/5/8通路对小鼠神经干细胞增殖的影响，进一步阐明胚胎神经发育异常的分子机制。方法 选取NE-4C细胞系，分为对照组和0.005、0.01、0.05、0.1、0.5、1、5、10、50、100、150和200 mmol/L肌醇处理组；应用...
Keyword ：
细胞增殖 细胞增殖 肌醇 肌醇 神经干细胞 神经干细胞 信号传导 信号传导 骨形成蛋白类 骨形成蛋白类
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| GB/T 7714 | 张妍 , 杨爱云 , 李莘 et al. 肌醇缺乏环境下骨形成蛋白/Smad1/5/8通路对小鼠神经干细胞增殖的影响 [J]. | 发育医学电子杂志 , 2022 , 10 (04) : 250-260 . |
| MLA | 张妍 et al. "肌醇缺乏环境下骨形成蛋白/Smad1/5/8通路对小鼠神经干细胞增殖的影响" . | 发育医学电子杂志 10 . 04 (2022) : 250-260 . |
| APA | 张妍 , 杨爱云 , 李莘 , 王秀伟 , 官臻 , 梁颖超 et al. 肌醇缺乏环境下骨形成蛋白/Smad1/5/8通路对小鼠神经干细胞增殖的影响 . | 发育医学电子杂志 , 2022 , 10 (04) , 250-260 . |
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Abstract ：
实体瘤的低氧微环境是恶性肿瘤的重要特征之一，针对肿瘤低氧的靶向化疗药物为癌症治疗带来了新策略。偶氮苯中的偶氮基团具有低氧激活的特异性，能够在常氧条件下稳定存在而在低氧条件下发生还原裂解，因此一些偶氮苯衍生物前药也因其具有肿瘤低氧靶向潜力，近年来被开发并应用于临床研究。使用密度泛函理论(DFT)对在辅酶还原型黄素单核苷酸(FMNH)作用下的偶氮苯还原机理进行了研究。结果表明，优势反应路径为偶氮苯首先经过连续的两步1e~-/1H~+转移形成1,2-二苯肼，然后依次再发生第3次1e~-/1H~+转移、氮氮裂解和第4次1e~-/1H~+转移后最终形成两分子苯胺。其中，前两步1e~-/1H~+转移需要克...
Keyword ：
还原机理 还原机理 偶氮苯 偶氮苯 密度泛函理论 密度泛函理论 肿瘤低氧 肿瘤低氧 低氧激活前药 低氧激活前药
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| GB/T 7714 | 宋佳宸 , 郑大威 , 王圣博 et al. FMNH介导偶氮苯还原机理的密度泛函理论研究 [J]. | 化学试剂 , 2022 , 44 (11) : 1598-1604 . |
| MLA | 宋佳宸 et al. "FMNH介导偶氮苯还原机理的密度泛函理论研究" . | 化学试剂 44 . 11 (2022) : 1598-1604 . |
| APA | 宋佳宸 , 郑大威 , 王圣博 , 王娇娇 , 孙国辉 , 张娜 et al. FMNH介导偶氮苯还原机理的密度泛函理论研究 . | 化学试剂 , 2022 , 44 (11) , 1598-1604 . |
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Abstract ：
Chloroethylnitrosoureas (CENUs) exert antitumor activity via producing dG-dC interstrand crosslinks (ICLs). However, tumor resistance make it necessary to find novel strategies to improve the therapeutic effect of CENUs. 2-Deoxy-D-glucose (2-DG) is a well-known glycolytic inhibitor, which can reprogram tumor energy metabolism closely related to tumor resistance. Here, we investigated the chemosensitization effect of 2-DG on l,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) against glioblastoma cells and the underlying mechanisms. We found that 2-DG significantly increased the inhibitory effects of BCNU on tumor cells compared with BCNU alone, while 2 -DG showed no obvious enhancing effect on the BCNU-induced cytotoxicity for normal HaCaT and HA1800 cells. Proliferation, migration and invasion determinations presented the same trend as survival on tumor cells. 2-DG plus BCNU increased the energy deficiency through a more effective inhibition of glycolytic pathway. Notably, the combination of 2-DG and BCNU aggravated oxidative stress in glioblastoma cells, along with a significant decrease in glutathione (GSH) levels, and an increase in intracellular reactive oxygen species (ROS). Subse-quently, we demonstrated that the combination treatment led to increased apoptosis via activating mitochondria and endoplasmic reticulum stress (ERS) related apoptosis pathways. Finally, we found that the dG-dC level was significantly increased after 2-DG pretreatment compared to BCNU alone by HPLC-ESI-MS/MS analysis. Finally, in vivo, 2-DG plus BCNU significantly suppressed tumor growth with lower side effects compared with BCNU alone in tumor-bearing mice. In summary, we proposed that 2-DG may have potential to increase the sensitivity of glioblastoma cells to BCNU by regulating glycolysis, ROS and ERS pathways in clinical setting.
Keyword ：
Glioblastoma cells Glioblastoma cells Combination therapy Combination therapy BCNU BCNU 2-Deoxy-D-glucose 2-Deoxy-D-glucose Chemosensitization Chemosensitization Antitumor mechanism Antitumor mechanism
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| GB/T 7714 | Sun, Xiaodong , Fan, Tengjiao , Sun, Guohui et al. 2-Deoxy-D-glucose increases the sensitivity of glioblastoma cells to BCNU through the regulation of glycolysis, ROS and ERS pathways: In vitro and in vivo validation [J]. | BIOCHEMICAL PHARMACOLOGY , 2022 , 199 . |
| MLA | Sun, Xiaodong et al. "2-Deoxy-D-glucose increases the sensitivity of glioblastoma cells to BCNU through the regulation of glycolysis, ROS and ERS pathways: In vitro and in vivo validation" . | BIOCHEMICAL PHARMACOLOGY 199 (2022) . |
| APA | Sun, Xiaodong , Fan, Tengjiao , Sun, Guohui , Zhou, Yue , Huang, Yaxin , Zhang, Na et al. 2-Deoxy-D-glucose increases the sensitivity of glioblastoma cells to BCNU through the regulation of glycolysis, ROS and ERS pathways: In vitro and in vivo validation . | BIOCHEMICAL PHARMACOLOGY , 2022 , 199 . |
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