The Experts below are selected from a list of 4521 Experts worldwide ranked by ideXlab platform
Bao-jing Zhang - One of the best experts on this subject based on the ideXlab platform.
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A highly selective near infrared fluorescent probe for Carboxylesterase 2 and its biological applications.
Journal of materials chemistry. B, 2021Co-Authors: Xin-yue Zhang, Jia-hao Liang, Xiangge Tian, Bao-jing Zhang, Hui-lian Huang, Lei Feng, Tian-tian Liu, Cheng-peng SunAbstract:Carboxylesterase 2 (CES 2) is a key enzyme in the activation of the prodrug irinotecan (CPT-11) in the treatment against colorectal cancer and also has some relationship with the side effect of CPT-11 in clinical applications. Herein, a near infrared (NIR) fluorescent probe (DSAB) has been designed for CES 2 which possesses the advantages of prominent selectivity and high sensitivity, and DSAB has been successfully applied for the imaging of endogenous CES 2 in living cells. Moreover, a high-throughput screening method for CES 2 inhibitors has been established using DSAB and discovered four novel CES 2 inhibitors from various herbal medicines. These results fully demonstrated that DSAB is a promising molecular tool for the investigation of the biological functions of CES 2 in living systems and the discovery of novel CES 2 inhibitors for the treatment of CES 2 related physiological diseases.
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Investigation of the inhibitory effect of protostanes on human Carboxylesterase 2 and their interaction: Inhibition kinetics and molecular stimulations.
International journal of biological macromolecules, 2020Co-Authors: Rong Bai, Xiangge Tian, Xiaokui Huo, Bao-jing Zhang, Jian-kun Yan, Hui-lian Huang, Xinyu Zhao, Wen-yu Zhao, Cheng-peng SunAbstract:Abstract Carboxylesterase 2 (CES 2), plays a pivotal role in endobiotic homeostasis and xenobiotic metabolism. Protostanes, the major constituents of the genus Alisma, display a series of pharmacological activities. Despite the extensive studies of pharmacological activities, the investigation on inhibitory effects of protostanes against CES 2 is rarely reported. In this study, the inhibitory activities of a library of protostanes (1–25) against human CES 2 were investigated for the first time, using 6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl benzoate (DDAB) as the specific fluorescent probe for human CES 2. Compounds 1, 2, 7, 8, 12, 13, 18, 19, and 25 showed strong inhibitory effects towards CES 2. For the most potent compounds 1, 7, 13, and 25, the inhibition kinetics were further investigated, and these four protostanes were all uncompetitive inhibitors against human CES 2 with the inhibition constant (Ki) values ranging from 0.89 μM to 2.83 μM. In addition, molecular docking and molecular dynamics stimulation were employed to analyze the potential interactions between these protostanes and CES 2, and amino acid residue Gln422 was identified to play a crucial role in the strong inhibition of protostanes towards CES 2.
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Demethylbellidifolin isolated from Swertia bimaculate against human Carboxylesterase 2: Kinetics and interaction mechanism merged with docking simulations
Bioorganic chemistry, 2019Co-Authors: Tian-tian Liu, Jia-hao Liang, Xiangge Tian, Xiaokui Huo, Lei Feng, Jing Ning, Xin-yue Zhang, Song Zhang, Bao-jing ZhangAbstract:Abstract In this study, forty-nine kinds of traditional Chinese medicines (TCMs) were evaluated for their inhibitory activities against human Carboxylesterase 2 (HCE 2) using a human liver microsome (HLM) system. Swertia bimaculata showed significant inhibition on HCE 2 at 10 μg/mL among forty-nine kinds of TCMs. The extract of Swertia bimaculata was separated by preparative HPLC to afford demethylbellidifolin (1) identified by MS, 1H NMR, and 13C NMR spectra. Demethylbellidifolin (1) was assayed for its inhibitory HCE 2 effect by HCE 2-mediated DDAB hydrolysis, and its potential IC50 value was 3.12 ± 0.64 μM. Demethylbellidifolin (1) was assigned as a mixed-type competitive inhibitor with the inhibiton constant Ki value of 6.87 µM by Lineweaver-Burk and slope plots. Living cell imaging was conducted to corroborate its inhibitory HCE 2 activity. Molecular docking indicated potential interactions of demethylbellidifolin (1) with HCE 2 through two hydrogen bonds of the C-3 and C-5 hydroxy groups with amino acid residues Glu227 and Ser228 in the catalytic cavity, respectively.
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phytochemical constituents from uncaria rhynchophylla in human Carboxylesterase 2 inhibition kinetics and interaction mechanism merged with docking simulations
Phytomedicine, 2018Co-Authors: Ya-li Wang, Jia-hao Liang, Xiangge Tian, Cheng-peng Sun, Xiaokui Huo, Peipei Dong, Bao-jing ZhangAbstract:Abstract Background Carboxylesterases (CEs) belong to the serine hydrolase family, and are in charge of hydrolyzing chemicals with carboxylic acid ester and amide functional groups via Ser-His-Glu. Uncaria rhynchophylla (Miq.) Miq. ex Havil. is a famous traditional Chinese medicine used in managing hyperpyrexia, epilepsy, preeclampsia, and hypertension in China. Hypothesis/purpose To discover the potential natural human Carboxylesterase 2 (hCE 2) inhibitors from U. rhynchophylla. Methods Compounds were obtained from the hooks of U. rhynchophylla by silica gel and preparative HPLC. Their structures were elucidated by using HRESIMS, 1D and 2D NMR spectra. Their inhibitory activeties and inhibition kinetics against hCE 2 were assayed by the fluorescent probe, and potential mechanisms were also investigated by molecular docking. Results Twenty-three compounds, including a new phenolic acid uncariarhyine A (1), eight known triterpenoids (2–9), and ten known aromatic derivatives (10, 13–16, and 19–23), were isolated from U. rhynchophylla. Compounds 1–5, 7, 9, and 15 showed significant inhibitory activities against hCE 2 with IC50 values from 4.01 ± 0.61 µM to 18.60 ± 0.21 µM, and their inhibition kinetic analysis results revealed that compounds 1, 5, 9, and 15 were non-competitive; compounds 3 and 4 were mixed-type, and compounds 2 and 7 were uncompetitive. Molecular docking studies indicated inhibition mechanisms of compounds 1–5, 7, 9, and 15 against hCE 2. Conclusion Our present findings highlight potential natural hCE 2 inhibitors from U. rhynchophylla.
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Phytochemical constituents from Uncaria rhynchophylla in human Carboxylesterase 2 inhibition: Kinetics and interaction mechanism merged with docking simulations.
Phytomedicine : international journal of phytotherapy and phytopharmacology, 2018Co-Authors: Ya-li Wang, Jia-hao Liang, Xiangge Tian, Cheng-peng Sun, Xiaokui Huo, Peipei Dong, Bao-jing ZhangAbstract:Carboxylesterases (CEs) belong to the serine hydrolase family, and are in charge of hydrolyzing chemicals with carboxylic acid ester and amide functional groups via Ser-His-Glu. Uncaria rhynchophylla (Miq.) Miq. ex Havil. is a famous traditional Chinese medicine used in managing hyperpyrexia, epilepsy, preeclampsia, and hypertension in China. To discover the potential natural human Carboxylesterase 2 (hCE 2) inhibitors from U. rhynchophylla. Compounds were obtained from the hooks of U. rhynchophylla by silica gel and preparative HPLC. Their structures were elucidated by using HRESIMS, 1D and 2D NMR spectra. Their inhibitory activeties and inhibition kinetics against hCE 2 were assayed by the fluorescent probe, and potential mechanisms were also investigated by molecular docking. Twenty-three compounds, including a new phenolic acid uncariarhyine A (1), eight known triterpenoids (2-9), and ten known aromatic derivatives (10, 13-16, and 19-23), were isolated from U. rhynchophylla. Compounds 1-5, 7, 9, and 15 showed significant inhibitory activities against hCE 2 with IC50 values from 4.01 ± 0.61 µM to 18.60 ± 0.21 µM, and their inhibition kinetic analysis results revealed that compounds 1, 5, 9, and 15 were non-competitive; compounds 3 and 4 were mixed-type, and compounds 2 and 7 were uncompetitive. Molecular docking studies indicated inhibition mechanisms of compounds 1-5, 7, 9, and 15 against hCE 2. Our present findings highlight potential natural hCE 2 inhibitors from U. rhynchophylla. Copyright © 2018 Elsevier GmbH. All rights reserved.
Xiangge Tian - One of the best experts on this subject based on the ideXlab platform.
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A highly selective near infrared fluorescent probe for Carboxylesterase 2 and its biological applications.
Journal of materials chemistry. B, 2021Co-Authors: Xin-yue Zhang, Jia-hao Liang, Xiangge Tian, Bao-jing Zhang, Hui-lian Huang, Lei Feng, Tian-tian Liu, Cheng-peng SunAbstract:Carboxylesterase 2 (CES 2) is a key enzyme in the activation of the prodrug irinotecan (CPT-11) in the treatment against colorectal cancer and also has some relationship with the side effect of CPT-11 in clinical applications. Herein, a near infrared (NIR) fluorescent probe (DSAB) has been designed for CES 2 which possesses the advantages of prominent selectivity and high sensitivity, and DSAB has been successfully applied for the imaging of endogenous CES 2 in living cells. Moreover, a high-throughput screening method for CES 2 inhibitors has been established using DSAB and discovered four novel CES 2 inhibitors from various herbal medicines. These results fully demonstrated that DSAB is a promising molecular tool for the investigation of the biological functions of CES 2 in living systems and the discovery of novel CES 2 inhibitors for the treatment of CES 2 related physiological diseases.
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Investigation of the inhibitory effect of protostanes on human Carboxylesterase 2 and their interaction: Inhibition kinetics and molecular stimulations.
International journal of biological macromolecules, 2020Co-Authors: Rong Bai, Xiangge Tian, Xiaokui Huo, Bao-jing Zhang, Jian-kun Yan, Hui-lian Huang, Xinyu Zhao, Wen-yu Zhao, Cheng-peng SunAbstract:Abstract Carboxylesterase 2 (CES 2), plays a pivotal role in endobiotic homeostasis and xenobiotic metabolism. Protostanes, the major constituents of the genus Alisma, display a series of pharmacological activities. Despite the extensive studies of pharmacological activities, the investigation on inhibitory effects of protostanes against CES 2 is rarely reported. In this study, the inhibitory activities of a library of protostanes (1–25) against human CES 2 were investigated for the first time, using 6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl benzoate (DDAB) as the specific fluorescent probe for human CES 2. Compounds 1, 2, 7, 8, 12, 13, 18, 19, and 25 showed strong inhibitory effects towards CES 2. For the most potent compounds 1, 7, 13, and 25, the inhibition kinetics were further investigated, and these four protostanes were all uncompetitive inhibitors against human CES 2 with the inhibition constant (Ki) values ranging from 0.89 μM to 2.83 μM. In addition, molecular docking and molecular dynamics stimulation were employed to analyze the potential interactions between these protostanes and CES 2, and amino acid residue Gln422 was identified to play a crucial role in the strong inhibition of protostanes towards CES 2.
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Endoplasmic Reticulum Targeting Ratiometric Fluorescent Probe for Carboxylesterase 2 Detection in Drug-Induced Acute Liver Injury
Analytical chemistry, 2019Co-Authors: Xiangge Tian, Lei Feng, Fei Yan, Jingyuan Zheng, Xiaolin Cui, Lingling Jin, Tony D. JamesAbstract:Carboxylesterase 2 (CES2), an endoplasmic reticulum (ER) located phase I enzyme, plays a vital role in the metabolism of various endogenous and exogenous substances, and is regarded as an important target for the design of prodrugs. Unfortunately, superior highly selective ER targeting fluorescent probes for monitoring of CES2 are not currently available. Herein, we report an ER targeting CES2 selective and sensitive ratiometric fluorescent probe ERNB based on the ER localizing group p-toluenesulfonamide. ERNB possessed high specificity, sensitivity, and exhibited excellent subcellular localization when compared to commercial ER tracker, and was used to image CES2 in the ER of living cells. Additionally, using ERNB we evaluated the CES2 regulation under d,l-dithiothreitol and tunicamycin-induced ER stress. Furthermore, we determined the down regulation of CES2 activity and expression in the acetaminophen-induced acute liver injury model. On the basis of these results, we conclude that ERNB is a promising tool for highlighting the role of CES2 in the ER and in exploring the role of CES2 in the development of diseases associated with ER stress.
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Demethylbellidifolin isolated from Swertia bimaculate against human Carboxylesterase 2: Kinetics and interaction mechanism merged with docking simulations
Bioorganic chemistry, 2019Co-Authors: Tian-tian Liu, Jia-hao Liang, Xiangge Tian, Xiaokui Huo, Lei Feng, Jing Ning, Xin-yue Zhang, Song Zhang, Bao-jing ZhangAbstract:Abstract In this study, forty-nine kinds of traditional Chinese medicines (TCMs) were evaluated for their inhibitory activities against human Carboxylesterase 2 (HCE 2) using a human liver microsome (HLM) system. Swertia bimaculata showed significant inhibition on HCE 2 at 10 μg/mL among forty-nine kinds of TCMs. The extract of Swertia bimaculata was separated by preparative HPLC to afford demethylbellidifolin (1) identified by MS, 1H NMR, and 13C NMR spectra. Demethylbellidifolin (1) was assayed for its inhibitory HCE 2 effect by HCE 2-mediated DDAB hydrolysis, and its potential IC50 value was 3.12 ± 0.64 μM. Demethylbellidifolin (1) was assigned as a mixed-type competitive inhibitor with the inhibiton constant Ki value of 6.87 µM by Lineweaver-Burk and slope plots. Living cell imaging was conducted to corroborate its inhibitory HCE 2 activity. Molecular docking indicated potential interactions of demethylbellidifolin (1) with HCE 2 through two hydrogen bonds of the C-3 and C-5 hydroxy groups with amino acid residues Glu227 and Ser228 in the catalytic cavity, respectively.
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A natural inhibitor from Alisma orientale against human Carboxylesterase 2: Kinetics, circular dichroism spectroscopic analysis, and docking simulation.
International journal of biological macromolecules, 2019Co-Authors: Rong Bai, Jia-hao Liang, Xiangge Tian, Xiaokui Huo, Lei Feng, Jing Ning, Tian-tian Liu, Cheng-peng SunAbstract:As a part of our searching for natural human Carboxylesterase 2 (human CES 2) inhibitors from traditional Chinese medicine, we found that the extract of Alisma orientale significantly inhibited human CES 2 in vitro. The investigation on A. orientale led to the isolation of a new protostane-type triterpenoid alismanin I (1). Its structure was determined according to HRESIMS, 1D and 2D NMR spectra. Alismanin I (1) displayed significantly inhibitory activity against human CES 2 with IC50 value of 1.31 ± 0.09 μM assayed by human CES 2-mediated DDAB hydrolysis. According to its inhibition kinetic result, compound 1 was a noncompetitive type inhibitor, and its Ki was 3.65 μM. Its inhibitory effect was confirmed in living cell level through a visual manner. The potential interaction mechanism of compound 1 with human CES 2 was also analyzed by circular dichroism (CD) spectrum and molecular docking.
Lei Feng - One of the best experts on this subject based on the ideXlab platform.
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A highly selective near infrared fluorescent probe for Carboxylesterase 2 and its biological applications.
Journal of materials chemistry. B, 2021Co-Authors: Xin-yue Zhang, Jia-hao Liang, Xiangge Tian, Bao-jing Zhang, Hui-lian Huang, Lei Feng, Tian-tian Liu, Cheng-peng SunAbstract:Carboxylesterase 2 (CES 2) is a key enzyme in the activation of the prodrug irinotecan (CPT-11) in the treatment against colorectal cancer and also has some relationship with the side effect of CPT-11 in clinical applications. Herein, a near infrared (NIR) fluorescent probe (DSAB) has been designed for CES 2 which possesses the advantages of prominent selectivity and high sensitivity, and DSAB has been successfully applied for the imaging of endogenous CES 2 in living cells. Moreover, a high-throughput screening method for CES 2 inhibitors has been established using DSAB and discovered four novel CES 2 inhibitors from various herbal medicines. These results fully demonstrated that DSAB is a promising molecular tool for the investigation of the biological functions of CES 2 in living systems and the discovery of novel CES 2 inhibitors for the treatment of CES 2 related physiological diseases.
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Endoplasmic Reticulum Targeting Ratiometric Fluorescent Probe for Carboxylesterase 2 Detection in Drug-Induced Acute Liver Injury
Analytical chemistry, 2019Co-Authors: Xiangge Tian, Lei Feng, Fei Yan, Jingyuan Zheng, Xiaolin Cui, Lingling Jin, Tony D. JamesAbstract:Carboxylesterase 2 (CES2), an endoplasmic reticulum (ER) located phase I enzyme, plays a vital role in the metabolism of various endogenous and exogenous substances, and is regarded as an important target for the design of prodrugs. Unfortunately, superior highly selective ER targeting fluorescent probes for monitoring of CES2 are not currently available. Herein, we report an ER targeting CES2 selective and sensitive ratiometric fluorescent probe ERNB based on the ER localizing group p-toluenesulfonamide. ERNB possessed high specificity, sensitivity, and exhibited excellent subcellular localization when compared to commercial ER tracker, and was used to image CES2 in the ER of living cells. Additionally, using ERNB we evaluated the CES2 regulation under d,l-dithiothreitol and tunicamycin-induced ER stress. Furthermore, we determined the down regulation of CES2 activity and expression in the acetaminophen-induced acute liver injury model. On the basis of these results, we conclude that ERNB is a promising tool for highlighting the role of CES2 in the ER and in exploring the role of CES2 in the development of diseases associated with ER stress.
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Demethylbellidifolin isolated from Swertia bimaculate against human Carboxylesterase 2: Kinetics and interaction mechanism merged with docking simulations
Bioorganic chemistry, 2019Co-Authors: Tian-tian Liu, Jia-hao Liang, Xiangge Tian, Xiaokui Huo, Lei Feng, Jing Ning, Xin-yue Zhang, Song Zhang, Bao-jing ZhangAbstract:Abstract In this study, forty-nine kinds of traditional Chinese medicines (TCMs) were evaluated for their inhibitory activities against human Carboxylesterase 2 (HCE 2) using a human liver microsome (HLM) system. Swertia bimaculata showed significant inhibition on HCE 2 at 10 μg/mL among forty-nine kinds of TCMs. The extract of Swertia bimaculata was separated by preparative HPLC to afford demethylbellidifolin (1) identified by MS, 1H NMR, and 13C NMR spectra. Demethylbellidifolin (1) was assayed for its inhibitory HCE 2 effect by HCE 2-mediated DDAB hydrolysis, and its potential IC50 value was 3.12 ± 0.64 μM. Demethylbellidifolin (1) was assigned as a mixed-type competitive inhibitor with the inhibiton constant Ki value of 6.87 µM by Lineweaver-Burk and slope plots. Living cell imaging was conducted to corroborate its inhibitory HCE 2 activity. Molecular docking indicated potential interactions of demethylbellidifolin (1) with HCE 2 through two hydrogen bonds of the C-3 and C-5 hydroxy groups with amino acid residues Glu227 and Ser228 in the catalytic cavity, respectively.
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A natural inhibitor from Alisma orientale against human Carboxylesterase 2: Kinetics, circular dichroism spectroscopic analysis, and docking simulation.
International journal of biological macromolecules, 2019Co-Authors: Rong Bai, Jia-hao Liang, Xiangge Tian, Xiaokui Huo, Lei Feng, Jing Ning, Tian-tian Liu, Cheng-peng SunAbstract:As a part of our searching for natural human Carboxylesterase 2 (human CES 2) inhibitors from traditional Chinese medicine, we found that the extract of Alisma orientale significantly inhibited human CES 2 in vitro. The investigation on A. orientale led to the isolation of a new protostane-type triterpenoid alismanin I (1). Its structure was determined according to HRESIMS, 1D and 2D NMR spectra. Alismanin I (1) displayed significantly inhibitory activity against human CES 2 with IC50 value of 1.31 ± 0.09 μM assayed by human CES 2-mediated DDAB hydrolysis. According to its inhibition kinetic result, compound 1 was a noncompetitive type inhibitor, and its Ki was 3.65 μM. Its inhibitory effect was confirmed in living cell level through a visual manner. The potential interaction mechanism of compound 1 with human CES 2 was also analyzed by circular dichroism (CD) spectrum and molecular docking.
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diterpenoids from the roots of euphorbia ebracteolata and their inhibitory effects on human Carboxylesterase 2
Phytochemistry, 2018Co-Authors: An-hua Wang, Xiangge Tian, Xiaokui Huo, Bao-jing Zhang, Yonglei Cui, Lei Feng, Jing-ming Jia, Sa Deng, Chao WangAbstract:A chemical investigation of the roots of Euphorbia ebracteolata identified eighteen diterpenoids and glycosides. On the basis of spectroscopic data, they were determined to be ent-kauranes, ent-atisanes, tigliane derivatives, ingenane, and ent-abietanes, among which were eleven previously undescribed diterpenoids. The inhibitory effects of the isolated compounds against human Carboxylesterase 2 (hCE-2) were evaluated in vitro, which revealed moderate inhibitory effects with IC50 values < 50 μM. Next, the inhibitory kinetics were evaluated for the putative hCE-2 inhibitor 4β,9α,16,20-tetrahydroxy-14(13 → 12)-abeo-12αH-1,6-tigliadiene-3,13-dione (IC50 3.88 μM), and results indicated competitive inhibition with Ki 4.94 μM. Additionally, none of the diterpenoids showed cytotoxic effects against five human tumor cell lines as determined by MTT assays.
Ling Yang - One of the best experts on this subject based on the ideXlab platform.
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Construction and application of a high-content analysis for identifying human Carboxylesterase 2 inhibitors in living cell system
Analytical and Bioanalytical Chemistry, 2020Co-Authors: Lijuan Xue, Xingkai Qian, Qiang Jin, Ya-di Zhu, Xiaoyu Wang, Dan-dan Wang, Ling YangAbstract:Human Carboxylesterase 2 (hCE2), one of the most principal drug-metabolizing enzymes, catalyzes the hydrolysis of a variety of endogenous esters, anticancer agents, and environmental toxicants. The significant roles of hCE2 in both endobiotic and xenobiotic metabolism sparked great interest in the discovery and development of efficacious and selective inhibitors. However, the safe and effective inhibitors of hCE2 are scarce, due to the lack of efficient screening and evaluation systems for complex biological systems. To offer a solution to this problem, a high-content analysis (HCA)–based cell imaging and multiparametric assay method was constructed for evaluating the inhibitory effect and safety of hCE2 inhibitors in living cell system. In this study, we first established a cell imaging–based method for identifying hCE2 inhibitors at the living cell level with hCE2 fluorescent probe NCEN. Meanwhile, two nuclear probes, Hoechst 33342 and PI, were integrated to evaluate the potential cytotoxicity of compounds simultaneously. Then, the accuracy of the HCA-based method was verified by the LC-FD-based method with a positive inhibitor BNPP, and the results showed that the HCA-based method exhibited excellent precision, robustness, and reliability. Finally, the newly established HCA-based multiparametric assay panel was successfully applied to re-evaluate a series of reported hCE2 inhibitors in living cells. In summary, the HCA-based multiparametric method could serve as an efficient tool for the accuracy measurement inhibitory effect and cytotoxicity of compounds against hCE2 in living cell system.
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Identification and characterization of naturally occurring inhibitors against human Carboxylesterase 2 in White Mulberry Root-bark
Fitoterapia, 2016Co-Authors: Ya-jing Liu, Dan-dan Wang, Jie Hou, Yan-fang Liu, Yong-shan Jiang, Xinmiao Liang, Ling YangAbstract:White Mulberry Root-bark (WMR) is an edible Chinese herbal used for the treatment of inflammation, nephritis and asthma. This study aimed to investigate the inhibitory effects of ethanol extract from WMR against human Carboxylesterase 2 (hCE2), as well as to identity and character natural hCE2 inhibitors in this herbal. Our results demonstrated that the ethanol extract of WMR displayed potent inhibitory effects against hCE2, while three major bioactive constitutes in WMR were identified on the basis of LC fingerprinting combined with activity-based screening of LC fractions. Three bioactive compounds including SD, KG and SC were efficiently identified by comparison of LC retention times, UV and MS spectral data, with the help of authentic standards. The inhibition potentials and inhibition types of these natural compounds against hCE2 were further investigated in human liver microsomes. The results demonstrated that these bioactive compounds are potent non-competitive inhibitors against hCE2, with the Ki values ranging from 0.76μM to 1.09μM. All these findings suggested that three abundant natural compounds in WMR displayed potent inhibitory effects against hCE2, which could be used as lead compounds to develop more potent hCE2 inhibitors for the alleviation of hCE2-mediated severe delayed-onset diarrhea.
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a highly selective near infrared fluorescent probe for Carboxylesterase 2 and its bioimaging applications in living cells and animals
Biosensors and Bioelectronics, 2016Co-Authors: Qiang Jin, Dan-dan Wang, Lei Feng, Jie Hou, Ziru Dai, Jiayue Wang, Jingnan Cui, Shiguo Sun, Ling YangAbstract:A near-infrared fluorescent probe (DDAB) for highly selective and sensitive detection of Carboxylesterase 2 (CE2) has been designed, synthesized, and systematically studied both in vitro and in vivo. Upon addition of CE2, the ester bond of DDAB could be rapidly cleaved and then release a near-infrared (NIR) fluorophore DDAO, which brings a remarkable yellow-to-blue color change and strong NIR fluorescence emission in physiological solutions. The newly developed probe exhibits excellent properties including good specificity, ultrahigh sensitivity and high imaging resolution. Moreover, DDAB has been applied to measure the real activities of CE2 in complex biological samples, as well as to screen CE2 inhibitors by using tissue preparations as the enzymes sources. The probe has also been successfully used to detect endogenous CE2 in living cells and in vivo for the first time, and the results demonstrate that such detection is highly reliable. All these prominent features of DDAB make it holds great promise for further investigation on CE2-associated biological process and for exploring the physiological functions of CE2 in living systems.
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design synthesis and structure activity relationship study of glycyrrhetinic acid derivatives as potent and selective inhibitors against human Carboxylesterase 2
European Journal of Medicinal Chemistry, 2016Co-Authors: Liwei Zou, Qiang Jin, Ling Yang, Jie Hou, Ping Wang, Kun Zhou, Dacheng HaoAbstract:Human Carboxylesterase 2 (hCE2), one of the major Carboxylesterases in the human intestine and various tumour tissues, plays important roles in the oral bioavailability and treatment outcomes of ester- or amide-containing drugs or prodrugs, such as anticancer agents CPT-11 (irinotecan) and LY2334737 (gemcitabine). In this study, 18β-glycyrrhetinic acid (GA), the most abundant pentacyclic triterpenoid from natural source, was selected as a reference compound for the development of potent and specific inhibitors against hCE2. Simple semi-synthetic modulation on GA was performed to obtain a series of GA derivatives. Structure-activity relationship analysis brought novel insights into the structure modification of GA. Converting the 11-oxo-12-ene of GA to 12-diene moiety, and C-3 hydroxyl and C-30 carboxyl group to 3-O-β-carboxypropionyl and ethyl ester respectively, led to a significant enhancement of the inhibitory effect on hCE2 and the selectivity over hCE1. These exciting findings inspired us to design and synthesize the more potent compound 15 (IC50 0.02 μM) as a novel and highly selective inhibitor against hCE2, which was 3463-fold more potent than the parent compound GA and demonstrated excellent selectivity (>1000-fold over hCE1). The molecular docking study of compound 15 and the active site of hCE1 and hCE2 demonstrated that the potent and selective inhibition of compound 15 toward hCE2 could partially be attributed to its relatively stronger interactions with hCE2 than with hCE1.
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a two photon ratiometric fluorescent probe for imaging Carboxylesterase 2 in living cells and tissues
ACS Applied Materials & Interfaces, 2015Co-Authors: Qiang Jin, Dan-dan Wang, Lei Feng, Ping Wang, Liwei Zou, Ziru Dai, Zhihong Liu, Jiayue Wang, Jingnan Cui, Ling YangAbstract:In this study, a two-photon ratiometric fluorescent probe NCEN has been designed and developed for highly selective and sensitive sensing of human Carboxylesterase 2 (hCE2) based on the catalytic properties and substrate preference of hCE2. Upon addition of hCE2, the probe could be readily hydrolyzed to release 4-amino-1,8-naphthalimide (NAH), which brings remarkable red-shift in fluorescence (90 nm) spectrum. The newly developed probe exhibits good specificity, ultrahigh sensitivity, and has been successfully applied to determine the real activities of hCE2 in complex biological samples such as cell and tissue preparations. NCEN has also been used for two-photon imaging of intracellular hCE2 in living cells as well as in deep-tissues for the first time, and the results showed that the probe exhibited high ratiometric imaging resolution and deep-tissue imaging depth. All these findings suggested that this probe holds great promise for applications in bioimaging of endogenous hCE2 in living cells and in exploring the biological functions of hCE2 in complex biological systems.
Xiaokui Huo - One of the best experts on this subject based on the ideXlab platform.
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Investigation of the inhibitory effect of protostanes on human Carboxylesterase 2 and their interaction: Inhibition kinetics and molecular stimulations.
International journal of biological macromolecules, 2020Co-Authors: Rong Bai, Xiangge Tian, Xiaokui Huo, Bao-jing Zhang, Jian-kun Yan, Hui-lian Huang, Xinyu Zhao, Wen-yu Zhao, Cheng-peng SunAbstract:Abstract Carboxylesterase 2 (CES 2), plays a pivotal role in endobiotic homeostasis and xenobiotic metabolism. Protostanes, the major constituents of the genus Alisma, display a series of pharmacological activities. Despite the extensive studies of pharmacological activities, the investigation on inhibitory effects of protostanes against CES 2 is rarely reported. In this study, the inhibitory activities of a library of protostanes (1–25) against human CES 2 were investigated for the first time, using 6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl benzoate (DDAB) as the specific fluorescent probe for human CES 2. Compounds 1, 2, 7, 8, 12, 13, 18, 19, and 25 showed strong inhibitory effects towards CES 2. For the most potent compounds 1, 7, 13, and 25, the inhibition kinetics were further investigated, and these four protostanes were all uncompetitive inhibitors against human CES 2 with the inhibition constant (Ki) values ranging from 0.89 μM to 2.83 μM. In addition, molecular docking and molecular dynamics stimulation were employed to analyze the potential interactions between these protostanes and CES 2, and amino acid residue Gln422 was identified to play a crucial role in the strong inhibition of protostanes towards CES 2.
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Demethylbellidifolin isolated from Swertia bimaculate against human Carboxylesterase 2: Kinetics and interaction mechanism merged with docking simulations
Bioorganic chemistry, 2019Co-Authors: Tian-tian Liu, Jia-hao Liang, Xiangge Tian, Xiaokui Huo, Lei Feng, Jing Ning, Xin-yue Zhang, Song Zhang, Bao-jing ZhangAbstract:Abstract In this study, forty-nine kinds of traditional Chinese medicines (TCMs) were evaluated for their inhibitory activities against human Carboxylesterase 2 (HCE 2) using a human liver microsome (HLM) system. Swertia bimaculata showed significant inhibition on HCE 2 at 10 μg/mL among forty-nine kinds of TCMs. The extract of Swertia bimaculata was separated by preparative HPLC to afford demethylbellidifolin (1) identified by MS, 1H NMR, and 13C NMR spectra. Demethylbellidifolin (1) was assayed for its inhibitory HCE 2 effect by HCE 2-mediated DDAB hydrolysis, and its potential IC50 value was 3.12 ± 0.64 μM. Demethylbellidifolin (1) was assigned as a mixed-type competitive inhibitor with the inhibiton constant Ki value of 6.87 µM by Lineweaver-Burk and slope plots. Living cell imaging was conducted to corroborate its inhibitory HCE 2 activity. Molecular docking indicated potential interactions of demethylbellidifolin (1) with HCE 2 through two hydrogen bonds of the C-3 and C-5 hydroxy groups with amino acid residues Glu227 and Ser228 in the catalytic cavity, respectively.
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A natural inhibitor from Alisma orientale against human Carboxylesterase 2: Kinetics, circular dichroism spectroscopic analysis, and docking simulation.
International journal of biological macromolecules, 2019Co-Authors: Rong Bai, Jia-hao Liang, Xiangge Tian, Xiaokui Huo, Lei Feng, Jing Ning, Tian-tian Liu, Cheng-peng SunAbstract:As a part of our searching for natural human Carboxylesterase 2 (human CES 2) inhibitors from traditional Chinese medicine, we found that the extract of Alisma orientale significantly inhibited human CES 2 in vitro. The investigation on A. orientale led to the isolation of a new protostane-type triterpenoid alismanin I (1). Its structure was determined according to HRESIMS, 1D and 2D NMR spectra. Alismanin I (1) displayed significantly inhibitory activity against human CES 2 with IC50 value of 1.31 ± 0.09 μM assayed by human CES 2-mediated DDAB hydrolysis. According to its inhibition kinetic result, compound 1 was a noncompetitive type inhibitor, and its Ki was 3.65 μM. Its inhibitory effect was confirmed in living cell level through a visual manner. The potential interaction mechanism of compound 1 with human CES 2 was also analyzed by circular dichroism (CD) spectrum and molecular docking.
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phytochemical constituents from uncaria rhynchophylla in human Carboxylesterase 2 inhibition kinetics and interaction mechanism merged with docking simulations
Phytomedicine, 2018Co-Authors: Ya-li Wang, Jia-hao Liang, Xiangge Tian, Cheng-peng Sun, Xiaokui Huo, Peipei Dong, Bao-jing ZhangAbstract:Abstract Background Carboxylesterases (CEs) belong to the serine hydrolase family, and are in charge of hydrolyzing chemicals with carboxylic acid ester and amide functional groups via Ser-His-Glu. Uncaria rhynchophylla (Miq.) Miq. ex Havil. is a famous traditional Chinese medicine used in managing hyperpyrexia, epilepsy, preeclampsia, and hypertension in China. Hypothesis/purpose To discover the potential natural human Carboxylesterase 2 (hCE 2) inhibitors from U. rhynchophylla. Methods Compounds were obtained from the hooks of U. rhynchophylla by silica gel and preparative HPLC. Their structures were elucidated by using HRESIMS, 1D and 2D NMR spectra. Their inhibitory activeties and inhibition kinetics against hCE 2 were assayed by the fluorescent probe, and potential mechanisms were also investigated by molecular docking. Results Twenty-three compounds, including a new phenolic acid uncariarhyine A (1), eight known triterpenoids (2–9), and ten known aromatic derivatives (10, 13–16, and 19–23), were isolated from U. rhynchophylla. Compounds 1–5, 7, 9, and 15 showed significant inhibitory activities against hCE 2 with IC50 values from 4.01 ± 0.61 µM to 18.60 ± 0.21 µM, and their inhibition kinetic analysis results revealed that compounds 1, 5, 9, and 15 were non-competitive; compounds 3 and 4 were mixed-type, and compounds 2 and 7 were uncompetitive. Molecular docking studies indicated inhibition mechanisms of compounds 1–5, 7, 9, and 15 against hCE 2. Conclusion Our present findings highlight potential natural hCE 2 inhibitors from U. rhynchophylla.
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Phytochemical constituents from Uncaria rhynchophylla in human Carboxylesterase 2 inhibition: Kinetics and interaction mechanism merged with docking simulations.
Phytomedicine : international journal of phytotherapy and phytopharmacology, 2018Co-Authors: Ya-li Wang, Jia-hao Liang, Xiangge Tian, Cheng-peng Sun, Xiaokui Huo, Peipei Dong, Bao-jing ZhangAbstract:Carboxylesterases (CEs) belong to the serine hydrolase family, and are in charge of hydrolyzing chemicals with carboxylic acid ester and amide functional groups via Ser-His-Glu. Uncaria rhynchophylla (Miq.) Miq. ex Havil. is a famous traditional Chinese medicine used in managing hyperpyrexia, epilepsy, preeclampsia, and hypertension in China. To discover the potential natural human Carboxylesterase 2 (hCE 2) inhibitors from U. rhynchophylla. Compounds were obtained from the hooks of U. rhynchophylla by silica gel and preparative HPLC. Their structures were elucidated by using HRESIMS, 1D and 2D NMR spectra. Their inhibitory activeties and inhibition kinetics against hCE 2 were assayed by the fluorescent probe, and potential mechanisms were also investigated by molecular docking. Twenty-three compounds, including a new phenolic acid uncariarhyine A (1), eight known triterpenoids (2-9), and ten known aromatic derivatives (10, 13-16, and 19-23), were isolated from U. rhynchophylla. Compounds 1-5, 7, 9, and 15 showed significant inhibitory activities against hCE 2 with IC50 values from 4.01 ± 0.61 µM to 18.60 ± 0.21 µM, and their inhibition kinetic analysis results revealed that compounds 1, 5, 9, and 15 were non-competitive; compounds 3 and 4 were mixed-type, and compounds 2 and 7 were uncompetitive. Molecular docking studies indicated inhibition mechanisms of compounds 1-5, 7, 9, and 15 against hCE 2. Our present findings highlight potential natural hCE 2 inhibitors from U. rhynchophylla. Copyright © 2018 Elsevier GmbH. All rights reserved.