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Xun Liao - One of the best experts on this subject based on the ideXlab platform.

  • screening of Lipase Inhibitors from scutellaria baicalensis extract using Lipase immobilized on magnetic nanoparticles and study on the inhibitory mechanism
    Analytical and Bioanalytical Chemistry, 2016
    Co-Authors: Xiaolan Jiang, Jian Liang, Jinjie Hu, Xun Liao
    Abstract:

    Scutellaria baicalensis is a traditional Chinese medicinal plant possessing a wide variety of biological activities. In this work, Lipase immobilized on magnetic nanoparticles (LMNPs) was used as solid phase extract absorbent for screening of Lipase Inhibitors from this plant. Three flavonoids were found to bind to LMNPs and were identified as baicalin, wogonin, and oroxylin A by liquid chromatography–mass spectrometry (HPLC-MS). Their IC50 values were determined to be 229.22 ± 12.67, 153.71 ± 9.21, and 56.07 ± 4.90 μM, respectively. Fluorescence spectroscopy and molecular docking were used to probe the interactions between these flavonoids and Lipase. All the flavonoids quenched the fluorescence of Lipase statically by forming new complexes, implying their affinities with the enzyme. The thermodynamic analysis suggested that van der Waals force and hydrogen bond were the main forces between wogonin and Lipase, while hydrophobic force was the main force for the other two flavonoids. The results from a molecular docking study further revealed that all of them could insert into the pocket of Lipase binding to a couple of amino acid residues.

  • fast identification of Lipase Inhibitors in oolong tea by using Lipase functionalised fe3o4 magnetic nanoparticles coupled with uplc ms ms
    Food Chemistry, 2015
    Co-Authors: Li Yuan, Jian Liang, Xun Liao
    Abstract:

    Abstract Oolong tea is an important member in tea family, which claims for various health benefits such as preventing obesity and improving lipid metabolism. In this work, using pancreatic Lipase (PL) functionalised magnetic nanoparticles (PL-MNPs) as solid phase extraction absorbent in combination with ultra-high performance liquid chromatography–mass spectrometry (UPLC–MS), we developed a method for rapid screening and identification of Lipase Inhibitors from oolong tea. Three PL ligands were selectively extracted and identified as (−)-epigallocatechin-3-O-gallate (EGCG), (−)-gallocatechin-3-O-gallate (GCG) and (−)-epicatechin-3-O-gallate (ECG). Their Lipase inhibitory activities were significantly higher than those non-ligands. Structure–activity analysis revealed that the presence of a galloyl moiety in the structure was required for binding to PL-MNPs, and therefore, exhibiting a strong inhibition on the enzyme. Taking advantages of the specificity in enzyme binding and the convenience of magnetic separation, this method has great potential for fast screening of Lipase Inhibitors from natural resources.

  • fast identification of Lipase Inhibitors in oolong tea by using Lipase functionalised fe3o4 magnetic nanoparticles coupled with uplc ms ms
    Food Chemistry, 2015
    Co-Authors: Yuanting Zhu, Li Yuan, Jian Liang, Xiaoyun Ren, Yiming Liu, Xun Liao
    Abstract:

    Oolong tea is an important member in tea family, which claims for various health benefits such as preventing obesity and improving lipid metabolism. In this work, using pancreatic Lipase (PL) functionalised magnetic nanoparticles (PL-MNPs) as solid phase extraction absorbent in combination with ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS), we developed a method for rapid screening and identification of Lipase Inhibitors from oolong tea. Three PL ligands were selectively extracted and identified as (-)-epigallocatechin-3-O-gallate (EGCG), (-)-gallocatechin-3-O-gallate (GCG) and (-)-epicatechin-3-O-gallate (ECG). Their Lipase inhibitory activities were significantly higher than those non-ligands. Structure-activity analysis revealed that the presence of a galloyl moiety in the structure was required for binding to PL-MNPs, and therefore, exhibiting a strong inhibition on the enzyme. Taking advantages of the specificity in enzyme binding and the convenience of magnetic separation, this method has great potential for fast screening of Lipase Inhibitors from natural resources.

  • Lipase ligands in nelumbo nucifera leaves and study of their binding mechanism
    Journal of Agricultural and Food Chemistry, 2014
    Co-Authors: Yuanting Zhu, Jian Liang, Yiming Liu, Yanwei Jia, Lisheng Ding, Xun Liao
    Abstract:

    Lotus (Nelumbo nucifera) leaves have been widely used in weight-loss foods to prevent obesity in China. In this work, a facile procedure based on ligand fishing was developed to isolate and identify Lipase Inhibitors present in lotus leaves. Highly stable and active Lipase-Fe3O4 superparamagnetic nanoparticle conjugates (LMNPs) were prepared and used as baits. Two flavonoids in lotus leaf extract were found to bind to the baits and were identified as quercetin-3-O-β-d-arabinopyranosyl-(1→2)- β-d-galactopyranoside (1) and quercetin-3-O-β-d-glucuronide (4) based on electrospray ionization-mass spectrometric analyses. Their 50% inhibitory concentrations on Lipase (IC50) were 52.9 ± 3.2 and 17.1 ± 1.5 μg/mL, respectively. In addition, they were found to significantly quench the fluorescence of Lipase, suggesting their strong affinities with this enzyme, which was further evidenced by molecular docking. Ligand fishing based on LMNPs shows great power for fast screening and identification of Lipase Inhibitors present in edible and medicinal plants.

Zhihong Cheng - One of the best experts on this subject based on the ideXlab platform.

  • direct coupling of thin layer chromatography bioautography with electrostatic field induced spray ionization mass spectrometry for separation and identification of Lipase Inhibitors in lotus leaves
    Analytica Chimica Acta, 2017
    Co-Authors: Lei Zhang, Jihe Tang, Zhihong Cheng, Yao Kong, Xiaohui Lu, Tao Wu
    Abstract:

    Abstract In situ profiling compounds in complex matrices is important technology to develop in analytic chemistry. The aim of this study is to develop a direct coupling method of thin layer chromatography (TLC) to mass spectrometry (MS) via electrostatic field induced spray ionization (EFISI). We proposed a surface treatment method of normal-phase thin layer chromatography (TLC) plates with dimethyl silicone oil coating which successfully allowed TLC to couple to MS via EFISI. Different parameters affecting the ionization efficiency were investigated and optimized, including silicone oil concentrations, air-drying times, applied voltages, and TLC plate types. This optimized TLC-EFISI-MS method was successfully applied to examine Lipase inhibitory components present in lotus leaves. Six active alkaloids including three aporphines and three benzylisoquinolines were profiled with their MS n ( n  = 4) data, or with a comparison with reference substances. This is the first report on the coupling EFISI-MS to TLC or TLC bioautography for in situ identification of active natural products.

  • direct coupling of thin layer chromatography bioautography with electrostatic field induced spray ionization mass spectrometry for separation and identification of Lipase Inhibitors in lotus leaves
    Analytica Chimica Acta, 2017
    Co-Authors: Lei Zhang, Jihe Tang, Zhihong Cheng, Jiyao Shi, Yao Kong
    Abstract:

    In situ profiling compounds in complex matrices is important technology to develop in analytic chemistry. The aim of this study is to develop a direct coupling method of thin layer chromatography (TLC) to mass spectrometry (MS) via electrostatic field induced spray ionization (EFISI). We proposed a surface treatment method of normal-phase thin layer chromatography (TLC) plates with dimethyl silicone oil coating which successfully allowed TLC to couple to MS via EFISI. Different parameters affecting the ionization efficiency were investigated and optimized, including silicone oil concentrations, air-drying times, applied voltages, and TLC plate types. This optimized TLC-EFISI-MS method was successfully applied to examine Lipase inhibitory components present in lotus leaves. Six active alkaloids including three aporphines and three benzylisoquinolines were profiled with their MSn (n = 4) data, or with a comparison with reference substances. This is the first report on the coupling EFISI-MS to TLC or TLC bioautography for in situ identification of active natural products.

  • a new tlc bioautographic assay for qualitative and quantitative estimation of Lipase Inhibitors
    Phytochemical Analysis, 2016
    Co-Authors: Jihe Tang, Jinge Zhou, Qingjiu Tang, Zhihong Cheng
    Abstract:

    Introduction Lipase inhibitory assays based on TLC bioautography have made recent progress; however, an assay with greater substrate specificity and quantitative capabilities would advance the efficacy of this particular bioassay. Objective To address these limitations, a new TLC bioautographic assay for detecting Lipase Inhibitors was developed and validated in this study. Methods The new TLC bioautographic assay was based on reaction of Lipase with β-naphthyl myristate and the subsequent formation of the purple dye between β-naphthol and Fast Blue B salt (FBB). The relative Lipase inhibitory capacity (RLIC) was determined by a TLC densitometry with fluorescence detection, expressed as orlistat equivalents in millimoles on a per sample weight basis. Six pure compounds and three natural extracts were evaluated for their potential Lipase inhibitory activities by this TLC bioautographic assay. Results The β-naphthyl myristate as the substrate improved the detection sensitivity and specificity significantly. The limit of detection (LOD) of this assay was 0.01 ng for orlistat, the current treatment for obesity. This assay has acceptable accuracy (92.07–105.39%), intra-day and inter-day precisions [relative standard deviation (RSD), 2.64–4.40%], as well as intra-plate and inter-plate precisions (RSD, 1.8–4.9%). Conclusion The developed method is rapid, simple, stable, and specific for screening and estimation of the potential Lipase Inhibitors. Copyright © 2015 John Wiley & Sons, Ltd.

Jihe Tang - One of the best experts on this subject based on the ideXlab platform.

  • direct coupling of thin layer chromatography bioautography with electrostatic field induced spray ionization mass spectrometry for separation and identification of Lipase Inhibitors in lotus leaves
    Analytica Chimica Acta, 2017
    Co-Authors: Lei Zhang, Jihe Tang, Zhihong Cheng, Yao Kong, Xiaohui Lu, Tao Wu
    Abstract:

    Abstract In situ profiling compounds in complex matrices is important technology to develop in analytic chemistry. The aim of this study is to develop a direct coupling method of thin layer chromatography (TLC) to mass spectrometry (MS) via electrostatic field induced spray ionization (EFISI). We proposed a surface treatment method of normal-phase thin layer chromatography (TLC) plates with dimethyl silicone oil coating which successfully allowed TLC to couple to MS via EFISI. Different parameters affecting the ionization efficiency were investigated and optimized, including silicone oil concentrations, air-drying times, applied voltages, and TLC plate types. This optimized TLC-EFISI-MS method was successfully applied to examine Lipase inhibitory components present in lotus leaves. Six active alkaloids including three aporphines and three benzylisoquinolines were profiled with their MS n ( n  = 4) data, or with a comparison with reference substances. This is the first report on the coupling EFISI-MS to TLC or TLC bioautography for in situ identification of active natural products.

  • direct coupling of thin layer chromatography bioautography with electrostatic field induced spray ionization mass spectrometry for separation and identification of Lipase Inhibitors in lotus leaves
    Analytica Chimica Acta, 2017
    Co-Authors: Lei Zhang, Jihe Tang, Zhihong Cheng, Jiyao Shi, Yao Kong
    Abstract:

    In situ profiling compounds in complex matrices is important technology to develop in analytic chemistry. The aim of this study is to develop a direct coupling method of thin layer chromatography (TLC) to mass spectrometry (MS) via electrostatic field induced spray ionization (EFISI). We proposed a surface treatment method of normal-phase thin layer chromatography (TLC) plates with dimethyl silicone oil coating which successfully allowed TLC to couple to MS via EFISI. Different parameters affecting the ionization efficiency were investigated and optimized, including silicone oil concentrations, air-drying times, applied voltages, and TLC plate types. This optimized TLC-EFISI-MS method was successfully applied to examine Lipase inhibitory components present in lotus leaves. Six active alkaloids including three aporphines and three benzylisoquinolines were profiled with their MSn (n = 4) data, or with a comparison with reference substances. This is the first report on the coupling EFISI-MS to TLC or TLC bioautography for in situ identification of active natural products.

  • a new tlc bioautographic assay for qualitative and quantitative estimation of Lipase Inhibitors
    Phytochemical Analysis, 2016
    Co-Authors: Jihe Tang, Jinge Zhou, Qingjiu Tang, Zhihong Cheng
    Abstract:

    Introduction Lipase inhibitory assays based on TLC bioautography have made recent progress; however, an assay with greater substrate specificity and quantitative capabilities would advance the efficacy of this particular bioassay. Objective To address these limitations, a new TLC bioautographic assay for detecting Lipase Inhibitors was developed and validated in this study. Methods The new TLC bioautographic assay was based on reaction of Lipase with β-naphthyl myristate and the subsequent formation of the purple dye between β-naphthol and Fast Blue B salt (FBB). The relative Lipase inhibitory capacity (RLIC) was determined by a TLC densitometry with fluorescence detection, expressed as orlistat equivalents in millimoles on a per sample weight basis. Six pure compounds and three natural extracts were evaluated for their potential Lipase inhibitory activities by this TLC bioautographic assay. Results The β-naphthyl myristate as the substrate improved the detection sensitivity and specificity significantly. The limit of detection (LOD) of this assay was 0.01 ng for orlistat, the current treatment for obesity. This assay has acceptable accuracy (92.07–105.39%), intra-day and inter-day precisions [relative standard deviation (RSD), 2.64–4.40%], as well as intra-plate and inter-plate precisions (RSD, 1.8–4.9%). Conclusion The developed method is rapid, simple, stable, and specific for screening and estimation of the potential Lipase Inhibitors. Copyright © 2015 John Wiley & Sons, Ltd.

Hui Deng - One of the best experts on this subject based on the ideXlab platform.

  • Monoacylglycerol Lipase Inhibitors: modulators for lipid metabolism in cancer malignancy, neurological and metabolic disorders.
    Acta pharmaceutica Sinica. B, 2019
    Co-Authors: Hui Deng
    Abstract:

    Abstract Monoacylglycerol Lipase (MAGL) is a serine hydrolase that plays a crucial role catalysing the hydrolysis of monoglycerides into glycerol and fatty acids. It links the endocannabinoid and eicosanoid systems together by degradation of the abundant endocannabinoid 2-arachidaoylglycerol into arachidonic acid, the precursor of prostaglandins and other inflammatory mediators. MAGL Inhibitors have been considered as important agents in many therapeutic fields, including anti-nociceptive, anxiolytic, anti-inflammatory, and even anti-cancer. Currently, ABX-1431, a first-in-class inhibitor of MAGL, is entering clinical phase 2 studies for neurological disorders and other diseases. This review summarizes the diverse (patho)physiological roles of MAGL and will provide an overview on the development of MAGL Inhibitors. Although a large number of MAGL Inhibitors have been reported, novel Inhibitors are still required, particularly reversible ones.

  • structure kinetics relationships and molecular dynamics show crucial role for heterocycle leaving group in irreversible diacylglycerol Lipase Inhibitors
    Journal of Medicinal Chemistry, 2019
    Co-Authors: Antonius P A Janssen, Jacob M A Van Hengst, Olivier J M Bequignon, Gerard J P Van Westen, Hui Deng, Mario Van Der Stelt
    Abstract:

    Drug discovery programs of covalent irreversible, mechanism-based enzyme Inhibitors often focus on optimization of potency as determined by IC50-values in biochemical assays. These assays do not allow the characterization of the binding activity (Ki) and reactivity (kinact) as individual kinetic parameters of the covalent Inhibitors. Here, we report the development of a kinetic substrate assay to study the influence of the acidity (pKa) of heterocyclic leaving group of triazole urea derivatives as diacylglycerol Lipase (DAGL)-α Inhibitors. Surprisingly, we found that the reactivity of the Inhibitors did not correlate with the pKa of the leaving group, whereas the position of the nitrogen atoms in the heterocyclic core determined to a large extent the binding activity of the inhibitor. This finding was confirmed and clarified by molecular dynamics simulations on the covalently bound Michaelis–Menten complex. A deeper understanding of the binding properties of covalent serine hydrolase Inhibitors is expecte...

  • activity based protein profiling reveals off target proteins of the faah inhibitor bia 10 2474
    Science, 2017
    Co-Authors: Annelot C M Van Esbroeck, Antonius P A Janssen, Daisuke Ogasawara, Marc P Baggelaar, Armand B Cognetta, Guy Shpak, Mark Van Der Kroeg, Vasudev Kantae, Femke M S De Vrij, Hui Deng
    Abstract:

    A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH Inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomic methods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several Lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous Lipase Inhibitors have the potential to cause metabolic dysregulation in the nervous system.

  • triazole ureas act as diacylglycerol Lipase Inhibitors and prevent fasting induced refeeding
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Hui Deng, Sander Kooijman, Adrianus M C H Van Den Nieuwendijk, Daisuke Ogasawara, Floris Van Dalen, Marc P Baggelaar, Freek J Janssen, Richard J B H N Van Den Berg, Hans Den Dulk, Benjamin F Cravatt
    Abstract:

    Triazole ureas constitute a versatile class of irreversible Inhibitors that target serine hydrolases in both cells and animal models. We have previously reported that triazole ureas can act as selective and CNS-active Inhibitors for diacylglycerol Lipases (DAGLs), enzymes responsible for the biosynthesis of 2-arachidonoylglycerol (2-AG) that activates cannabinoid CB1 receptor. Here, we report the enantio- and diastereoselective synthesis and structure–activity relationship studies. We found that 2,4-substituted triazole ureas with a biphenylmethanol group provided the most optimal scaffold. Introduction of a chiral ether substituent on the 5-position of the piperidine ring provided ultrapotent inhibitor 38 (DH376) with picomolar activity. Compound 38 temporarily reduces fasting-induced refeeding of mice, thereby emulating the effect of cannabinoid CB1-receptor inverse agonists. This was mirrored by 39 (DO34) but also by the negative control compound 40 (DO53) (which does not inhibit DAGL), which indicates...

  • triazole ureas act as diacylglycerol Lipase Inhibitors and prevent fasting induced refeeding
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Hui Deng, Sander Kooijman, Daisuke Ogasawara, Marc P Baggelaar, Freek J Janssen, Adrianus M C H Van Den Nieuwendijk, Tom Van Der Wel, Floris Van Dalen, Richard J B H N Van Den Berg, Hans Den Dulk
    Abstract:

    Triazole ureas constitute a versatile class of irreversible Inhibitors that target serine hydrolases in both cells and animal models. We have previously reported that triazole ureas can act as selective and CNS-active Inhibitors for diacylglycerol Lipases (DAGLs), enzymes responsible for the biosynthesis of 2-arachidonoylglycerol (2-AG) that activates cannabinoid CB1 receptor. Here, we report the enantio- and diastereoselective synthesis and structure-activity relationship studies. We found that 2,4-substituted triazole ureas with a biphenylmethanol group provided the most optimal scaffold. Introduction of a chiral ether substituent on the 5-position of the piperidine ring provided ultrapotent inhibitor 38 (DH376) with picomolar activity. Compound 38 temporarily reduces fasting-induced refeeding of mice, thereby emulating the effect of cannabinoid CB1-receptor inverse agonists. This was mirrored by 39 (DO34) but also by the negative control compound 40 (DO53) (which does not inhibit DAGL), which indicates the triazole ureas may affect the energy balance in mice through multiple molecular targets.

Yao Kong - One of the best experts on this subject based on the ideXlab platform.