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Human carboxylesterase

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https://www.readbyqxmd.com/read/29321244/silencing-carboxylesterase-1-in-human-thp-1-macrophages-perturbs-genes-regulated-by-pparg-rxr-and-rar-rxr-downregulation-of-cyp27a1-lxr%C3%AE-signaling
#1
Lee C Mangum, Xiang Hou, Abdolsamad Borazjani, Jung Hwa Lee, Matthew K Ross, J Allen Crow
Macrophage foam cells store excess cholesterol as cholesteryl esters, which need to be hydrolyzed for cholesterol efflux. We recently reported that silencing expression of carboxylesterase 1 (CES1) in human THP-1 macrophages (CES1KD macrophages) reduced cholesterol uptake and decreased expression of CD36 and scavenger receptor-A in cells loaded with acetylated low-density lipoprotein (acLDL). Here, we report that CES1KD macrophages exhibit reduced transcription of cytochrome P450 27A1 ( CYP27A1 ) in non-loaded and acLDL-loaded cells...
January 10, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29310316/fluorescein-diacetate-fda-and-its-analogue-as-substrates-for-pi-class-glutathione-s-transferase-gstp1-and-their-biological-application
#2
Yuuta Fujikawa, Taiki Nampo, Masaya Mori, Manami Kikkawa, Hideshi Inoue
Pi class glutathione S-transferase (GSTP1) is highly expressed in various cancerous cells and pre-neoplastic legions, where it is involved in apoptotic resistance or metabolism of several anti-tumour chemotherapeutics. Therefore, GSTP1 is a marker of malignant and pre-malignant cells and is a promising target for visualization and drug development. Here we demonstrate that fluorescein diacetate (FDA), a fluorescent probe used for vital staining, is a fluorescently activated by esterolytic activity of human GSTP1 (hGSTP1) selectively among various cytosolic GSTs...
March 1, 2018: Talanta
https://www.readbyqxmd.com/read/29289670/a-novel-quantification-method-for-serine-hydrolases-in-cellular-expression-system-using-fluorophosphonate-biotin-probe
#3
Amira Abdel-Daim, Kayoko Ohura, Teruko Imai
In the present study, we established a quantitative western blotting method to measure the expression level of recombinant serine hydrolases based on their catalytic mechanism. Fluorophosphonate (FP) biotin was selected as a universal probe to quantify their expression level, since FP moiety irreversibly inhibits serine hydrolases through strong stoichiometric binding to active serine residue. The linearity of detection using FP-biotin was assessed on three serine hydrolases; human carboxylesterase (CES) 1, butyrylcholinesterase and porcine liver esterases (PLE)...
December 28, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29240983/human-ugt2b7-is-the-major-isoform-responsible-for-the-glucuronidation-of-clopidogrel-carboxylate
#4
Jin-Zi Ji, Bei-Bei Huang, Tong-Tong Gu, Ting Tai, Huan Zhou, Yu-Meng Jia, Qiong-Yu Mi, Meng-Ran Zhang, Hong-Guang Xie
Clopidogrel is predominantly hydrolyzed to clopidogrel carboxylic acid (CCA) by carboxylesterase 1, and subsequently CCA is glucuronidated to clopidogrel aryl glucuronide (CAG) by uridine diphosphate-glucuronosyltransferases (UGTs); however, the UGT isoenzymes glucuronidating CCA remain unidentified to date. In this study, the glucuronidation of CCA was screened with pooled human liver microsomes (HLMs) and 7 human recombinant UGT (rUGT) isoforms. Results indicated that rUGT2B7 exhibited the highest catalytical activity for the CCA glucuronidation as measured with a mean Vmax value of 120...
December 14, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29210644/carboxylesterase-inhibitors-an-update
#5
Li-Wei Zou, Qiang Jin, Dan-Dan Wang, Qing-Kai Qian, Da-Cheng Hao, Guang-Bo Ge, Ling Yang
Mammalian carboxylesterases are key serine hydrolases that catalyze the hydrolysis of a wide variety of ester compounds into the corresponding carboxylic acids and alcohols. In human, two major carboxylesterases, CES1 and CES2, have been identified and well-studied over the past decade. CES1 inhibitors have potential applications in the treatment of hypertriglyceridaemia, obesity and type 2 diabetes, owing to that this enzyme plays prominent role in the metabolism of cholesteryl esters. CES2 plays crucial roles in the metabolic activation of many prodrugs including anticancer agents capecitabine and CPT-11...
December 4, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29209217/arylacetamide-deacetylase-is-involved-in-vicagrel-bioactivation-in-humans
#6
Jinfang Jiang, Xiaoyan Chen, Dafang Zhong
Vicagrel, a structural analog of clopidogrel, is now being developed as a thienopyridine antiplatelet agent in a phase II clinical trial in China. Some studies have shown that vicagrel undergoes complete first-pass metabolism in human intestine, generating the hydrolytic metabolite 2-oxo-clopidogrel via carboxylesterase-2 (CES2) and subsequently the active metabolite H4 via CYP450s. This study aimed to identify hydrolases other than CES2 that are involved in the bioactivation of vicagrel in human intestine...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29183156/a-bioactive-new-protostane-type-triterpenoid-from-alisma-plantago-aquatica-subsp-orientale-sam-sam
#7
Ya-Li Wang, Jian-Chao Zhao, Jia-Hao Liang, Xiang-Ge Tian, Xiao-Kui Huo, Lei Feng, Jing Ning, Chao Wang, Bao-Jing Zhang, Gang Chen, Ning Li, Cheng-Peng Sun
A new protostane-type triterpenoid, 5β,29-dihydroxy alisol A (1) was isolated from Alisma plantago-aquatica subsp. orientale (Sam.) Sam. as well as 12-deoxyphorbol-13α-pentadecanoate (2). We first report the presence of compound 2 in the genus Alisma. Their structures were established on the basis of 1D and 2D NMR, and HRESIMS spectroscopic analyses. All the isolated compounds were assayed for their inhibitory effects against human carboxylesterase 2 (HCE-2). Compounds 1 and 2 displayed inhibitory activities against HCE-2 with IC50 values of 29...
November 28, 2017: Natural Product Research
https://www.readbyqxmd.com/read/29175444/17%C3%AE-estradiol-suppresses-carboxylesterases-by-activating-c-jun-ap-1-pathway-in-primary-human-and-mouse-hepatocytes
#8
Lili Wu, Muhammad Zubair Hafiz, Yu Guan, Shuangcheng He, Jing Xiong, Wei Liu, Bingfang Yan, Xiaoping Li, Jian Yang
In order to study the influence of estrogen on carboxylesterases, we investigated the effects of 17β-estradiol on CES1 (Ces1d) and CES2 (Ces1e) in human and mouse hepatocytes. After being treated with 17β-estradiol, the mRNA levels of CES1 and CES2 decreased by 29~39% and 28~55%, respectively, in the human hepatocytes from four donors. Consistently, the hydrolysis of para-nitrophenylacetate decreased markedly by 32% induced by 17β-estradiol. Moreover, 17β-estradiol decreased CES1 and CES2 by 45% and 47% respectively at protein levels...
November 22, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29155040/radiolabelled-soman-binding-to-sera-from-rats-guinea-pigs-and-monkeys
#9
David E Lenz, Douglas Cerasoli, Donald M Maxwell
Soman is a highly toxic organophosphorus chemical warfare compound that binds rapidly and irreversibility to a variety of serine active enzymes, i.e., butyryl- and acetyl-cholinesterases and carboxylesterase. The in vivo toxicity of soman has been reported to vary significantly in different animal species, such as rats and guinea pigs or non-human primates. This species variation makes it difficult to identify appropriate animal models for therapeutic drug development under the US Food and Drug Administration (FDA) Animal Rule...
November 15, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/29113833/the-role-of-genetic-background-in-susceptibility-to-chemical-warfare-nerve-agents-across-rodent-and-non-human-primate-models
#10
REVIEW
Liana M Matson, Hilary S McCarren, C Linn Cadieux, Douglas M Cerasoli, John H McDonough
Genetics likely play a role in various responses to nerve agent exposure, as genetic background plays an important role in behavioral, neurological, and physiological responses to environmental stimuli. Mouse strains or selected lines can be used to identify susceptibility based on background genetic features to nerve agent exposure. Additional genetic techniques can then be used to identify mechanisms underlying resistance and sensitivity, with the ultimate goal of developing more effective and targeted therapies...
November 4, 2017: Toxicology
https://www.readbyqxmd.com/read/29073340/liver-targeted-small-molecule-inhibitors-of-proprotein-convertase-subtilisin-kexin-type-9-synthesis
#11
Kim Francis McClure, David W Piotrowski, Donna Petersen, Liuqing Wei, Jun Xiao, Allyn T Londregan, Adam Kamlet, Anne-Marie Dechert-Schmitt, Brian Raymer, Roger B Ruggeri, Daniel Canterbury, Chris Limberakis, Spiros Liras, Paul DaSilva-Jardine, Robert G Dullea, Paula M Loria, Benjamin Reidich, Christopher T Salatto, Heather Eng, Emi Kimoto, Karen Atkinson, Amanda King-Ahmad, Dennis Scott, Kevin Beaumont, Jeffrey R Chabot, Michael Bolt, Kevin Maresca, Kenneth Dahl, Ryosuke Arakawa, Akihiro Takano, Christer Halladin
Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. Herein we describe a liver-targeted drug candidate that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved via prodrugs susceptible to cleavage by carboxylesterase 1...
October 26, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/29054529/development-of-amide-based-fluorescent-probes-for-selective-measurement-of-carboxylesterase-1-activity-in-tissue-extracts
#12
Sean D Kodani, Morgane Barthélemy, Shizuo G Kamita, Bruce Hammock, Christophe Morisseau
Carboxylesterases are well known for their role in the metabolism of xenobiotics. However, recent studies have also implicated carboxylesterases in regulating a number of physiological processes including metabolic homeostasis and macrophage development, underlying the need to quantify them individually. Unfortunately, current methods for selectively measuring the catalytic activity of individual carboxylesterases are not sufficiently sensitive to support many biological studies. In order to develop a more sensitive and selective method to measure the activity of human carboxylesterase 1 (hCE1), we generated and tested novel substrates with a fluorescent aminopyridine leaving group...
December 15, 2017: Analytical Biochemistry
https://www.readbyqxmd.com/read/29029320/insecticidal-mechanism-of-wintergreen-oil-against-the-health-pest-paederus-fuscipes-coleoptera-staphylinidae
#13
Zhiping Liu, Qiang Zhang, Xuan Wu, Wei Yu, Shengquan Guo
Paederus fuscipes, a health pest, causes dermatitis linearis in humans. Wintergreen oil exhibits optimal insecticidal activity against P. fuscipes. However, the insecticidal mechanism remains unclear not only in P. fuscipes but also in other pests. In this study, we explored the insecticidal mechanism of wintergreen oil in terms of its effect on the activity of acetylcholinesterase (AChE) enzyme and detoxifying enzymes (carboxylesterase, glutathione-S-transferase, and mixed function oxidase); such effect was studied by fumigation both in vivo and in vitro in P...
October 4, 2017: Journal of Medical Entomology
https://www.readbyqxmd.com/read/28985084/controlling-plasma-stability-of-hydroxamic-acids-a-medchem-toolbox
#14
Paul Hermant, Damien Bosc, Catherine Piveteau, Ronan Gealageas, BaoVy Lam, Cyril Ronco, Matthieu Roignant, Hasina Tolojanahary, Ludovic Jean, Pierre-Yves Renard, Mohamed Lemdani, Marilyne Bourotte, Adrien Herledan, Corentin Bedart, Alexandre Biela, Florence Leroux, Benoit Deprez, Rebecca Deprez-Poulain
Hydroxamic acids are outstanding zinc chelating groups that can be used to design potent and selective metalloenzyme inhibitors in various therapeutic areas. Some hydroxamic acids display a high plasma clearance resulting in poor in vivo activity, though they may be very potent compounds in vitro. We designed a 57-member library of hydroxamic acids to explore the structure-plasma stability relationships in these series and to identify which enzyme(s) and which pharmacophores are critical for plasma stability...
October 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28966098/difference-in-substrate-specificity-of-carboxylesterase-and-arylacetamide-deacetylase-between-dogs-and-humans
#15
Tomohiro Yoshida, Tatsuki Fukami, Takaya Kurokawa, Saki Gotoh, Akifumi Oda, Miki Nakajima
Carboxylesterase (CES) and arylacetamide deacetylase (AADAC) are the major enzymes responsible for the hydrolysis of various clinical drugs. Our recent study demonstrated that the identity of the responsible hydrolase can be roughly surmised based on the chemical structures of compounds in humans. Dogs are used for preclinical studies in drug development, but the substrate specificities of dog CES and AADAC remain to be clarified. The purpose of this study is to characterize their substrate specificities. We prepared recombinant dog CES1, CES2, and AADAC...
January 1, 2018: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28838926/a-comprehensive-functional-assessment-of-carboxylesterase-1-nonsynonymous-polymorphisms
#16
Xinwen Wang, Nada Rida, Jian Shi, Audrey H Wu, Barry E Bleske, Hao-Jie Zhu
Carboxylesterase 1 (CES1) is the predominant human hepatic hydrolase responsible for the metabolism of many clinically important medications. CES1 expression and activity vary markedly among individuals; and genetic variation is a major contributing factor to CES1 interindividual variability. In this study, we comprehensively examined the functions of CES1 nonsynonymous single nucleotide polymorphisms (nsSNPs) and haplotypes using transfected cell lines and individual human liver tissues. The 20 candidate variants include CES1 nsSNPs with a minor allele frequency >0...
November 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28820941/a-photoactivatable-probe-for-super-resolution-imaging-of-enzymatic-activity-in-live-cells
#17
Elias A Halabi, Zacharias Thiel, Nils Trapp, Dorothea Pinotsi, Pablo Rivera-Fuentes
A dual-activatable, fluorogenic probe was developed to sense esterase activity with single-molecule resolution. Without enzymatic pre-activation, the diazoindanone-based probe has an electron-poor core and, upon irradiation, undergoes Wolff rearrangement to give a ring-expanded xanthene core that is nonemissive. If the probe is pre-activated by carboxylesterases, the tricyclic core becomes electron-rich, and the photoinduced Wolff rearrangement produces a highly emissive rhodol dye. Live-cell and solution studies confirmed the selectivity of the probe and revealed that the photoactivated dye does not diffuse away from the original location of activation because the intermediate ketene forms a covalent bond with surrounding macromolecules...
September 5, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28782481/rational-approaches-design-strategies-structure-activity-relationship-and-mechanistic-insights-for-esterase-inhibitors
#18
Harbinder Singh, Jatinder Vir Singh, Navdeep Kaur, Mohit Sanduja, Gurpreet Singh, Preet Mohinder Singh Bedi, Sahil Sharma
BACKGROUND: Esterase is an enzyme that splits esters into an acid and alcohol. Varieties of esterases are present in human body to control diverse set of cellular processes and execute their specific functions. It can be seen that any increase in metabolites produced by these enzymes lead to severe pathological conditions like Alzheimer disease, hypercholesterolemia etc. OBJECTIVE: Numerous esterase inhibitors have been developed and reported by the researchers around the globe, but not systematically summarized yet...
August 7, 2017: Mini Reviews in Medicinal Chemistry
https://www.readbyqxmd.com/read/28760607/phenolic-glycosides-and-monoterpenoids-from-the-roots-of-euphorbia-ebracteolata-and-their-bioactivities
#19
An-Hua Wang, Xiao-Kui Huo, Lei Feng, Cheng-Peng Sun, Sa Deng, Hou-Li Zhang, Bao-Jing Zhang, Xiao-Chi Ma, Jing-Ming Jia, Chao Wang
The bioactive substance investigation of Euphorbia ebracteolata obtained 17 compounds by various chromatographic techniques. Their structures were elucidated using widely spectroscopic data, including ESI-MS, HRESI-MS, CD, 1D- and 2D-NMR, which gave 5 new phenolic glucosides and 4 new monoterpenoids. The phenolic glucosides and monoterpenoids showed the inhibitory effect against the human carboxylesterase-2 (hCE-2) using a fluorescence bioassay in vitro, with the strongest inhibitor compound 4 (IC50 7.17μM)...
September 2017: Fitoterapia
https://www.readbyqxmd.com/read/28737453/the-metabolism-and-drug-drug-interaction-potential-of-the-selective-prostacyclin-receptor-agonist-selexipag
#20
Carmela Gnerre, Jérôme Segrestaa, Swen Seeland, Päivi Äänismaa, Thomas Pfeifer, Stephane Delahaye, Ruben de Kanter, Tomohiko Ichikawa, Tetsuhiro Yamada, Alexander Treiber
- The metabolism of selexipag has been studied in vivo in man and the main excreted metabolites were identified. Also, metabolites circulating in human plasma have been structurally identified and quantified. - The main metabolic pathway of selexipag in man is the formation of the active metabolite ACT-333679. Other metabolic pathways include oxidation and dealkylation reactions. All primary metabolites undergo subsequent hydrolysis of the sulphonamide moiety to their corresponding acids. ACT-333679 undergoes conjugation with glucuronic acid and aromatic hydroxylation to P10, the main metabolite detected in human faeces...
July 24, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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