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Jie Li, Domenico Bullara, Xuewen Du, Hongjian He, Stavroula Sofou, Ioannis G Kevrekidis, Irving R Epstein, Bing Xu
Recent studies have demonstrated that enzyme-instructed self-assembly (EISA) in extra- or intracellular environments can serve as a multistep process for controlling cell fate. There is little knowledge, however, about the kinetics of EISA in the complex environments in or around cells. Here we design and synthesize three dipeptidic precursors (LD-1-SO3, DL-1-SO3, DD-1-SO3), consisting of diphenylalanine (L-Phe-D-Phe, D-Phe-L-Phe, D-Phe-D-Phe, respectively) as the backbone, which are capped by 2-(naphthalen-2-yl)acetic acid at the N-terminal and by 2-(4-(2-aminoethoxy)-4-oxobutanamido)ethane-1-sulfonic acid at the C- 2 terminal...
March 14, 2018: ACS Nano
Laura Hedges, Susan Brown, Audrey Vardy, Edward Doyle, Miyoung Yoon, Thomas G Osimitz, Brian G Lake
1. The metabolism of deltamethrin (DLM), cis-permethrin (CPM) and trans-permethrin (TPM) was studied in liver microsomes, liver cytosol and plasma from male Sprague-Dawley rats aged 15, 21 and 90 days and from adult humans. 2. DLM and CPM were metabolised by rat hepatic microsomal cytochrome P450 (CYP) enzymes and to a lesser extent by microsomal and cytosolic carboxylesterase (CES) enzymes, whereas TPM was metabolised to a greater extent by CES enzymes. 3. In human liver, DLM and TPM were mainly metabolised by CES enzymes, whereas CPM was metabolised by CYP and CES enzymes...
March 14, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Ailing Hui, Huayang Yin, Zheng Zhang, An Zhou, Jingchao Chen, Li Yang, Zeyu Wu, Wencheng Zhang
Tetramethylpyrazine was introduced to the structure of danshensu (DSS) as P-glycoprotein (P-gp)-inhibiting carrier, designing some novel brain-targeting DSS-pyrazine derivatives via prodrug delivery strategy. Following the virtual screening, three DSS-pyrazine esters (DT1, DT2, DT3) were selected because of their better prediction parameters related to brain-targeting. Among them, DT3 was thought to be a promising candidate due to its appropriate bioreversible property in vitro release assay. Further investigation with regard to DT3's brain-targeting effects in vivo was also reported in this study...
March 9, 2018: Drug Delivery and Translational Research
Femke M de Man, Andrew K L Goey, Ron H N van Schaik, Ron H J Mathijssen, Sander Bins
Since its clinical introduction in 1998, the topoisomerase I inhibitor irinotecan has been widely used in the treatment of solid tumors, including colorectal, pancreatic, and lung cancer. Irinotecan therapy is characterized by several dose-limiting toxicities and large interindividual pharmacokinetic variability. Irinotecan has a highly complex metabolism, including hydrolyzation by carboxylesterases to its active metabolite SN-38, which is 100- to 1000-fold more active compared with irinotecan itself. Several phase I and II enzymes, including cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase (UGT) 1A, are involved in the formation of inactive metabolites, making its metabolism prone to environmental and genetic influences...
March 8, 2018: Clinical Pharmacokinetics
Yitao Chen, Yangsheng Wu, Yuanxiao Yang, Zhiwei Xu, Junfeng Tong, Zheming Li, Xiaojie Zhou, Changyu Li
The main actions of metformin are as follows: To reduce hyperglycemia via the suppression of gluconeogenesis, improve glucose uptake and insulin sensitivity, and stimulate activation of adenosine monophosphate‑activated protein kinase during the treatment of diabetes mellitus. It is well known that metformin acts via complex mechanisms, including multitarget and multipathway mechanisms; however, the multitargeted antidiabetic genes of metformin remain obscure. The present study aimed to perform transcriptomic and proteomic analysis of potential therapeutic target genes in the liver of metformin‑treated Sprague‑Dawley rats with type 2 diabetes mellitus...
March 6, 2018: International Journal of Molecular Medicine
Antonino Biundo, Doris Ribitsch, Georg M Guebitz
Certain members of the carboxylesterase superfamily can act at the interface between water and water-insoluble substrates. However, nonnatural bulky polyesters usually are not efficiently hydrolyzed. In the recent years, the potential of enzyme engineering to improve hydrolysis of synthetic polyesters has been demonstrated. Regions on the enzyme surface have been modified by using site-directed mutagenesis in order to tune sorption processes through increased hydrophobicity of the enzyme surface. Such modifications can involve specific amino acid substitutions, addition of binding modules, or truncation of entire domains improving sorption properties and/or dynamics of the enzyme...
March 6, 2018: Applied Microbiology and Biotechnology
Masato Takahashi, Tomohiro Ogawa, Hiroshi Kashiwagi, Fumiya Fukushima, Misaki Yoshitsugu, Masami Haba, Masakiyo Hosokawa
It is necessary to consider the affinity of prodrugs for metabolic enzymes for efficient activation of the prodrugs in the body. Although many prodrugs have been synthesized with consideration of these chemical properties, there has been little study on the design of a structure with consideration of biological properties such as substrate recognition ability of metabolic enzymes. In this report, chemical synthesis and evaluation of indomethacin prodrugs metabolically activated by human carboxylesterase 1 (hCES1) are described...
February 21, 2018: Bioorganic & Medicinal Chemistry Letters
Randall J Binder, M Jason Hatfield, Liying Chi, Philip M Potter
Recently, a series of selective human carboxylesterase inhibitors have been identified based upon the tanshinones, with biologically active molecules containing a 1,2-dione group as part of a naphthoquinone core. Unfortunately, the synthesis of such compounds is complex. Here we describe a novel method for the generation of 1,2-dione containing diterpenoids using a unified approach, by which boronic acids are joined to vinyl bromo-cyclohexene derivatives via Suzuki coupling, followed by electrocyclization and oxidation to the o-phenanthroquinones...
February 19, 2018: European Journal of Medicinal Chemistry
Juan C Sanchez-Hernandez, Juan Manuel Ríos, Andrés M Attademo
Assessment of organophosphorus (OP) pesticide exposure in non-target organisms rarely involves non-neural molecular targets. Here we performed a 30-d microcosm experiment with Lumbricus terrestris to determine whether the activity of digestive enzymes (phosphatase, β-glucosidase, carboxylesterase and lipase) was sensitive to chlorpyrifos (5 mg kg-1 wet soil). Likewise, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were measured in the wall muscle and gastrointestinal tissues as indicators of OP exposure...
March 1, 2018: Ecotoxicology
Li Liu, Chaoqun Sun, Juan Yang, Ying Shi, Yijuan Long, Huzhi Zheng
We found that fluorescein possessed high visible-light-induced oxidase mimetic activity and could transform colorless 3,3',5,5'-tetramethylbenzidine (TMB) into blue oxidized TMB (oxTMB) without unstable and destructive H2O2 under visible light illumination. Instead, fluorescein uses oxygen as a mild and green electron acceptor, and its activity can be easily controlled by the switching "on/off" of visible light. In addition, the visible-light-induced catalytic mechanism was elucidated in detail and, as the main reactive species h+ and O2*- accounted for TMB oxidation...
February 28, 2018: Chemistry: a European Journal
Juan C Sanchez-Hernandez
The activation of biochar (carbonaceous material generated by pyrolysis of biomass) with extracellular enzymes generated from soil biological processes was studied via a 2-month microcosm using earthworms. The isolation of biochar particles (post-incubated biochar) from earthworm-treated soils allowed to confirm an enrichment of biochar with extracellular enzymes associated to biogeochemical (alkaline phosphatase, β-glucosidase and arylsulfatase) and bioremediation pathways (carboxylesterase). The hydrolytic activity of this biochar incubated with earthworms was up to 8 times higher compared with that of control biochar (incubated in earthworm-free soils)...
February 12, 2018: Journal of Hazardous Materials
Jia-Nan Li, Yun-Feng Cao, Rong-Rong He, Guang-Bo Ge, Bin Guo, Jing-Jing Wu
Shikonin, a natural naphthoquinone compound derived from the herb Lithospermum erythrorhizon, is widely used for its various pharmacological activities. However, its potential interactions with other medications by inhibiting human carboxylesterases 2 (hCE2) remain unknown. In this study, the inhibitory effects of shikonin on the activity of hCE2 in human liver microsomes are investigated by using fluorescein diacetate (FD), N-(2-butyl-1,3-dioxo-2,3-dihydro-1H-phenalen-6-yl)-2-chloroacetamide (NCEN), and CPT-11 as substrates of hCE2...
February 22, 2018: Phytotherapy Research: PTR
Zongxi Sun, Yali Wu, Bing Yang, Baochen Zhu, Shaonan Hu, Yang Lu, Bo Zhao, Shouying Du
Herb-drug interactions are important safety concerns in clinical practice. The interactions occur firstly in the intestinal absorption for orally administered drugs. Aspirin and Panax notoginseng saponins (PNS)-based drugs are often combined in China to prevent larger-artery atherosclerosis. Here, we aimed to characterize the aspirin transport across Caco-2 cell monolayers, a model of the intestinal absorption, and further to evaluate the influence of PNS on aspirin hydrolysis and the relating mechanisms. Transcellular transport of aspirin and the influence of PNS were explored using Caco-2 cell monolayers...
February 18, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Kristina Forsch, Verena Schöning, Lucia Disch, Beate Siewert, Matthias Unger, Jürgen Drewe
ETHNOPHARMACOLOGICAL RELEVANCE: Pyrrolizidine alkaloids (PAs) are secondary plant ingredients formed in many plant species to protect against predators. PAs are generally considered acutely hepatotoxic, genotoxic and carcinogenic. Up to now, only few in vitro and in vivo investigations were performed to evaluate their relative toxic potential. AIM OF THE STUDY: The aim was to develop an in vitro screening method of their cytotoxicity. MATERIALS AND METHODS: Human and rodent hepatocyte cell lines (HepG2 and H-4-II-E) were used to assess cytotoxicity of the PA lasiocarpine...
February 14, 2018: Journal of Ethnopharmacology
Henrik Berg Rasmussen, Majbritt Busk Madsen
The carboxylesterase 1 gene (CES1) encodes a hydrolase that metabolizes commonly used drugs. The CES1-related pseudogene, carboxylesterase 1 pseudogene 1 (CES1P1), has been implicated in gene exchange with CES1 and in the formation of hybrid genes including the carboxylesterase 1A2 gene (CES1A2). Hence, the CES1 region is complex. Using in silico PCR and alignment, we assessed the specificity of PCR-assisted procedures for genotyping CES1, CES1A2 and CES1P1 in studies identified in PubMed. We identified 33 such studies and excluded those that were not the first to use a procedure or lacked sequence information...
February 10, 2018: Drug Metabolism and Personalized Therapy
Zi-Miao Weng, Guang-Bo Ge, Tong-Yi Dou, Ping Wang, Ping-Kun Liu, Xin-Hui Tian, Nan Qiao, Yang Yu, Li-Wei Zou, Qi Zhou, Wei-Dong Zhang, Jie Hou
Human carboxylesterases (hCEs) are key enzymes from the serine hydrolase superfamily. Among all identified hCEs, human carboxylesterase 2 (hCE2) plays crucial roles in the metabolic activation of ester drugs including irinotecan and flutamide. Selective and potent hCE2 inhibitors could be used to alleviate the toxicity induced by hCE2-substrate drugs. In this study, more than fifty flavonoids were collected to assay their inhibitory effects against hCE2 using a fluorescence-based method. The results demonstrated that C3 and C6 hydroxy groups were essential for hCE2 inhibition, while O-glycosylation or C-glycosylation would lead to the loss of hCE2 inhibition...
January 9, 2018: Bioorganic Chemistry
Jan Machal, Ota Hlinomaz
BACKGROUND: Various antiplatelet drugs are used following acute coronary syndromes (ACS). Of them, adenosine diphosphate receptor P2Y12 inhibitors clopidogrel, prasugrel and ticagrelor are currently used for post-ACS long-term treatment. Although they act on the same receptor, they differ in pharmacodynamics and pharmacokinetics. Several enzymes and transporters involved in the metabolism of P2Y12 inhibitors show genetic variability with functional impact. This includes P-glycoprotein, carboxylesterase 1 and, most notably, CYP2C19 that is important in clopidogrel activation...
February 5, 2018: Current Vascular Pharmacology
Morena Gabriele, Paola Puccini, Marco Lucchi, Anna Vizziello, Pier Giovanni Gervasi, Vincenzo Longo
Lungs are pharmacologically active organs and the pulmonary drug metabolism is of interest for inhaled drugs design. Carboxylesterases (CESs) are enzymes catalyzing the hydrolysis of many structurally different ester, amide and carbamate chemicals, including prodrugs. For the first time, the presence, kinetics, inhibition and inter-individual variations of the major liver CES isozymes (CES1 and CES2) were investigated in cytosol and microsomes of human lungs from 20 individuals using 4-nitrophenyl acetate (pNPA), 4-methylumbelliferyl acetate (4-MUA), and fluorescein diacetate (FD) as substrates the rates of hydrolysis (Vmax) for pNPA and 4-MUA, unlike FD, were double in microsomes than in cytosol...
January 29, 2018: Biochemical Pharmacology
Peter R Bradshaw, Ian D Wilson, Rachel Upcott Gill, Philip J Butler, Clive Dilworth, Toby J Athersuch
The release of aromatic amines from drugs and other xenobiotics resulting from the hydrolysis of metabolically labile amide bonds presents a safety risk through several mechanisms, including geno-, hepato- and nephrotoxicity. Whilst multiple in vitro systems used for studying metabolic stability display serine hydrolase activity, responsible for the hydrolysis of amide bonds, they vary in their efficiency and selectivity. Using a range of amide-containing probe compounds (0.5-10 µM), we have investigated the hydrolytic activity of several rat, minipig and human-derived in vitro systems - including Supersomes, microsomes, S9 fractions and hepatocytes - with respect to their previously observed human in vivo metabolism...
February 5, 2018: Scientific Reports
Jie Zhou, Xuewen Du, Cristina Berciu, Steven J Del Signore, Xiaoyi Chen, Natsuko Yamagata, Avital A Rodal, Daniela Nicastro, Bing Xu
Most of the peptides used for promoting cellular uptake bear positive charges. In our previous study, we reported an example of taurine (bearing negative charges in physiological conditions) promoting cellular uptake of D-peptides. Taurine, conjugated to a small D-peptide via an ester bond, promotes the cellular uptake of this D-peptide. Particularly, intracellular carboxylesterase (CES) instructs the D-peptide to self-assemble and to form nanofibers, which largely disfavors efflux and further enhances the intracellular accumulation of the D-peptide, as supported by that the addition of CES inhibitors partially impaired cellular uptake of this molecule in mammalian cell lines...
January 6, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
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