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#33595329   2021/02/17 To Up

Carboxylesterase Activities and Protein Expression in Rabbit and Pig Ocular Tissues.

Hydrolytic reactions constitute an important pathway of drug metabolism and a significant route of prodrug activation. Many ophthalmic drugs and prodrugs contain ester groups that greatly enhance their permeation across several hydrophobic barriers in the eye before the drugs are either metabolized or released, respectively, hydrolysis. Thus, the development of ophthalmic drug therapy requires the thorough profiling of substrate specificities, activities, and expression levels of ocular esterases. However, such information is scant in the literature, especially for preclinical species often used in ophthalmology such as rabbits and pigs. Therefore, our aim was to generate systematic information on the activity and expression of carboxylesterases (CESs) and arylacetamide deacetylase (AADAC) in seven ocular tissue homogenates from these two species. The hydrolytic activities were measured using a generic esterase substrate (4-nitrophenyl acetate) and, in the absence of validated substrates for rabbit and pig enzymes, with selective substrates established for human CES1, CES2, and AADAC (d-luciferin methyl ester, fluorescein diacetate, procaine, and phenacetin). Kinetics and inhibition studies were conducted using these substrates and, again due to a lack of validated rabbit and pig CES inhibitors, with known inhibitors for the human enzymes. Protein expression levels were measured using quantitative targeted proteomics. Rabbit ocular tissues showed significant variability in the expression of CES1 (higher in cornea, lower in conjunctiva) and CES2 (higher in conjunctiva, lower in cornea) and a poor correlation of CES expression with hydrolytic activities. In contrast, pig tissues appear to express only CES1, and CES3 and AADAC seem to be either low or absent, respectively, in both species. The current study revealed remarkable species and tissue differences in ocular hydrolytic enzymes that can be taken into account in the design of esterase-dependent prodrugs and drug conjugates, the evaluation of ocular effects of systemic drugs, and in translational and toxicity studies.
Anam Hammid, John K Fallon, Toni Lassila, Giulia Salluce, Philip C Smith, Ari Tolonen, Achim Sauer, Arto Urtti, Paavo Honkakoski

1582 related Products with: Carboxylesterase Activities and Protein Expression in Rabbit and Pig Ocular Tissues.

1000 TESTS/0.65ml200ul100ug Lyophilized100ug Lyophilized100ug Lyophilized100ug Lyophilized100ug Lyophilized100ug Lyophilized25mg100ug Lyophilized100ug Lyophilized100ug Lyophilized

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#33446525   2021/01/14 To Up

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Human arylacetamide deacetylase (AADAC) plays a role in the detoxification or activation of drugs and is sometimes involved in the incidence of toxicity by catalyzing hydrolysis reactions. AADAC prefers compounds with relatively small acyl groups, such as acetyl groups. Eslicarbazepine acetate, an antiepileptic drug, is a prodrug rapidly hydrolyzed to eslicarbazepine. We sought to clarify whether AADAC might be responsible for the hydrolysis of eslicarbazepine acetate. Eslicarbazepine acetate was efficiently hydrolyzed by human intestinal and liver microsomes and recombinant human AADAC. The hydrolase activities in human intestinal and liver microsomes were inhibited by epigallocatechin gallate, a specific inhibitor of AADAC, by 82% and 88% of the control, respectively. The hydrolase activities in liver microsomes from 25 human livers were significantly correlated ( = 0.87, < 0.001) with AADAC protein levels, suggesting that the enzyme AADAC is responsible for the hydrolysis of eslicarbazepine acetate. The effects of genetic polymorphisms of on eslicarbazepine acetate hydrolysis were examined by using the constructed recombinant AADAC variants with T74A, V172I, R248S, V281I, N366K, or X400Q. AADAC variants with R248S or X400Q showed lower activity than wild type (5% or 21%, respectively), whereas those with V172I showed higher activity than wild type (174%). Similar tendencies were observed in the other 4 substrates of AADAC; that is, -nitrophenyl acetate, ketoconazole, phenacetin, and rifampicin. Collectively, we found that eslicarbazepine acetate is specifically and efficiently hydrolyzed by human AADAC, and several polymorphic alleles would be a factor affecting the enzyme activity and drug response. This is the first study to clarify that AADAC is responsible for the activation of eslicarbazepine acetate, an antiepileptic prodrug, to eslicarbazepine, an active form, in the human liver and intestines. In addition, we found that several polymorphic alleles would be a factor affecting the enzyme activity and drug response.
Keiya Hirosawa, Tatsuki Fukami, Kiyomichi Tashiro, Yoshiyuki Sakai, Fumiya Kisui, Masataka Nakano, Miki Nakajima

1476 related Products with: .



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#33374006   // To Up

Decreased plasma rifapentine concentrations associated with AADAC single nucleotide polymorphism in adults with tuberculosis.

Rifapentine exposure is associated with bactericidal activity against Mycobacterium tuberculosis, but high interindividual variation in plasma concentrations is encountered.
Marc Weiner, Jon Gelfond, Teresa L Johnson-Pais, Melissa Engle, John L Johnson, William C Whitworth, Erin Bliven-Sizemore, Pheona Nsubuga, Susan E Dorman, Rada Savic,

1066 related Products with: Decreased plasma rifapentine concentrations associated with AADAC single nucleotide polymorphism in adults with tuberculosis.

1mg21 mg0.05 mg1mlUnit

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#33005292   // To Up

Identification of a nine-gene prognostic signature for gastric carcinoma using integrated bioinformatics analyses.

Gastric carcinoma (GC) is one of the most aggressive primary digestive cancers. It has unsatisfactory therapeutic outcomes and is difficult to diagnose early.
Kun-Zhe Wu, Xiao-Hua Xu, Cui-Ping Zhan, Jing Li, Jin-Lan Jiang

1535 related Products with: Identification of a nine-gene prognostic signature for gastric carcinoma using integrated bioinformatics analyses.

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#32943033   2020/09/17 To Up

Five gene signatures were identified in the prediction of overall survival in resectable pancreatic cancer.

Although genes have been previously detected in pancreatic cancer (PC), aberrant genes that play roles in resectable pancreatic cancer should be further assessed.
Chao Wu, Zuowei Wu, Bole Tian

2565 related Products with: Five gene signatures were identified in the prediction of overall survival in resectable pancreatic cancer.



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#32922348   2020/08/14 To Up

Association of Genetic Variation in the 3'UTR of LHX6, IMMP2L, and AADAC With Tourette Syndrome.

Tourette Syndrome (TS) is a neurodevelopmental disorder that presents with motor and vocal tics early in childhood. The aim of this study was to investigate genetic variants in the 3' untranslated region (3'UTR) of TS candidate genes with a putative link to microRNA (miRNA) mediated regulation or gene expression. We used an approach to identify 32 variants in the 3'UTR of 18 candidate genes putatively changing the binding site for miRNAs. In a sample composed of TS cases and controls ( = 290), as well as TS family trios ( = 148), we performed transmission disequilibrium test (TDT) and meta-analysis. We found positive association of rs3750486 in the LIM homeobox 6 (LHX6) gene ( = 0.021) and rs7795011 in the inner mitochondrial membrane peptidase subunit 2 (IMMP2L) gene ( = 0.029) with TS in our meta-analysis. The TDT showed an over-transmission of the A allele of rs1042201 in the arylacetamide deacetylase (AADAC) gene in TS patients ( = 0.029). This preliminary study provides further support for the involvement of LHX6, IMMP2L, and AADAC genes, as well as epigenetic mechanisms, such as altered miRNA mediated gene expression regulation in the etiology of TS.
Luca Pagliaroli, Andrea Vereczkei, Shanmukha Sampath Padmanabhuni, Zsanett Tarnok, Luca Farkas, Peter Nagy, Renata Rizzo, Tomasz Wolanczyk, Urszula Szymanska, Mira Kapisyzi, Entela Basha, Anastasia Koumoula, Christos Androutsos, Vaia Tsironi, Iordanis Karagiannidis, Peristera Paschou, Csaba Barta

2527 related Products with: Association of Genetic Variation in the 3'UTR of LHX6, IMMP2L, and AADAC With Tourette Syndrome.

1 5 G100 μg

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#32619519   // To Up

Translational Research in Culture: AADAC, Diabetes, and Cardiovascular Disease.

Many type 2 diabetes patients develop cardiovascular disease (CVD) while some are protected. Toyohara et al. (2020) find that elevated arylacetamide deacetylase (AADAC) expression in vascular smooth muscle cells (dVSMCs) differentiated from patient-derived induced pluripotent stem cells is associated with cardioprotection. AADAC overexpression alters multiple dVSMC properties and decreases murine CVD.
Ashish Misra, Edward A Fisher

1875 related Products with: Translational Research in Culture: AADAC, Diabetes, and Cardiovascular Disease.

50 UG100 1 mg4/120 Packing /sleeve/bo1-99 mg/ml/ea price x 296 testscase

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#32521634   2020/06/08 To Up

Influence of Single Nucleotide Polymorphisms on Rifampin Pharmacokinetics in Tuberculosis Patients.

Rifampin (RF) is metabolized in the liver into an active metabolite 25-desacetylrifampin and excreted almost equally via biliary and renal routes. Various influx and efflux transporters influence RF disposition during hepatic uptake and biliary excretion. Evidence has also shown that Vitamin D deficiency (VDD) and Vitamin D receptor (VDR) polymorphisms are associated with tuberculosis (TB). Hence, genetic polymorphisms of metabolizing enzymes, drug transporters and/or their transcriptional regulators and VDR and its pathway regulators may affect the pharmacokinetics of RF. In this narrative review, we aim to identify literature that has explored the influence of single nucleotide polymorphisms (SNPs) of genes encoding drug transporters and their transcriptional regulators (SLCO1B1, ABCB1, PXR and CAR), metabolizing enzymes (CES1, CES2 and AADAC) and VDR and its pathway regulators (VDR, CYP27B1 and CYP24A1) on plasma RF concentrations in TB patients on antitubercular therapy. Available reports to date have shown that there is a lack of any association of , , , and genetic variants with plasma concentrations of RF. Further evidence is required from a more comprehensive exploration of the association of , and Vitamin D pathway gene variants with RF pharmacokinetics in distinct ethnic groups and a larger population to reach conclusive information.
Levin Thomas, Sonal Sekhar Miraj, Mallayasamy Surulivelrajan, Muralidhar Varma, Chidananda S V Sanju, Mahadev Rao

2279 related Products with: Influence of Single Nucleotide Polymorphisms on Rifampin Pharmacokinetics in Tuberculosis Patients.

1 mg10 ug100ug5mgInhibitor0.1ml100ug Lyophilized100 100ul10200ul

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#32413331   2020/05/14 To Up

Patient hiPSCs Identify Vascular Smooth Muscle Arylacetamide Deacetylase as Protective against Atherosclerosis.

Although susceptibility to cardiovascular disease (CVD) is different for every patient, why some patients with type 2 diabetes mellitus (T2DM) develop CVD while others are protected has not yet been clarified. Using T2DM-patient-derived human induced pluripotent stem cells (hiPSCs), we found that in patients protected from CVD, there was significantly elevated expression of an esterase, arylacetamide deacetylase (AADAC), in vascular smooth muscle cells (VSMCs). We overexpressed this esterase in human primary VSMCs and VSMCs differentiated from hiPSCs and observed that the number of lipid droplets was significantly diminished. Further metabolomic analyses revealed a marked reduction in storage lipids and an increase in membrane phospholipids, suggesting changes in the Kennedy pathway of lipid bioassembly. Cell migration and proliferation were also significantly decreased in AADAC-overexpressing VSMCs. Moreover, apolipoprotein E (Apoe)-knockout mice overexpressing VSMC-specific Aadac showed amelioration of atherosclerotic lesions. Our findings suggest that higher AADAC expression in VSMCs protects T2DM patients from CVD.
Takafumi Toyohara, Filip Roudnicky, Mary H C Florido, Toshiaki Nakano, Haojie Yu, Shunsuke Katsuki, Minjin Lee, Torsten Meissner, Max Friesen, Lance S Davidow, Leon Ptaszek, Takaaki Abe, Lee L Rubin, Alexandre C Pereira, Masanori Aikawa, Chad A Cowan

1277 related Products with: Patient hiPSCs Identify Vascular Smooth Muscle Arylacetamide Deacetylase as Protective against Atherosclerosis.

500 tests200ul100ul 2 ml Ready-to-use 100ul 100ul1 ml100ul100 μg100ul

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#31726091   2019/11/11 To Up

Strain and sex differences in drug hydrolase activities in rodent livers.

Carboxylesterase (CES) 1, CES2, and arylacetamide deacetylase (AADAC) are the major drug hydrolases in humans, and they have different substrate preferences. Because rodents are widely used in preclinical studies, we aimed to clarify the extent of the species, strain, and sex differences in hydrolase activity in rats and mice. Hydrolase activities for 24 compounds were evaluated in Fischer 344, Sprague-Dawley, and Wistar-Imamichi rat liver microsomes (RLM) and Balb/c, C3H/He, C57BL/6J, and ddY mouse liver microsomes (MLM) by comparing the results with the activities in human liver microsomes (HLM). Imidapril hydrolase activities in RLM from all strains were substantially higher than those in MLM and HLM, whereas oseltamivir was hardly hydrolyzed in rodents, although both are specific substrates of CES1 in humans. In rats, males tended to show higher hydrolase activities for most human CES1 substrates than females. Hydrolase activities for irinotecan and procaine, which are CES2 substrates in humans, tended to be higher in RLM and MLM than in HLM. Rifamycins, substrates of human AADAC, were not hydrolyzed in RLM and MLM. The results of this study provide important information about the species, strain, and sex differences in hydrolase activities in rats and mice.
Fumiya Kisui, Tatsuki Fukami, Masataka Nakano, Miki Nakajima

2754 related Products with: Strain and sex differences in drug hydrolase activities in rodent livers.

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