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https://www.readbyqxmd.com/read/29351555/omega-3-fatty-acid-desaturase-gene-family-from-two-%C3%AF-3-sources-salvia-hispanica-and-perilla-frutescens-cloning-characterization-and-expression
#1
Yufei Xue, Baojun Chen, Aung Naing Win, Chun Fu, Jianping Lian, Xue Liu, Rui Wang, Xingcui Zhang, Yourong Chai
Omega-3 fatty acid desaturase (ω-3 FAD, D15D) is a key enzyme for α-linolenic acid (ALA) biosynthesis. Both chia (Salvia hispanica) and perilla (Perilla frutescens) contain high levels of ALA in seeds. In this study, the ω-3 FAD gene family was systematically and comparatively cloned from chia and perilla. Perilla FAD3, FAD7, FAD8 and chia FAD7 are encoded by single-copy (but heterozygous) genes, while chia FAD3 is encoded by 2 distinct genes. Only 1 chia FAD8 sequence was isolated. In these genes, there are 1 to 6 transcription start sites, 1 to 8 poly(A) tailing sites, and 7 introns...
2018: PloS One
https://www.readbyqxmd.com/read/29348805/synthesis-and-sar-of-1-2-3-4-tetrahydroisoquinoline-based-cxcr4-antagonists
#2
Robert J Wilson, Edgars Jecs, Eric J Miller, Huy H Nguyen, Yesim A Tahirovic, Valarie M Truax, Michelle B Kim, Katie M Kuo, Tao Wang, Chi Shing Sum, Mary E Cvijic, Anthony A Paiva, Gretchen M Schroeder, Lawrence J Wilson, Dennis C Liotta
CXCR4 is the most common chemokine receptor expressed on the surface of many cancer cell types. In comparison to normal cells, cancer cells overexpress CXCR4, which correlates with cancer cell metastasis, angiogenesis, and tumor growth. CXCR4 antagonists can potentially diminish the viability of cancer cells by interfering with CXCL12-mediated pro-survival signaling and by inhibiting chemotaxis. Herein, we describe a series of CXCR4 antagonists that are derived from (S)-5,6,7,8-tetrahydroquinolin-8-amine that has prevailed in the literature...
January 11, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29348267/toll-like-receptor-9-dependent-ampk%C3%AE-activation-occurs-via-tak1-and-contributes-to-rhoa-rock-signaling-and-actin-polymerization-in-vascular-smooth-muscle-cells
#3
Cameron G McCarthy, Camilla Ferreira Wenceslau, Safia Ogbi, Theodora Szasz, R Clinton Webb
Traditionally, Toll-like receptor (TLR)9 signals through a MyD88-dependent cascade that results in pro-inflammatory gene transcription. Recently it was reported that TLR9 also participates in a stress tolerance signaling cascade in non-immune cells. In this non-canonical pathway, TLR9 binds to and inhibits sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2), modulating intracellular calcium handling, and subsequently resulting in the activation of 5'-AMP-activated protein kinase (AMPK)α. We have previously reported TLR9 causes increased contraction in isolated arteries; however, the mechanisms underlying this vascular dysfunction need to be further clarified...
January 18, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29345044/preclinical-characterisation-of-absorption-distribution-metabolism-and-excretion-properties-of-tak-063
#4
Kimio Tohyama, Miyako Sudo, Akio Morohashi, Suguru Kato, Junzo Takahashi, Yoshihiko Tagawa
TAK-063 is currently being developed to treat schizophrenia. In this study, we investigated the absorption, distribution, metabolism and excretion (ADME) properties of TAK-063 using several paradigms. Following oral administration of TAK-063 at 0.3 mg/kg, bioavailability of TAK-063 was 27.4% in rats and 49.5% in dogs with elimination half-lives of 3.1 hr in rats and 3.7 hr in dogs. TAK-063 is a highly permeable compound without P-glycoprotein (P-gp) or breast cancer resistance protein substrate liability and can be readily absorbed into systemic circulation via the intestine...
January 17, 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29343943/the-oral-bioavailability-excretion-and-cytochrome-p450-inhibition-properties-of-epiberberine-an-in-vivo-and-in-vitro-evaluation
#5
Ning Chen, Xiao-Yan Yang, Chang-E Guo, Xin-Ning Bi, Jian-Hua Chen, Hong-Ying Chen, Hong-Pin Li, Hong-Ying Lin, Yu-Jie Zhang
Epiberberine (EPI) is a novel and potentially effective therapeutic and preventive agent for diabetes and cardiovascular disease. To evaluate its potential value for drug development, a specific, sensitive and robust high-performance liquid chromatography-tandem mass spectrometry assay for the determination of EPI in rat biological samples was established. This assay was used to study the pharmacokinetics, bioavailability and excretion of EPI in rats after oral administration. In addition, a cocktail method was used to compare the inhibition characteristics of EPI on cytochrome P450 (CYP450) isoforms in human liver microsomes (HLMs) and rat liver microsomes (RLMs)...
2018: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29343608/direct-quantification-of-cytochromes-p450-and-drug-transporters-a-rapid-targeted-mass-spectrometry-based-immunoassay-panel-for-tissues-and-cell-culture-lysates
#6
Frederik Weib, Helen Sophie Hammer, Kathrin Klein, Hannes Planatscher Planatscher, Ulrich M Zanger, Agneta Noren, Christine Wegler, Per Artursson, Thomas O Joos, Oliver Poetz
The quantification of drug metabolizing enzymes and transporters has recently been revolutionized on the basis of targeted proteomic approaches. Isotope-labeled peptides are used as standards for the quantification of the corresponding proteins in enzymatically fragmented samples. However, hurdles in these approaches are low throughput and tedious sample pre-fractionation steps prior to mass spectrometry read-out. We have developed an assay platform using sensitive and selective immunoprecipitation coupled with mass spectrometric read-out allowing the quantification of proteins directly from whole cell lysates using less than 20,000 cells per analysis...
January 17, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29342418/functional-characterization-of-9-cyp2a13-allelic-variants-by-assessment-of-nicotine-c-oxidation-and-coumarin-7-hydroxylation
#7
Masaki Kumondai, Hiroki Hosono, Masamitsu Maekawa, Hiroaki Yamaguchi, Nariyasu Mano, Akifumi Oda, Noriyasu Hirasawa, Masahiro Hiratsuka
Cytochrome P450 2A13 (CYP2A13) is responsible for the metabolism of chemical compounds such as nicotine, coumarin, and tobacco-specific nitrosamine. Several of these compounds have been recognized as procarcinogens activated by CYP2A13. We recently showed that CYP2A13*2 contributes to inter-individual variations observed in bladder cancer susceptibility because CYP2A13*2 might cause a decrease in enzymatic activity. Other CYP2A13 allelic variants may also affect cancer susceptibility. In this study, we performed an in vitro analysis of the wild-type enzyme (CYP2A13...
November 22, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29341029/in-vitro-and-in-situ-absorption-and-metabolism-of-sesquiterpenes-from-petasites-hybridus-extracts
#8
Lucia Disch, Kristina Forsch, Beate Siewert, Jürgen Drewe, Gert Fricker
Petasites hybridus extract is used in the treatment of seasonal allergic rhinitis. The aim of this study was to evaluate the active constituent petasin and its isomers isopetasin and neopetasin (petasins) in the P. hybridus extract Ze 339 for liberation, dissolution, absorption, and metabolism. The determination of pH-dependent thermodynamic solubility was performed via the shake-flask method. Petasins exhibited a low solubility that was pH independent. In vivo, the concentration of solute drugs is decreased continuously by intestinal absorption...
January 16, 2018: Planta Medica
https://www.readbyqxmd.com/read/29339225/metabolism-and-pharmacokinetics-of-a-potent-n-acylindole-antagonist-of-the-oxe-receptor-for-the-eosinophil-chemoattractant-5-oxo-6-8-11-14-eicosatetraenoic-acid-5-oxo-ete-in-rats-and-monkeys
#9
Chintam Nagendra Reddy, Hussam Alhamza, Shishir Chourey, Qiuji Ye, Vivek Gore, Chantal Cossette, Sylvie Gravel, Irina Slobodchikova, Dajana Vuckovic, Joshua Rokach, William S Powell
We previously identified the indole 264 as a potent in vitro antagonist of the human OXE receptor that mediates the actions of the powerful eosinophil chemoattractant 5-oxo-ETE. No antagonists of this receptor are currently commercially available or are being tested in clinical studies. The lack of a rodent ortholog of the OXE receptor has hampered progress in this area because of the unavailability of commonly used mouse or rat animal models. In the present study, we examined the feasibility of using the cynomolgus monkey as an animal model to investigate the efficacy of orally administered 264 in future in vivo studies...
January 12, 2018: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29337682/adverse-effects-of-organophosphorus-pesticides-on-the-liver-a-brief-summary-of-four-decades-of-research
#10
Somayyeh Karami-Mohajeri, Ahmad Ahmadipour, Hamid-Reza Rahimi, Mohammad Abdollahi
Organophosphorus pesticides (OPs) are widely used volatile pesticides that have harmful effects on the liver in acute and chronic exposures. This review article summarises and discusses a wide collection of studies published over the last 40 years reporting on the effects of OPs on the liver, in an attempt to propose general mechanisms of OP hepatotoxicity and possible treatment. Several key biological processes have been reported as involved in OP-induced hepatotoxicity such as disturbances in the antioxidant defence system, oxidative stress, apoptosis, and mitochondrial and microsomal metabolism...
December 20, 2017: Arhiv za Higijenu Rada i Toksikologiju
https://www.readbyqxmd.com/read/29334584/in-vitro-and-in-vivo-metabolite-identification-of-a-novel-benzimidazole-compound-zln005-by-lc-ms-ms
#11
Wenchao Sun, Khoa Dinh Nguyen, William L Fitch, Samuel D Banister, Hongxiang Tang, Xiaolan Zhang, Lewis Yu, Edgar G Engleman, Jayakumar Rajadas
RATIONALE: A novel benzimidazole compound ZLN005 was previously identified as a transcriptional activator of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in certain metabolic tissues. Upregulation of PGC-1α by ZLN005 has been shown to have beneficial effect in a diabetic mouse model and in a coronary artery disease model in vitro. ZLN005 could also have therapeutic potential in neurodegenerative diseases involving down-regulation of PGC-1α. Given the phenotypic efficacy of ZLN005 in several animal models of human disease, its metabolic profile was investigated to guide the development of novel therapeutics using ZLN005 as the lead compound...
January 15, 2018: Rapid Communications in Mass Spectrometry: RCM
https://www.readbyqxmd.com/read/29331654/in-vitro-and-in-vivo-metabolic-activation-of-rhein-and-characterization-of-glutathione-conjugates-derived-from-rhein
#12
Yang Xu, Xu Mao, Boyang Qin, Ying Peng, Jiang Zheng
Rhein (RH), 4,5-dihydroxyanthrauinone-2-carboxylic acid, is found in rhubarb (Dahuang), a traditional herbal medicine. RH has reportedly demonstrated multiple pharmacologic properties. Previous studies have also shown that RH induced hepatotoxicity, but the mechanisms of the adverse effect remain unknown. The major objective of the present study was to study the metabolic pathways of RH in order to identify potential reactive metabolites. One mono-hydroxylation metabolite (M1) was detected in urine and bile of rats given RH...
January 10, 2018: Chemico-biological Interactions
https://www.readbyqxmd.com/read/29329790/plant-derived-mpges-1-inhibitors-or-suppressors-a-new-emerging-trend-in-the-search-for-small-molecules-to-combat-inflammation
#13
REVIEW
Haroon Khan, Kannan R R Rengasamy, Aini Pervaiz, Seyed Mohammad Nabavi, Atanas G Atanasov, Mohammad A Kamal
Inflammation comprises the reaction of the body to injury, in which a series of changes of the terminal vascular bed, blood, and connective tissue tends to eliminate the injurious agent and to repair the damaged tissue. It is a complex process, which involves the release of diverse regulatory mediators. The current anti-inflammatory agents are challenged by multiple side effects and thus, new effective therapies are highly needed. The aim of this review is to summarize the described microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors or transcriptional suppressors from medicinal plants, which could be an ideal approach in the management of inflammatory disorders, but need further clinical trials in order to be ultimately validated...
December 23, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29329665/bioactivation-of-1-chloro-2-hydroxy-3-butene-an-in-vitro-metabolite-of-1-3-butadiene-by-rat-liver-microsomes
#14
Ye Wang, Ying-Xin Yu, Yang Luan, Jing An, Dong-Guang Yin, Xin-Yu Zhang
1-Chloro-2-hydroxy-3-butene (CHB) is an in vitro metabolite of 1,3-butadiene, a rodent/human carcinogen. To search for an approach detecting CHB in vivo, it is vital to obtain a full understanding of CHB metabolism. Previously, we demonstrated that CHB was bioactivated to 1-chloro-3-buten-2-one (CBO) by alcohol dehydrogenase. However, CHB metabolism by cytochrome P450s has not been reported. Thus, in the present study, CHB metabolism by rat liver microsomes was investigated. The results showed that CHB was converted to 1-chloro-3,4-epoxy-2-butanol (CEB) and CBO...
January 9, 2018: Chemico-biological Interactions
https://www.readbyqxmd.com/read/29327455/bioactivity-guided-fractionation-of-methanolic-extract-of-terminalia-arjuna-for-its-cyp3a-and-cyp2d-inhibition-in-rat-liver-microsomes
#15
Alice Varghese, Prachi Saboo, Sarika Wairkar
Terminalia arjuna (T. arjuna) is an Indian medicinal plant belonging to the family combretaceae and possesses numerous therapeutic activities including its immense cardio protective activity. In the present work, methanolic bark extract of T. arjuna was evaluated for the CYP3A and CYP2D inhibition potential in rat liver microsomes (RLM). Further, the methanolic bark extract was fractionated successively using increasing polarity solvents starting with petroleum ether, chloroform, ethyl acetate and n-butanol...
January 12, 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29327113/storage-stability-study-of-porcine-hepatic-and-intestinal-cytochrome-p450-isoenzymes-by-use-of-a-newly-developed-and-fully-validated-highly-sensitive-hplc-ms-ms-method
#16
Wim Schelstraete, Mathias Devreese, Siska Croubels
Microsomes are an ideal medium to investigate cytochrome P450 (CYP450) enzyme-mediated drug metabolism. However, before microsomes are prepared, tissues can be stored for a long time. Studies about the stability of these enzymes in porcine hepatic and intestinal tissues upon storage are lacking. To be able to investigate CYP450 stability in microsomes prepared from these tissues, a highly sensitive and rapid HPLC-MS/MS method for the simultaneous determination of six CYP450 metabolites in incubation medium was developed and validated...
January 11, 2018: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/29326490/investigation-of-in-vitro-absorption-distribution-metabolism-and-excretion-and-in-vivo-pharmacokinetics-of-paromomycin-influence-on-oral-bioavailability
#17
M Jakir S K Pinjari, Rahul Somani, Ritu M Gilhotra
OBJECTIVE: The objective of this study is to investigate in vitro Caco2 permeability, metabolism and in vivo pharmacokinetic (PK) properties of paromomycin to develop an efficient dosage form with improved oral bioavailability. MATERIALS AND METHODS: For the purpose, Caco2 permeability assay, mouse microsomal stability assay and in vivo PKs in male BALB/c mice were performed. RESULTS: In Caco-2 permeability assay, paromomycin showed negligible permeability in the apical to basolateral (A-to-B) direction and vice versa (B-to-A)...
July 2017: Indian Journal of Pharmacology
https://www.readbyqxmd.com/read/29325280/-clinical-value-of-anti-liver-kidney-microsomal-1-antibody-in-patients-with-liver-disease
#18
Y Han, H P Yan, H Y Liao, L M Sun, Y L Huang, C Y Huang, H P Zhang, X D Zhang, X Q Bian, M X Ren, X F Du, Y M Liu
Objective: To investigate the clinical and laboratory features of patients with liver disease and positive anti-liver/kidney microsomal-1 (anti-LKM-1) antibody, and to provide a reference for clinical diagnosis and differential diagnosis. Methods: The clinical data of patients with positive anti-LKM-1 antibody who were treated in our hospital from 2006 to 2016 were collected, and clinical and laboratory features were analyzed and compared. An analysis was also performed for special cases. Results: The measurement of related autoantibodies was performed for about 100 thousand case-times, and 15 patients were found to have positive anti-LKM-1 antibody...
November 20, 2017: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
https://www.readbyqxmd.com/read/29322864/effects-of-danshen-tablets-on-pharmacokinetics-of-atorvastatin-calcium-in-rats-and-its-potential-mechanism
#19
Sen Sun, Rong Wang, Jie Fan, Guoqing Zhang, Hai Zhang
CONTEXT: Danshen tablets (DST), an effective traditional Chinese multi-herbal formula, are often combined with atorvastatin calcium (AC) for treating coronary heart disease in the clinic. OBJECTIVE: This study investigated the effects of DST on the pharmacokinetics of AC and the potential mechanism. MATERIALS AND METHODS: The pharmacokinetics of AC (1 mg/kg) with or without pretreatment of DST (100 mg/kg) were investigated using LC-MS/MS...
December 2018: Pharmaceutical Biology
https://www.readbyqxmd.com/read/29322841/the-effect-of-lycopene-on-cytochrome-p450-isoenzymes-and-p-glycoprotein-by-using-human-liver-microsomes-and-caco-2-cell-monolayer-model
#20
Lingti Kong, Chunli Song, Linhu Ye, Jian Xu, Daohua Guo, Qingping Shi
Lycopene is widely used as a dietary supplement. However, the effects of lycopene on cytochrome P450 (CYP) enzymes or P-glycoprotein (P-gp) are not comprehensive. The present study was performed to investigate the effects of lycopene on the CYP enzymes and P-gp activity. A cocktail method was used to evaluate the activities of CYP3A4, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. Caco-2 cell monolayer model was carried out to assay lycopene on P-gp activity. The results indicated that lycopene had a moderate inhibitory effect on CYP2E1, with IC50 value of 43...
January 11, 2018: International Journal of Food Sciences and Nutrition
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