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https://www.readbyqxmd.com/read/28542812/modulating-nasal-mucosal-permeation-using-metabolic-saturation-and-enzyme-inhibition-techniques
#1
Varsha Dhamankar, Maureen D Donovan
OBJECTIVE: Presystemic elimination resulting from local enzymatic degradation can play a key role in limiting the bioavailability of intranasally administered drugs. The aim of this study was to evaluate the transfer of a metabolically susceptible drug across the nasal mucosa to illustrate the relative contributions of drug diffusivity and metabolic susceptibility on overall nasal mucosal permeation and to understand the effects of changes in enzymatic activity on the transfer across nasal epithelial and submucosal tissues...
May 23, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28541707/identification-of-a-potent-selective-and-efficacious-phosphatidylinositol-3-kinase-%C3%AE-pi3k%C3%AE-inhibitor-for-the-treatment-of-immunological-disorders
#2
Qingjie Liu, Qing Shi, David Marcoux, Douglas G Batt, Lyndon Cornelius, Lan-Ying Qin, Zheming Ruan, James Neels, Myra Beaudoin Bertrand, Anurag S Srivastava, Ling Li, Robert Joseph Cherney, Hua Gong, Scott H Watterson, Carolyn Weigelt, Kathleen M Gillooly, Kim W McIntyre, Jenny H Xie, Mary T Obermeier, Aberra Fura, Bogdan Sleczka, Kevin Stefanski, R Marcus Fancher, Shweta Padmanabhan, Thatipamula Rp, Ipsit Kundu, Kallem Rajareddy, Rodney Smith, James K Hennan, Dezhi Xing, Jingsong Fan, Paul C Levesque, Qian Ruan, Sidney Pitt, Rosemary Zhang, Donna Pedicord, Jie Pan, Melissa Yarde, Hao Lu, Jonathan Lippy, Christine Goldstine, Stacey Skala, Richard A Rampulla, Arvind Mathur, Anuradha Gupta, Pirama Nayagam Arunachalam, John S Sack, Jodi K Muckelbauer, Mary Ellen Cvijic, Luisa M Salter-Cid, Rajeev S Bhide, Michael A Poss, John Hynes, Percy H Carter, John E Macor, Stefan Ruepp, Gary L Schieven, Joseph A Tino
PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work towards the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay...
May 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28541695/discovery-of-potent-selective-stem-cell-factor-receptor-platelet-derived-growth-factor-receptor-alpha-c-kit-pdgfr%C3%AE-dual-inhibitor-for-the-treatment-of-imatinib-resistant-gastrointestinal-stromal-tumors-gists
#3
Yanli Lu, Fei Mao, Xiaokang Li, Xinyu Zheng, Manjiong Wang, Qing Xu, Jin Zhu, Jian Li
c-KIT and platelet derived growth factor receptor alpha (PDGFRα) kinase play an important role in gastrointestinal stromal tumors (GISTs). Here, we have discovered an c-KIT/PDGFRα dual inhibitor, compound 31, with single-digit nanomolar potency against c-KIT and PDGFRα. Compared to Imatinib (1), 31 showed better antiproliferative efficacy against various TEL-c-KIT/PDGFRα-BaF3 isogenic cells, including three 1-resistant BaF3 cell lines, as well as against GIST-T1 and GIST-882 cell lines. Furthermore, compound 31 showed a good KinomeScan selectivity (468 kinases) (S score (1) = 0...
May 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28541672/impacts-of-unregulated-novel-brominated-flame-retardants-on-human-liver-thyroid-deiodination-and-sulfotransferation
#4
Tristan Alexander Smythe, Craig M Butt, Heather M Stapleton, Kerri Pleskach, Geemitha Ratnayake, Chae Yoon Song, Nicole Riddell, Alex Konstantinov, Gregg Thomas Tomy
The inhibitory effects of five novel brominated flame retardants: 1,2-bis(2,4,5-tribromophenoxy)ethane (BTBPE), decabromodiphenylethane (DBDPE), 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB), bis(2-ethylhexyl)tetrabromophthalate (BEH-TEBP), and β-tetrabromoethylcyclohexane (β-TBECH) on thyroid hormone deiodinase (DIO) and sulfotransferase (SULT) activity were investigated using human in vitro liver microsomal and cytosolic bioassays. Enzymatic activity was measured by incubating active human liver sub-cellular fractions with thyroid hormones (T4 and rT3 separately) and measuring changes in thyroid hormone (T4, T3, rT3, and 3,3'-T2) concentrations...
May 25, 2017: Environmental Science & Technology
https://www.readbyqxmd.com/read/28539716/prevention-mechanism-of-2-3-5-4-tetrahydroxy-stilbene-2-o-%C3%AE-d-glucoside-on-lipid-accumulation-in-steatosis-hepatic-l-02-cell
#5
Pei Lin, Jian-Mei Lu, Yan-Fang Wang, Wen Gu, Rong-Hua Zhao, Jie Yu
AIM: 2,3,5,4'-Tetrahydroxy-stilbene-2-O-β-d-glucoside (TSG), a natural stilbene, shows great activities in hepatic lipid regulation, especially for hepatic triglyceride lowering. However, information about its mechanisms on biosynthesis and degradation of triglyceride is still limited. This research pays close attention to clarify the mechanism of TSG on prevention of hepatic lipid accumulation. MATERIALS AND METHODS: TSG was given to steatosis hepatocyte L-02 cell induced by fat emulsion incubation...
April 2017: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/28539714/evaluation-of-herb-drug-interactions-of-hovenia-dulcis-fruit-extracts
#6
Jong Suk Park, Shaheed Ur Rehman, In Sook Kim, Min Sun Choi, Chun-Soo Na, Hye Hyun Yoo
BACKGROUND: Hovenia dulcis (Rhamnaceae) fruits are popularly used as herbal medicines or dietary supplements in Asian countries due to functions such as liver protection and detoxification from alcohol poisoning. Accordingly, it is very likely for dietary supplemental products, including H. dulcis fruit extracts, to be taken with prescription drugs. OBJECTIVE: In this study, possible food-drug interactions involving H. dulcis fruit extracts were evaluated based on the inhibition of cytochrome P450 (CYP) enzyme activity...
April 2017: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/28539295/-value-of-ultrasound-shear-wave-elasticity-imaging-in-diagnosis-of-hashimoto-s-thyroiditis
#7
Wei Wang, Hai-Ning Zheng, Qiong Wang, Yi-Xiao Han, Qing-Gui Ye, Chao-Yang Wen
OBJECTIVE: To investigate the correlation between Young's modulus of the thyroid tissue measured by in shear wave elastography (SWE) and the clinical manifestations of Hashimoto's thyroiditis in different stages. METHODS: A total of 104 patients with the clinical diagnosis of Hashimoto's thyroiditis were enrolled in this study, including 26 with hyperthyroidism, 29 with normal thyroid function, 27 with subclinical hypothyroidism, 22 with clinical hypothyroidism, with 50 healthy volunteers serving as the healthy control group...
May 20, 2017: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
https://www.readbyqxmd.com/read/28537728/antimalarial-inhibitors-targeting-serine-hydroxymethyltransferase-shmt-with-in-vivo-efficacy-and-analysis-of-their-binding-mode-based-on-x-ray-cocrystal-structures
#8
Geoffrey Schwertz, Matthias C Witschel, Matthias Rottmann, Roger Bonnert, Ubolsree Leartsakulpanich, Penchit Chitnumsub, Aritsara Jaruwat, Wanwipa Ittarat, Anja Schäfer, Raphael A Aponte, Susan A Charman, Karen L White, Abhijit Kundu, Surajit Sadhukhan, Mel Lloyd, Gail M Freiberg, Myron Srikumaran, Marc Siggel, Adrian Zwyssig, Pimchai Chaiyen, François Diederich
Target-based approaches towards new antimalarial treatments are highly valuable to prevent resistance development. We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3...
May 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28536195/discovery-of-a-widespread-metabolic-pathway-within-and-among-phenolic-xenobiotics
#9
Pahriya Ashrap, Guomao Zheng, Yi Wan, Tong Li, Wenxin Hu, Wenjuan Li, Hong Zhang, Zhaobin Zhang, Jianying Hu
Metabolism is an organism's primary defense against xenobiotics, yet it also increases the production of toxic metabolites. It is generally recognized that phenolic xenobiotics, a group of ubiquitous endocrine disruptors, undergo rapid phase II metabolism to generate more water-soluble glucuronide and sulfate conjugates as a detoxification pathway. However, the toxicological effects of the compounds invariably point to the phase I metabolic cytochrome P450 enzymes. Here we show that phenolic xenobiotics undergo an unknown metabolic pathway to form more lipophilic and bioactive products...
May 23, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28536020/%C3%B0-valuation-of-biocompatibility-and-antioxidant-efficiency-of-chitosan-alginate-nanoparticles-loaded-with-quercetin
#10
Denitsa Aluani, Virginia Tzankova, Magdalena Kondeva-Burdina, Yordan Yordanov, Elena Nikolova, Feodor Odzhakov, Alexandar Apostolov, Tzvetanka Markova, Krassimira Yoncheva
The present study deals with development and evaluation of the safety profile of chitosan/alginate nanoparticles as a platform for delivery of a natural antioxidant quercetin. The nanoparticles were prepared by varying the ratios between both biopolymers giving different size and charge of the formulations. The biocompatibility was explored in vitro in cells from different origin: cultivated HepG2 cells, isolated primary rat hepatocytes, isolated murine spleen lymphocytes and macrophages. In vivo toxicological evaluation was performed after repeated 14-day oral administration to rats...
May 20, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28532270/predominant-contributions-of-carboxylesterase-1-and-2-in-hydrolysis-of-anordrin-in-humans
#11
Jinfang Jiang, Xiaoyan Chen, Dafang Zhong
1. Anordrin (2α, 17α-diethynyl-A-nor-5α-androstane-2β, 17β-diol diproprionate) is post-coital contraceptive drug that is on the market in China for more than 30 years. This study aims to elucidate enzymes involved in anordrin hydrolysis, and to evaluate the significant role of carboxylesterases in anordrin hydrolysis in humans. 2. Human liver and intestinal microsomes, recombinant human carboxylesterase were selected as enzyme sources. In human liver microsomes, intrinsic clearance was 684 ± 83 μL/min/mg protein, which was considerably higher than the value of intestine microsomes (94...
May 22, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28532263/establishment-and-assessment-of-a-novel-in-vitro-bio-pk-pd-system-in-predicting-the-in-vivo-pharmacokinetics-and-pharmacodynamics-of-cyclophosphamide
#12
Shanshan Tong, Hong Sun, Caifu Xue, Hanmei Chen, Jing Liu, Huiying Yang, Ning Zhou, Xiaoqiang Xiang, Weimin Cai
1. A novel bio-pharmacokinetic/pharmacodynamic (PK/PD) system was established and assessed in predicting the PK parameters and PD effects of the model drug cyclophosphamide (CP) considering the interrelationships between drug metabolism, pharmacological effects and dynamic blood circulation processes in vitro. 2. The system contains a peristaltic pump, a reaction chamber with rat liver microsomes (RLMs) encapsulated in pluronic F127-acrylamide-bisacrylamide (FAB) hydrogels, an effector cell chamber and a recirculating pipeline...
May 23, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28527914/impact-of-hepatic-p450-mediated-biotransformation-on-the-disposition-and-respiratory-tract-toxicity-of-inhaled-naphthalene
#13
Nataliia Kovalchuk, Jacklyn Kelty, Lei Li, Matthew Hartog, Qing-Yu Zhang, Patricia Edwards, Laura Van Winkle, Xinxin Ding
We determined whether a decrease in hepatic microsomal cytochrome P450 activity would impact lung toxicity induced by inhalation exposure to naphthalene (NA), a ubiquitous environmental pollutant. The liver-Cpr-null (LCN) mouse showed decreases in microsomal metabolism of NA in liver, but not lung, compared to wild-type (WT) mouse. Plasma levels of NA and NA-glutathione conjugates (NA-GSH) were both higher in LCN than in WT mice after a 4-h nose-only NA inhalation exposure at 10ppm. Levels of NA were also higher in lung and liver of LCN, compared to WT, mice, following exposure to NA at 5 or 10ppm...
May 17, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28527325/dyslipidemia-management-update
#14
REVIEW
Yingzi Chang, Jacques Robidoux
Association of hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD) is well established. Reducing low-density lipoprotein-cholesterol (LDL-C) and raising high-density lipoprotein-cholesterol (HDL-C) have been the therapeutic targets to reduce the risk of ASCVD. Cholesterol-lowering medications have been used to provide both primary and secondary prevention of ASCVD for many years by reducing the absorption and reabsorption, promoting excretion, or decreasing the synthesis of cholesterol. Within the past five years, several new classes of cholesterol-lowering drugs have been tested and approved for patients with hypercholesterolemia that are not well controlled by conventional therapy (ezetimibe, bile-acid sequestrants, and statins)...
May 17, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28525869/hepatic-microsomal-metabolism-of-bde-47-and-bde-99-by-lesser-snow-geese-and-japanese-quail
#15
Lisa K Krieger, András Szeitz, Stelvio M Bandiera
In the present study, we investigated the oxidative biotransformation of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) by liver microsomes from wild lesser snow geese (Chen caerulescens caerulescens) and domesticated Japanese quail (Coturnix japonica). Formation of hydroxy-metabolites was analyzed using an ultra-high performance liquid chromatography-tandem mass spectrometry-based method. Incubation of BDE-47 with avian liver microsomes produced sixteen hydroxy-metabolites, eight of which were identified using authentic standards...
May 10, 2017: Chemosphere
https://www.readbyqxmd.com/read/28523102/design-and-synthesis-of-mercaptoacetamides-as-potent-selective-and-brain-permeable-histone-deacetylase-6-inhibitors
#16
Wei Lv, Guangming Zhang, Cyril Barinka, James H Eubanks, Alan P Kozikowski
A series of nonhydroxamate HDAC6 inhibitors were prepared in our effort to develop potent and selective compounds for possible use in central nervous system (CNS) disorders, thus obviating the genotoxicity often associated with the hydroxamates. Halogens are incorporated in the cap groups of the designed mercaptoacetamides in order to increase brain accessibility. The indole analogue 7e and quinoline analogue 13a displayed potent HDAC6 inhibitory activity (IC50, 11 and 2.8 nM) and excellent selectivity against HDAC1...
May 11, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28514664/lack-of-mttp-activity-in-pluripotent-stem-cell-derived-hepatocytes-and-cardiomyocytes-abolishes-apob-secretion-and-increases-cell-stress
#17
Ying Liu, Donna M Conlon, Xin Bi, Katherine J Slovik, Jianting Shi, Hailey I Edelstein, John S Millar, Ali Javaheri, Marina Cuchel, Evanthia E Pashos, Jahangir Iqbal, M Mahmood Hussain, Robert A Hegele, Wenli Yang, Stephen A Duncan, Daniel J Rader, Edward E Morrisey
Abetalipoproteinemia (ABL) is an inherited disorder of lipoprotein metabolism resulting from mutations in microsomal triglyceride transfer protein (MTTP). In addition to expression in the liver and intestine, MTTP is expressed in cardiomyocytes, and cardiomyopathy has been reported in several ABL cases. Using induced pluripotent stem cells (iPSCs) generated from an ABL patient homozygous for a missense mutation (MTTP(R46G)), we show that human hepatocytes and cardiomyocytes exhibit defects associated with ABL disease, including loss of apolipoprotein B (apoB) secretion and intracellular accumulation of lipids...
May 16, 2017: Cell Reports
https://www.readbyqxmd.com/read/28514663/fatty-acid-oxidation-in-zebrafish-adipose-tissue-is-promoted-by-1%C3%AE-25-oh-2d3
#18
Xuyan Peng, Guohui Shang, Wenqing Wang, Xiaowen Chen, Qiyong Lou, Gang Zhai, Dongliang Li, Zhenyu Du, Yali Ye, Xia Jin, Jiangyan He, Yi Zhang, Zhan Yin
1α,25(OH)2D3 (vitamin D3) is crucial for mineral homeostasis in mammals, but the precise effects of 1α,25(OH)2D3 in adipose tissue remain to be clarified in vivo. The initial 25-hydroxylation is catalyzed by liver microsomal cytochrome P450 2R1 (CYP2R1), which is conserved in vertebrates. To probe the physiological function(s) of 1α,25(OH)2D3 in teleosts, we generated two independent cyp2r1-deficient zebrafish lines. These mutants exhibit retarded growth and increased obesity, especially in the visceral adipose tissue (VAT)...
May 16, 2017: Cell Reports
https://www.readbyqxmd.com/read/28513572/synthesis-and-antiradical-activity-of-isoquercitrin-esters-with-aromatic-acids-and-their-homologues
#19
Eva Heřmánková-Vavříková, Alena Křenková, Lucie Petrásková, Christopher Steven Chambers, Jakub Zápal, Marek Kuzma, Kateřina Valentová, Vladimír Křen
Isoquercitrin, (IQ, quercetin-3-O-β-d-glucopyranoside) is known for strong chemoprotectant activities. Acylation of flavonoid glucosides with carboxylic acids containing an aromatic ring brings entirely new properties to these compounds. Here, we describe the chemical and enzymatic synthesis of a series of IQ derivatives at the C-6″. IQ benzoate, phenylacetate, phenylpropanoate and cinnamate were prepared from respective vinyl esters using Novozym 435 (Lipase B from Candida antarctica immobilized on acrylic resin)...
May 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28506876/role-of-prostacyclin-synthase-in-carcinogenesis
#20
REVIEW
Yuka Sasaki, Tsubasa Ochiai, Masaya Takamura, Yukihiro Kondo, Chieko Yokoyama, Shuntaro Hara
Prostacyclin (PGI2) synthase (PGIS) and microsomal prostaglandin (PG) E synthase-1 (PGES-1) functionally couple with inducible cyclooxygenase-2 (COX-2) as their upstream enzymes to produce PGI2 and PGE2, respectively. Non-steroidal anti-inflammatory drugs exert their pharmacological effects including antitumor effects by the inhibition of COX-2 and thereby suppress this PG biosynthesis. PGIS is abundantly expressed in vascular endothelial and smooth muscle cells and was shown to be critical for the regulation of platelet aggregation and vascular tone...
May 12, 2017: Prostaglandins & Other Lipid Mediators
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