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https://www.readbyqxmd.com/read/28431455/uhplc-q-tof-ms-ms-based-screening-and-characterization-of-metabolites-of-cnidilin-in-human-liver-microsomes
#1
Lin Yuan, Yuqian Zhang, Man Liao, Yanyan Liu, Changchen Wan, Lantong Zhang
Cnidilin is an active natural furocoumarin ingredient originating from well-known traditional Chinese medicine Radix Angelicae dahuricae. In the present study, an efficient approach was developed for the screening and identification of cnidilin metabolites using ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. In this approach, an on-line data acquisition method multiple mass defect filter (MMDF) combined with dynamic background subtraction was developed to trace all probable metabolites...
April 21, 2017: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/28428366/in-vitro-metabolism-of-oprozomib-an-oral-proteasome-inhibitor-role-of-epoxide-hydrolases-and-cytochrome-p450s
#2
Zhican Wang, Ying Fang, Juli Teague, Hansen Wong, Christophe Morisseau, Bruce D Hammock, Dan A Rock, Zhengping Wang
Oprozomib is an oral proteasome inhibitor currently under investigation in patients with hematologic malignancies or solid tumors. Oprozomib elicits potent pharmacological actions by forming a covalent bond with the active site N-terminal threonine of the 20S proteasome. Oprozomib has a short half-life across preclinical species and in patients due to systemic clearance via metabolism. Potential for drug-drug interactions (DDIs) could alter the exposure of this potent therapeutic therefore a thorough investigation of pathways responsible for metabolism is required...
April 20, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28426996/design-synthesis-sar-discussion-in%C3%A2-vitro-and-in%C3%A2-vivo-evaluation-of-novel-selective-egfr-modulator-to-inhibit-l858r-t790m-double-mutants
#3
Haoyang Zhang, Wenkui Wu, Chao Feng, Zhaogang Liu, Enhe Bai, Xueyuan Wang, Meng Lei, Hao Cheng, Huayun Feng, Jingmiao Shi, Jia Wang, Zhao Zhang, Tao Jin, Shanshan Chen, Shihe Hu, Yongqiang Zhu
Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 8 showed excellent enzyme inhibitory activities and selectivity with sub nanomolar IC50 values for both the single L858R and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 8 exhibited good microsomes stabilities and pharmacokinetic properties and lower binding affinity to hERG ion channel than AZD9291 and displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R and in vivo anticancer efficacy in a human NSCLC (H1975) xenograft mouse model...
April 14, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28426090/oleuropein-down-regulated-il-1%C3%AE-induced-inflammation-and-oxidative-stress-in-human-synovial-fibroblast-cell-line-sw982
#4
Maria Luisa Castejón, Maria Ángeles Rosillo, Tatiana Montoya, Alejandro González-Benjumea, Jose Maria Fernández-Bolaños, Catalina Alarcón-de-la-Lastra
Rheumatoid arthritis (RA) is a chronic and systemic inflammatory autoimmune disease mainly characterized by aggressive hyperproliferation of synovial fibroblasts (SFs). It is accompained by a massive infiltration of inflammatory immune cells inducing progressive matrix degradation, destruction of cartilage and bone erosion through the production of inflammatory mediators. Oleuropein is the most prevalent phenolic component in olive leaves, seed, pulp and peel of unripe olives and is responsible for the characteristic bitter taste of unprocessed olives...
April 20, 2017: Food & Function
https://www.readbyqxmd.com/read/28424858/electrochemical-simulation-of-biotransformation-reactions-of-citrinin-and-dihydroergocristine-compared-to-uv-irradiation-and-fenton-like-reaction
#5
Julia Keller, Hajo Haase, Matthias Koch
Mycotoxins occur widely in foodstuffs and cause a variety of mold-related health risks to humans and animals. Elucidation of the metabolic fate of mycotoxins and the growing number of newly discovered mycotoxins have enhanced the demand for fast and reliable simulation methods. The viability of electrochemistry coupled with mass spectrometry (EC/ESI-MS), Fenton-like oxidation, and UV irradiation for the simulation of oxidative phase I metabolism of the mycotoxins citrinin (CIT) and dihydroergocristine (DHEC) was investigated...
April 19, 2017: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/28424803/use-of-a-flumazenil-infusion-to-treat-chlordiazepoxide-toxicity
#6
I R Wallace, E C Campbell, M Trimble
"Alcohol detox" is a common presentation to acute medical services and is usually managed via standardised guidelines and protocols. We present a case of chlordiazepoxide toxicity, requiring repeated bolus doses and subsequently 24 hours of an intravenous infusion of flumazenil in response to guideline directed management of an alcohol withdrawal state. The use of prolonged flumazenil infusions to treat benzodiazepine toxicity is infrequently described. Chlordiazepoxide is metabolised in the hepatic microsomal pathway and hepatic impairment can lead to accumulation of toxic metabolites, which may have been the explanation for toxicity in this case...
2017: Acute Medicine
https://www.readbyqxmd.com/read/28421410/antiparasitic-sesquiterpenes-from-the-cameroonian-spice-scleria-striatinux-and-preliminary-in-vitro-and-in-silico-dmpk-assessment
#7
Kennedy D Nyongbela, Fidele Ntie-Kang, Thomas R Hoye, Simon M N Efange
The antiparasitic activity and preliminary in vitro and in silico drug metabolism and pharmacokinetic (DMPK) assessment of six isomeric sesquiterpenes (1-6), isolated from the Cameroonian spice Scleria striatinux De Wild (Cyperaceae) is reported. The study was prompted by the observation that two of the compounds (1 and 2) exhibited varying levels of antiparasitic activity on Plasmodium falciparum, Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania donovani. The in silico method employed a total of 46 descriptors, calculated using Schrödinger QikProp software...
April 18, 2017: Natural Products and Bioprospecting
https://www.readbyqxmd.com/read/28419443/loss-of-natural-killer-t-nkt-cells-promotes-pancreatic-cancer-in-lsl-kras-g12d-mice
#8
Naveena B Janakiram, Altaf Mohammed, Taylor Bryant, Rebekah Ritchie, Nicole Stratton, Lydgia Jackson, Stan Lightfoot, Doris M Benbrook, Adam Asch, Mark L Lang, Chinthalapally V Rao
Role of unique T cell population, Natural Killer T (NKT) cells which have similar functions like NK cells in PC is not yet evaluated. In order to address the regulatory roles of NKT cells on tumor progression through tumor-associated macrophages (TAM) and their production of microsomal prostaglandin E synthase-1 (mPGES-1) and 5-lipoxygenase (5-LOX) in (Kras)-driven pancreatic tumor (KPT) progression, we crossed CD1d(-/-) mice deficient in both iNKT and vNKT cells with the Kras(G12D) mice. Loss of NKT cells significantly increased pancreatic intraepithelial neoplasia lesions [PanINs] and also increased 5-LOX and mPGES-1 expressions in M2 type macrophages and cancer stem like cells in pancreatic tumors...
April 18, 2017: Immunology
https://www.readbyqxmd.com/read/28415902/metabolism-studies-on-hydroxygenkwanin-and-genkwanin-in-human-liver-microsomes-by-uhplc-q-tof-ms
#9
Lin Yuan, Caijuan Liang, Xinpeng Diao, Xiaoye Cheng, Man Liao, Lantong Zhang
Hydroxygenkwanin (HYGN) and genkwanin (GN) are major constituents of Genkwa Flos for the treatment of edema, ascites, cough, asthma, and cancer. This is a report about the investigation of the metabolic fate of HYGN and GN in human liver microsomes and the recombinant UGT enzymes by using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS). An on-line data acquisition method multiple mass defect filter (MMDF) combined with dynamic background subtraction (DBS) was developed to trace all probable metabolites...
April 18, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28415783/mass-spectral-analysis-of-the-multikinase-inhibitor-bzg-and-its-metabolites-and-analysis-of-their-binding-to-vascular-endothelial-growth-factor-receptor-2
#10
Yan Lou, Wenqi Qiu, Zhe Wu, Qian Wang, Yunqing Qiu, Su Zeng
We previously showed that BZG is a novel multitarget kinase inhibitor, which inhibited hepatocellular carcinoma in vivo and in vitro. In the present study, we used ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) to characterize BZG and its metabolites generated in vivo. The probable metabolic mechanism was further confirmed by analysis of Phase I and Phase II metabolism in liver microsomes and with recombinant enzymes. In addition, the binding affinities of BZG metabolites to vascular endothelial growth factor receptor 2 (VEGFR2) were predicted using electronic high throughput screening (eHiTS)...
March 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415021/in-vitro-investigation-of-metabolic-profiling-of-a-potent-topoisomerase-inhibitors-fluorescein-hydrazones-flhs-in-rlms-by-lc-ms-ms
#11
A F M Motiur Rahman, Nasser S Al-Shakliah, Wencui Yin, Adnan A Kadi
Metabolic profiling of newly reported two topoisomerase inhibitors namely fluorescein hydrazones (FLHs) were studied in rat liver microsomes (RLMs) and the data were acquired in a liquid chromatography (LC) ion trap mass spectrometry. (E)-3',6'-dihydroxy-2-((2-nitrobenzylidene)amino)spiro[isoindoline-1,9'-xanthen]-3-one (1) was bio-transformed into two mono-hydroxylated, one double hydroxylated and a tetra hydroxylated metabolites, on the other hand, (Z)-3',6'-dihydroxy-2-((2-oxoindolin-3-ylidene)amino)spiro[isoindoline-1,9'-xanthen]-3-one (2) was bio-transformed into eight possible metabolites by cleavage reduction, hydroxylation, cleavage reduction together with hydroxylated and azo-reduction in RLMs in presence of NADPH-generating system...
April 10, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28413749/targeted-fluoro-positioning-for-the-discovery-of-a-potent-and-highly-selective-matrix-metalloproteinase-inhibitor
#12
Thomas Fischer, Rainer Riedl
The incorporation of fluorine atoms into functional molecules is of wide interest in synthetic organic chemistry as well as cognate disciplines. In particular, in medicinal chemistry, there is a strong desire to positively influence the physicochemical molecular properties of drug compounds by introducing fluorine into biologically active molecules. Here, we present targeted fluoro positioning as the key design principle of converting a weak matrix metalloproteinase-13 (MMP-13) inhibitor into a very potent (IC50=6 nm) and highly selective (selectivity factors of >1000 over MMP-1, 2, 3, 7, 8, 9, 10, 12, 14) inhibitor with excellent plasma and microsomal stability, and no binding to the hERG channel (hERG: human ether-a-go-go related gene)...
April 2017: ChemistryOpen
https://www.readbyqxmd.com/read/28413634/involvement-of-regucalcin-gene-promoter-region-related-protein-p117-a-transcription-factor-in-human-obesity
#13
Masayoshi Yamaguchi, Tomiyasu Murata
Regucalcin gene promoter region-related protein-p117 (RGPR-p117; gene symbol, rgpr-117) was identified in 2001 as a novel transcription factor that specifically binds to a nuclear factor I consensus motif, TTGGC(N)6CC in the promoter region of the regucalcin (rgn) gene. The human RGPR-p117 gene consists of 26 exons spanning ~4.1 kbp and is localized on chromosome 1q25.2. The nuclear translocation of cytoplasm RGPR-p117 is mediated via the protein kinase C-dependent signaling pathway. Overexpression of RGPR-p117 enhances the transcription activity of rgn, and a protective effect on cell death by inhibition of gene expression levels of caspase-3, caspase-8 and FADD proteins that possess the TTGGC motif in the promoter region of those genes was revealed...
April 2017: Biomedical Reports
https://www.readbyqxmd.com/read/28413469/repairing-effects-of-icam-1-expressing-mesenchymal-stem-cells-in-mice-with-autoimmune-thyroiditis
#14
Shifeng Ma, Xiuhui Chen, Lihui Wang, Ying Wei, Yongqing Ni, Yanan Chu, Yuanlin Liu, Heng Zhu, Rongxiu Zheng, Yi Zhang
The aim of the present study was to determine the repairing effects of intercellular adhesion molecule (ICAM)-1-expressing mesenchymal stem cells (MSCs) in mice with autoimmune thyroiditis. Following induction of an experimental autoimmune thyroiditis (EAT) model, mice were randomly divided into the following groups (n=10 each): i) Normal control; and experimental groups that were subject to EAT induction, including ii) EAT model; and iii) primary MSC; iv) C3H10T1/2/MSC; v) C3H10T1/2-MIGR1/MSC; and vi) C3H10T1/2-MIGR1-ICAM-1/MSC, which were all administered the relevant cells...
April 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28412400/prediction-of-losartan-active-carboxylic-acid-metabolite-exposure-following-losartan-administration-using-static-and-physiologically-based-pharmacokinetic-models
#15
Hoa Q Nguyen, Jian Lin, Emi Kimoto, Ernesto Callegari, Susanna Tse, R Scott Obach
The aim of this study was to evaluate a strategy based on static and dynamic physiologically based pharmacokinetic (PBPK) modeling for the prediction of metabolite and parent drug area under the time-concentration curve ratio (AUCm/AUCp) and their PK profiles in humans using in vitro data when active transport processes are involved in disposition. The strategy was applied to losartan and its pharmacologically active metabolite carboxylosartan as test compounds. Hepatobiliary transport including transport-mediated uptake, canilicular and basolateral efflux, and metabolic clearance estimates were obtained from in vitro studies using human liver microsomes and sandwich cultured hepatocytes...
April 12, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28411455/identification-of-3-substituted-6-1-1h-1-2-3-triazolo-4-5-b-pyrazin-1-yl-ethyl-quinoline-derivatives-as-highly-potent-and-selective-mesenchymal-epithelial-transition-factor-c-met-inhibitors-via-metabolite-profiling-based-structural-optimization
#16
Fei Zhao, Le-Duo Zhang, Yu Hao, Na Chen, Rui Bai, Yu-Ji Wang, Chun-Chun Zhang, Gong-Sheng Li, Li-Jun Hao, Chen Shi, Jing Zhang, Yu Mao, Yi Fan, Guang-Xin Xia, Jian-Xin Yu, Yan-Jun Liu
c-Met/HGF signaling pathway plays an important role in cancer progression, and it was considered to be related to poor prognosis and drug resistance. Based on metabolite profiling of (S)-7-fluoro-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyrazin-1-yl)ethyl)quinoline (1), a series of 2-substituted or 3-substituted-6-(1-(1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)quinoline derivatives was rationally designed and evaluated. Most of the 3-substituted derivatives not only exhibited potent activities in both enzymatic and cellular assays, but also were stable in liver microsomes among different species (human, rat and monkey)...
April 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28408542/acyl-coa-lysophosphatidylethanolamine-acyltransferase-activity-affects-growth
#17
Katarzyna Jasieniecka-Gazarkiewicz, Ida Lager, Anders Carlsson, Katharina Gutbrod, Helga Peisker, Peter Dörmann, Sten Stymne, Antoni Banas
Arabidopsis contains two enzymes (encoded by the At1g80950 and At2g456702 genes) preferentially acylating lyso-phosphatidylethanolamine (LPE) with acyl-CoA, designated lyso-phosphatidylethanolamine acyltransferase 1 (LPEAT1) and lyso-phosphatidylethanolamine acyltransferase 2 (LPEAT2). T-DNA insertion mutants of lpeat2 and double mutants of lpeat1 lpeat2 showed impaired growth, smaller leaves, shorter roots, less seed setting and reduced lipid content per FW in roots and seeds and large increases in LPE and lyso-phosphatidylcholine (LPC) contents in leaves...
April 13, 2017: Plant Physiology
https://www.readbyqxmd.com/read/28408313/preventing-cardiovascular-heart-disease-promising-nutraceutical-and-non-nutraceutical-treatments-for-cholesterol-management
#18
REVIEW
T P Johnston, T A Korolenko, M Pirro, A Sahebkar
Hypercholesterolemia is one of the major risk factors for the development of cardiovascular disease. Atherosclerosis resulting from hypercholesterolemia causes many serious cardiovascular diseases. Statins are generally accepted as a treatment of choice for lowering low-density lipoprotein (LDL) cholesterol, which reduces coronary heart disease morbidity and mortality. Since statin use can be associated with muscle problems and other adverse symptoms, non-adherence and discontinuation of statin therapy often leads to inadequate control of plasma cholesterol levels and increased cardiovascular risk...
April 10, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28401020/control-of-tissue-size-and-development-by-a-regulatory-element-in-the-yorkie-3-utr
#19
Takanari Umegawachi, Hideki Yoshida, Hiromu Koshida, Momoko Yamada, Yasuyuki Ohkawa, Tetsuya Sato, Mikita Suyama, Henry M Krause, Masamitsu Yamaguchi
Regulation of the Hippo pathway via phosphorylation of Yorkie (Yki), the Drosophila homolog of human Yes-associated protein 1, is conserved from Drosophila to humans. Overexpression of a non-phosphorylatable form of Yki induces severe overgrowth in adult fly eyes. Here, we show that yki mRNA associates with microsomal fractions and forms foci that partially colocalize to processing bodies in the vicinity of endoplasmic reticulum. This localization is dependent on a stem-loop (SL) structure in the 3' untranslated region of yki...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28400824/melatonin-and-human-mitochondrial-diseases
#20
REVIEW
Reza Sharafati-Chaleshtori, Hedayatollah Shirzad, Mahmoud Rafieian-Kopaei, Amin Soltani
Mitochondrial dysfunction is one of the main causative factors in a wide variety of complications such as neurodegenerative disorders, ischemia/reperfusion, aging process, and septic shock. Decrease in respiratory complex activity, increase in free radical production, increase in mitochondrial synthase activity, increase in nitric oxide production, and impair in electron transport system and/or mitochondrial permeability are considered as the main factors responsible for mitochondrial dysfunction. Melatonin, the pineal gland hormone, is selectively taken up by mitochondria and acts as a powerful antioxidant, regulating the mitochondrial bioenergetic function...
2017: Journal of Research in Medical Sciences: the Official Journal of Isfahan University of Medical Sciences
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