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https://www.readbyqxmd.com/read/28918032/microrna-31-regulates-chemosensitivity-in-malignant-pleural-mesothelioma
#1
Hannah L Moody, Michael J Lind, Stephen G Maher
Malignant pleural mesothelioma (MPM) is associated with an extremely poor prognosis, and most patients initially are or rapidly become unresponsive to platinum-based chemotherapy. MicroRNA-31 (miR-31) is encoded on a genomic fragile site, 9p21.3, which is reportedly lost in many MPM tumors. Based on previous findings in a variety of other cancers, we hypothesized that miR-31 alters chemosensitivity and that miR-31 reconstitution may influence sensitivity to chemotherapeutics in MPM. Reintroduction of miR-31 into miR-31 null NCI-H2452 cells significantly enhanced clonogenic resistance to cisplatin and carboplatin...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28910443/spatiotemporally-controlled-ablation-of-klf5-results-in-dysregulated-epithelial-homeostasis-in-adult-mouse-corneas
#2
Chelsea L Loughner, Anil Tiwari, Doreswamy Kenchegowda, Sudha Swamynathan, Shivalingappa K Swamynathan
Purpose: Corneal epithelial (CE) homeostasis requires coordination between proliferation and differentiation. Here we examine the role of cell proliferation regulator Krüppel-like factor 5 (Klf5) in adult mouse CE homeostasis. Methods: Klf5 was ablated in a spatiotemporally restricted manner by inducing Cre expression in 8-week-old ternary transgenic Klf5LoxP/LoxP/Krt12rtTA/rtTA/Tet-O-Cre (Klf5Δ/ΔCE) mouse CE by administering doxycycline via chow. Normal chow-fed ternary transgenic siblings served as controls...
September 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28867436/effects-of-diosmetin-on-nine-cytochrome-p450-isoforms-ugts-and-three-drug-transporters-in-vitro
#3
Jun-Jun Chen, Jing-Xian Zhang, Xiang-Qi Zhang, Mei-Juan Qi, Mei-Zhi Shi, Jiao Yang, Ke-Zhi Zhang, Cheng Guo, Yong-Long Han
Diosmetin (3', 5, 7-trihydroxy-4'-methoxyflavone), a natural flavonoid from traditional Chinese herbs, has been used in various medicinal products because of its anticancer, antimicrobial, antioxidant, estrogenic and anti-inflammatory activity. However, flavonoids could affect the metabolic enzymes and cause drug-drug interactions (DDI), reducing the efficacy of co-administered drugs and potentially resulting in serious adverse reactions. To evaluate its potential to interact with co-administered drugs, the IC50 value of phase I cytochrome P450 enzymes (CYPs), phase II UDP-glucuronyltransferases (UGTs) and hepatic uptake transporters (organic cation transporters (OCTs), organic anion transporter polypeptides (OATPs) and Na(+)-taurocholate cotransporting polypeptides (NTCPs)) were examined in vitro by LC-MS/MS...
September 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28843219/molecular-response-to-imatinib-and-its-correlation-with-mrna-expression-levels-of-imatinib-influx-transporter-oct1-in-indian-chronic-myeloid-leukemia-patients
#4
S Chhikara, S Sazawal, T Seth, R Chaubey, K Singh, R Sharma, P Mishra, M Mahapatra, R Saxena
Background and objectives: Imatinib mesylate is approved for the treatment of Chronic Myeloid Leukemia (CML). About 20% of patients with CML do not respond to treatment with Imatinib either initially or because of acquired resistance. In addition to mutated BCR-ABL1 kinase, the organic cation transporter1 (OCT1, encoded by SLC22A1) has been considered to contribute to Imatinib resistance in patients with chronic myeloid leukemia (CML). OCT1 has been reported to be the main influx transporter involved in Imatinib uptake into CML cells...
August 27, 2017: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/28834135/the-pharmacogenetics-of-metformin-in-women-with-pcos-a-randomized-trial
#5
Andreas J T Pedersen, Tore Bjerregaard Stage, Dorte Glintborg, Marianne Andersen, Mette Marie Hougaard Christensen
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. PCOS is associated with obesity, dyslipidaemia and insulin resistance, and metformin treatment may improve such metabolic features. The effect of genetic variants in key metformin transporters, their transcriptional regulators or in metformin target genes on metformin response in women with PCOS is unclear. Associations between pharmacodynamic responses to metformin (changes in weight, lipid profile, insulin sensitivity evaluated by oral glucose tolerance testing) and polymorphisms in OCT1 (rs12208357 and rs72552763), HNF1A (rs1169288 and rs2464196), MATE1 (rs2289669 and rs2252281), MATE2-K (rs12943590) and ATM (rs11212617) were studied in 40 women with PCOS randomized to 12 months of treatment with metformin 1000 mg twice daily ± oral contraceptive pills (150 mg desogestrel + 30 μg ethinylestradiol)...
August 21, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28821623/proteolytic-cleavage-by-the-imp-complex-or-oct1-peptidase-controls-the-localization-of-the-yeast-peroxiredoxin-prx1-to-distinct-mitochondrial-compartments
#6
Fernando Gomes, Flavio Romero Palma, Mario H Barros, Eduardo T Tsuchida, Helena G Turano, Thiago G P Alegria, Marilene Demasi, Luis E S Netto
Yeast Prx1 is a mitochondrial 1-Cys peroxiredoxin that catalyzes the reduction of endogenously generated H2O2 Prx1 is synthesized on cytosolic ribosomes as a preprotein with a cleavable N-terminal presequence that is the mitochondrial targeting signal, but the mechanisms underlying Prx1 distribution to distinct mitochondrial subcompartments are unknown. Here, we provide direct evidence of the following dual mitochondrial localization of Prx1: a soluble form in the intermembrane space and a form in the matrix weakly associated with the inner mitochondrial membrane...
August 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28800539/development-of-a-rapid-and-sensitive-multiple-reaction-monitoring-proteomic-approach-for-quantification-of-transporters-in-human-liver-tissue
#7
Li Wang, Kasi J Rubadue, Jeffrey Alberts, David W Bedwell, Kenneth J Ruterbories
With increasing knowledge on the role of hepatic transporters in drug disposition, numerous efforts have been described to quantify the expression of human hepatic transporters. However, reported quantitative proteomic approaches often require long analysis times. Additionally, greater assay sensitivity is still necessary for less abundant transporters or limited quantity of samples (e.g. hepatocytes and liver tissue). In the present study, an LC-MS/MS method for rapid and simultaneous quantification of 12 hepatic transporters (BCRP, BSEP, MATE1, MRP2, MRP3, MRP4, NTCP, OATP1B1, 1B3, 2B1, OCT1, and P-gp) was developed...
September 1, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28791698/increased-systemic-exposure-and-stronger-cardiovascular-and-metabolic-adverse-reactions-to-fenoterol-in-individuals-with-heritable-oct1-deficiency
#8
Mladen V Tzvetkov, Johannes Matthaei, Sherin Pojar, Frank Faltraco, Sabrina Vogler, Thomas Prukop, Tina Seitz, Jürgen Brockmöller
Fenoterol is widely used anti-asthmatic and tocolytic agent, but high plasma concentrations of fenoterol may lead to severe and even fatal adverse reactions. We studied whether heritable deficiency of the liver organic cation transporter OCT1, a trait observed in 3% of Europeans and White Americans, affects fenoterol plasma concentrations and toxicity. OCT1 transported fenoterol with high affinity. OCT1 inhibition in human hepatocytes reduced fenoterol uptake 3-fold. After administration of 180 µg fenoterol to 39 healthy individuals, the OCT1-deficicient individuals (zero active OCT1 alleles, n=5) showed 1...
August 9, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28714373/targeting-mir-21-decreases-expression-of-multi-drug-resistant-genes-and-promotes-chemosensitivity-of-renal-carcinoma
#9
Kelly Gaudelot, Jean-Baptiste Gibier, Nicolas Pottier, Brigitte Hémon, Isabelle Van Seuningen, François Glowacki, Xavier Leroy, Christelle Cauffiez, Viviane Gnemmi, Sébastien Aubert, Michaël Perrais
Renal cell carcinoma, the most common neoplasm of adult kidney, accounts for about 3% of adult malignancies and is usually highly resistant to conventional therapy. MicroRNAs are a class of small non-coding RNAs, which have been previously shown to promote malignant initiation and progression. In this study, we focused our attention on miR-21, a well described oncomiR commonly upregulated in cancer. Using a cohort of 99 primary renal cell carcinoma samples, we showed that miR-21 expression in cancer tissues was higher than in adjacent non-tumor tissues whereas no significant difference was observed with stages, grades, and metastatic outcome...
July 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28699756/incorporation-of-a-biguanide-scaffold-enhances-drug-uptake-by-organic-cation-transporters-1-and-2
#10
Obinna N Obianom, Ana L Coutinho, Wei Yang, Hong Yang, Fengtian Xue, Yan Shu
Membrane transporters play a significant role in the transport of many endogenous and exogenous compounds. The knowledge of transporter substrate requirements has allowed further development of drugs that utilize them to ensure tissue permeation. In this study, we demonstrate that inclusion of a biguanide functionality can potentiate uptake by the organic cation transporters 1 and 2 (OCT1 and OCT2). We synthesized 18 pairs of structurally diverse compounds, each pair consisting of a parent amino compound and its biguanide analog; and then assessed their cellular uptake in HEK293 cells overexpressing human OCT1 or OCT2...
August 7, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28696229/mdr1-and-bcrp-transporter-mediated-drug-drug-interaction-between-rilpivirine-and-abacavir-and-effect-on-intestinal-absorption
#11
Josef Reznicek, Martina Ceckova, Zuzana Ptackova, Ondrej Martinec, Lenka Tupova, Lukas Cerveny, Frantisek Staud
Rilpivirine (TMC278) is a highly potent nonnucleoside reverse transcriptase inhibitor (NNRTI) representing an effective component of combination antiretroviral therapy (cART) in the treatment of HIV-positive patients. Many antiretroviral drugs commonly used in cART are substrates of ATP-binding cassette (ABC) and/or solute carrier (SLC) drug transporters and, therefore, are prone to pharmacokinetic drug-drug interactions (DDIs). The aim of our study was to evaluate rilpivirine interactions with abacavir and lamivudine on selected ABC and SLC transporters in vitro and assess its importance for pharmacokinetics in vivo Using accumulation assays in MDCK cells overexpressing selected ABC or SLC drug transporters, we revealed rilpivirine as a potent inhibitor of MDR1 and BCRP, but not MRP2, OCT1, OCT2, or MATE1...
September 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28603032/%C3%AE-2-adrenergic-receptor-mediated-in-vitro-regulation-of-human-hepatic-drug-transporter-expression-by-epinephrine
#12
Abdullah Mayati, Amélie Moreau, Claire Denizot, Bruno Stieger, Yannick Parmentier, Olivier Fardel
The catecholamine epinephrine is known to repress expression of hepatic drug metabolizing enzymes such as cytochromes P-450. The present study was designed to determine whether epinephrine may also target expression of main hepatic drug transporters, that play a major role in liver detoxification and are commonly coordinately regulated with drug detoxifying enzymes. Treatment of primary human hepatocytes with 10μM epinephrine for 24h repressed mRNA expression of various transporters, such as the sinusoidal influx transporters NTCP, OATP1B1, OATP2B1, OAT2, OAT7 and OCT1 and the efflux transporters MRP2, MRP3 and BSEP, whereas it induced that of MDR1, but failed to alter that of BCRP...
August 30, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28558868/anti-hyperuricemic-and-anti-inflammatory-actions-of-vaticaffinol-isolated-from-dipterocarpus-alatus-in-hyperuricemic-mice
#13
Yu-Sheng Chen, Chao-Jun Chen, Wei Yan, Hui-Ming Ge, Ling-Dong Kong
The present study was designed to examine the anti-hyperuricemic and anti-inflammatory effects and possible mechanisms of vaticaffinol, a resveratrol tetramer isolated from ethanol extracts of Dipterocarpus alatus, in oxonate-induced hyperuricemic mice. At 1 h after 250 mg·kg(-1) potassium oxonate was given, vaticaffinol at 20, 40, and 60 mg·kg(-1) was intragastrically administered to hyperuricemic mice once daily for seven consecutive days. Vaticaffinol significantly decreased serum uric acid levels and improved kidney function in hyperuricemic mice...
May 2017: Chinese Journal of Natural Medicines
https://www.readbyqxmd.com/read/28537559/enforcement-of-developmental-lineage-specificity-by-transcription-factor-oct1
#14
Zuolian Shen, Jinsuk Kang, Arvind Shakya, Marcin Tabaka, Elke A Jarboe, Aviv Regev, Dean Tantin
Embryonic stem cells co-express Oct4 and Oct1, a related protein with similar DNA-binding specificity. To study the role of Oct1 in ESC pluripotency and transcriptional control, we constructed germline and inducible-conditional Oct1-deficient ESC lines. ESCs lacking Oct1 show normal appearance, self-renewal and growth but manifest defects upon differentiation. They fail to form beating cardiomyocytes, generate neurons poorly, form small, poorly differentiated teratomas, and cannot generate chimeric mice. Upon RA-mediated differentiation, Oct1-deficient cells induce lineage-appropriate developmentally poised genes poorly while lineage-inappropriate genes, including extra-embryonic genes, are aberrantly expressed...
May 24, 2017: ELife
https://www.readbyqxmd.com/read/28499878/possible-role-of-organic-cation-transporters-in-the-distribution-of-11-c-sulpiride-a-dopamine-d2-receptor-antagonist
#15
Harumasa Takano, Sumito Ito, Xuan Zhang, Hiroshi Ito, Ming-Rong Zhang, Hiroshi Suzuki, Kazuya Maeda, Hiroyuki Kusuhara, Tetsuya Suhara, Yuichi Sugiyama
We synthesized [(11)C]sulpiride as a positron emission tomography probe for investigating the drug distribution in the human body. [(11)C]Sulpiride was injected to healthy male subjects in either tracer dose of [(11)C]sulpiride (approximately 222 MBq) or with therapeutic dose of sulpiride (500 mg, peroral) 3 h before the injection in a crossover fashion. Whole-body positron emission tomography imaging demonstrated that [(11)C]sulpiride accumulated exceedingly in the bladder, followed by liver, gall bladder, and kidney, respectively, at 30 min after the injection, whereas scarcely in the brain...
May 10, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28479364/involvement-of-organic-cation-transporters-in-the-kinetics-of-trimethylamine-n-oxide
#16
Takeshi Miyake, Tadahaya Mizuno, Tatsuki Mochizuki, Miyuki Kimura, Shunji Matsuki, Shin Irie, Ichiro Ieiri, Kazuya Maeda, Hiroyuki Kusuhara
Recent studies suggest that trimethylamine N-oxide (TMAO) is associated with the development of chronic kidney disease and heart failure. In this study, we investigated the importance of organic cation transporters (OCTs) in the clearance and tissue distribution of TMAO. The low-affinity and high-capacity transport of TMAO by mouse and human OCT1 and OCT2 was observed. Uptake and efflux of TMAO by the mouse hepatocytes as well as TMAO uptake into mouse kidney slices were significantly decreased by the addition of tetraethylammonium or Oct1/2 double knockout (dKO)...
May 4, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28470102/oct1-genetic-variants-are-associated-with-postoperative-morphine-related-adverse-effects-in-children
#17
Rajiv Balyan, Xue Zhang, Vidya Chidambaran, Lisa J Martin, Tomoyuki Mizuno, Tsuyoshi Fukuda, Alexander A Vinks, Senthilkumar Sadhasivam
AIM: Large interindividual variability in morphine pharmacokinetics (PK) could contribute to variability in morphine analgesia and adverse events. Respiratory depression (RD) and postoperative nausea and vomiting (PONV) are significant adverse drug response of intravenous morphine in the perioperative setting limiting its efficacy in achieving adequate surgical pain relief. OCT1 is a transporter in the liver that transports morphine from the bloodstream into hepatocytes. Earlier we reported association of genetic polymorphisms in OCT1 with morphine PK, and lower morphine clearance in Caucasian children as compared with African-American (AA) children...
May 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/28463838/engineering-the-rapid-adenovirus-production-and-amplification-rapa-cell-line-to-expedite-the-generation-of-recombinant-adenoviruses
#18
Qiang Wei, Jiaming Fan, Junyi Liao, Yulong Zou, Dongzhe Song, Jianxiang Liu, Jing Cui, Feng Liu, Chao Ma, Xue Hu, Li Li, Yichun Yu, Xiangyang Qu, Liqun Chen, Xinyi Yu, Zhicai Zhang, Chen Zhao, Zongyue Zeng, Ruyi Zhang, Shujuan Yan, Xingye Wu, Yi Shu, Russell R Reid, Michael J Lee, Jennifer Moritis Wolf, Tong-Chuan He
BACKGROUND/AIMS: While recombinant adenoviruses are among the most widely-used gene delivery vectors and usually propagated in HEK-293 cells, generating recombinant adenoviruses remains time-consuming and labor-intense. We sought to develop a rapid adenovirus production and amplification (RAPA) line by assessing human Ad5 genes (E1A, E1B19K/55K, pTP, DBP, and DNA Pol) and OCT1 for their contributions to adenovirus production. METHODS: Stable transgene expression in 293T cells was accomplished by using piggyBac system...
2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28456419/choroidal-imaging-with-swept-source-optical-coherence-tomography-in-patients-with-birdshot-chorioretinopathy-choroidal-reflectivity-and-thickness
#19
Anna I Dastiridou, Elodie Bousquet, Laura Kuehlewein, Tudor Tepelus, Dominique Monnet, Sawsen Salah, Antoine Brezin, Srinivas R Sadda
PURPOSE: To characterize choroidal thickness and choroidal reflectivity in the eyes of patients with birdshot chorioretinopathy (BSCR). DESIGN: Cross-sectional observational study. PARTICIPANTS: Two hundred twenty BSCR patients and 59 healthy controls. METHODS: Patients with BSCR and healthy controls underwent imaging of the macula in both eyes with a swept-source optical coherence tomography device (DRI-OCT1 Atlantis; Topcon)...
August 2017: Ophthalmology
https://www.readbyqxmd.com/read/28380657/genetic-polymorphisms-in-organic-cation-transporter-1-attenuates-hepatic-metformin-exposure-in-humans
#20
Elias Immanuel Ordell Sundelin, Lars Christian Gormsen, Jonas Brorson Jensen, Mikkel Holm Vendelbo, Steen Jakobsen, Ole Lajord Munk, Mette Marie Hougaard Christensen, Kim Brøsen, Jørgen Frøkiaer, Niels Jessen
Metformin has been used successfully to treat type 2 diabetes for decades. However, the efficacy of the drug varies considerably from patient to patient and this may in part be due to its pharmacokinetic properties. The aim of this study was to examine if common polymorphisms in SLC22A1, encoding the transporter protein OCT1, affect the hepatic distribution of metformin in humans. We performed non-invasive (11) C-metformin PET/CT to determine hepatic exposure in 12 subjects genotyped for variants in SLC22A1...
April 5, 2017: Clinical Pharmacology and Therapeutics
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