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efflux pump inhibition

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https://www.readbyqxmd.com/read/28202577/nimesulide-and-4-hydroxynimesulide-as-bile-acid-transporters-inhibitors-are-contributory-factors-for-drug-induced-cholestasis
#1
Lei Zhou, Xiaoyan Pang, Jingfang Jiang, Dafang Zhong, Xiaoyan Chen
Nimesulide (NIM) is a classic nonsteroidal anti-inflammatory drug. However, some patients treated with NIM suffered from cholestatic liver injury. For this reason, we investigated the potential mechanism underlying NIM-induced cholestasis by using in vivo and in vitro models. Oral administration of 100 mg/kg/day NIM to Wistar rats for 5 days increased the levels of plasma total bile acids, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase by 1.49-, 1.31-, 1.60-, and 1.29-fold, respectively...
February 15, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28173641/effects-of-adamantyl-derivatives-on-pharmacokinetic-behavior-of-paclitaxel-in-rats
#2
Kyung Mi Kim, Kyeong Lee, Kyusic Jang, Yae Seul Moon, Hwa Jeong Lee, Sandy Jeong Rhie
Paclitaxel (PTX) is one of the most frequently used anticancer agent for treating refractory ovarian cancer, metastatic breast cancer and non-small cell lung cancer. However, its oral administration is impeded by very low bioavailability (<5%) due to the P-glycopprotein (P-gp) efflux pump effect. This study investigated in vitro and in vivo P-gp inhibitory effects of adamantyl derivatives AC-603 and AC-786 in rats. Two adamantyl derivatives tested in this study increased the cytotoxicity of daunomycin (DNM) in P-gp overexpressed cell line by inhibiting P-gp efflux function...
February 6, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/28169223/insights-into-the-ion-coupling-mechanism-in-the-mate-transporter-norm-vc
#3
Alexander Krah, Ulrich Zachariae
Bacteria have developed a variety of different mechanisms to defend themselves from compounds that are toxic to them, such as antibiotics. One of these defence mechanisms is the expulsion of drugs or other noxious compounds by multidrug efflux pumps. Multidrug and toxic compound extrusion (MATE) transporters are efflux pumps that extrude metabolic waste and a variety of antibiotics out of the cell, using an ion gradient as energy source. They function via an alternative-access mechanism. When ions bind in the outward facing conformation, a large conformational change to the inward facing conformation is induced, from which the ion is released and the extruded chemical compound is bound...
February 7, 2017: Physical Biology
https://www.readbyqxmd.com/read/28161596/polygoni-multiflori-radix-derived-anthraquinones-alter-bile-acid-disposition-in-sandwich-cultured-rat-hepatocytes
#4
Li Kang, Luqin Si, Jing Rao, Dan Li, Ya Wu, Sanlan Wu, Minghui Wu, Sijie He, Wenwen Zhu, Yang Wu, Jiaqiang Xu, Gao Li, Jiangeng Huang
Hepatic adverse reaction associated with Polygoni Multiflori Radix (PMR) has been frequently reported in recent years. Highly-enriched anthraquinones (AQs) in PMR, such as emodin, chrysophanol and physcion, have been found to be hepatotoxic. In the present study, sandwich-cultured rat hepatocytes (SCRHs) were employed to investigate the effect of individual and combined AQs on the disposition of endogenous bile acids (BAs) and exogenous probe substrates including deuterium-labeled taurocholate (d5-TCA), glycochenodeoxycholic acid (d4-GCDCA) and 5 (and 6)-carboxy-2,7'dichlorofluorescein (CDF)...
February 1, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28160861/antibacterial-activity-of-epigallocatechin-3-gallate-egcg-and-its-synergism-with-%C3%AE-lactam-antibiotics-sensitizing-carbapenem-associated-multidrug-resistant-clinical-isolates-of-acinetobacter-baumannii
#5
Spencer Lee, Ghaida Saleh Al Razqan, Dong H Kwon
BACKGROUND: Infections caused by Acinetobacter baumannii were responsive to conventional antibiotic therapy. However, recently, carbapenem-associated multidrug resistant isolates have been reported worldwide and present a major therapeutic challenge. Epigallocatechin-3-Gallate (EGCG) extracted from green tea exhibits antibacterial activity. PURPOSE: We evaluated the antibacterial activity of EGCG and possible synergism with antibiotics in carbapenem-associated multidrug resistant A...
January 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28154323/exploration-of-molecular-targets-in-the-development-of-new-therapeutics-aimed-at-overcoming-multidrug-resistance
#6
Shozo Nishida, Masanobu Tsubaki
 Multidrug resistance (MDR) in cancer is a major problem in clinical settings: MDR correlates with a patient's poor prognosis and decreased quality of life. Recently, MDR was found to be involved in various signal pathways, so the inhibition of signal molecules by molecular targeting drugs may help overcome MDR. In addition, the acquisition of MDR is shown to be associated with the overexpression of drug efflux pumps such as P-glycoprotein (MDR1), which in turn affects the regulation of the expression of cell survival factors, B-cell leukemia protein 2 (Bcl-2) family proteins, etc...
2017: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/28153721/mir-138-indirectly-regulates-the-mdr1-promoter-by-nf-%C3%AE%C2%BAb-p65-silencing
#7
J L Requenez-Contreras, E S López-Castillejos, R Hernández-Flores, M A Moreno-Eutimio, J T Granados-Riveron, G U Martinez-Ruiz, G Aquino-Jarquin
MicroRNAs (miRNAs) are known to mediate post-transcriptional gene silencing in the cytoplasm and recent evidence indicates that may also possess nuclear roles in regulating gene expression. A recent study showed that miR-138 is involved in the multidrug resistance of leukemia cells through down-regulation of the drug efflux pump P-glycoprotein (P-gp), the protein encoded by the human multidrug-resistant ABCB1/MDR1 gene. However, the transcriptional regulatory mechanisms responsible remain to be elucidated. To deepen the description of the mechanism of transcriptional gene silencing on the MDR1 promoter, we initially performed a bioinformatics search for potential miR-138 binding sites in the MDR1 gene promoter sequence...
January 30, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28146280/assessment-of-bile-salt-export-pump-bsep-inhibition-in-membrane-vesicles-using-radioactive-and-lc-ms-based-detection-methods
#8
Lisa D Marroquin, Paul D Bonin, Julie Keefer, Thomas Schroeter
The bile salt export pump (BSEP, ABCB11) belongs to the ATP-binding-cassette superfamily of transporters and is predominately found in the liver. BSEP is an efflux transporter that plays a critical role in the secretion of bile salts into the bile. Inhibition of BSEP function by drugs can result in the buildup of bile salts in the liver and eventually leads to cholestasis and drug-induced liver injury (DILI). DILI is a major cause of withdrawal of drugs from the pharmaceutical market and accounts for >50% of acute liver failures...
February 1, 2017: Current Protocols in Toxicology
https://www.readbyqxmd.com/read/28143610/severe-toxicity-induced-by-accumulation-of-active-sunitinib-metabolite-in-a-japanese-patient-with-renal-cell-carcinoma-a-case-report
#9
Shinya Takasaki, Masafumi Kikuchi, Yoshihide Kawasaki, Akihiro Ito, Yoichi Arai, Hiroaki Yamaguchi, Nariyasu Mano
BACKGROUND: Sunitinib is a multi-targeted tyrosine kinase inhibitor that is approved for treatment of renal cell carcinoma as an oral anticancer drug. Therapeutic drug monitoring of total sunitinib (sunitinib and N-desethyl sunitinib) is used in our hospital to improve therapeutic efficacy, while preventing adverse effects. Here, we report the first case of a patient with metastatic renal cell carcinoma undergoing hemodialysis and presenting severe adverse events induced by the accumulation of N-desethyl sunitinib...
February 1, 2017: Journal of Medical Case Reports
https://www.readbyqxmd.com/read/28132103/polymorphisms-in-the-multidrug-resistance-1-gene-related-to-glucocorticoid-response-in-rheumatoid-arthritis-treatment
#10
Bart V J Cuppen, Katerina Pardali, Maarten C Kraan, Anne C A Marijnissen, Linda Yrlid, Marita Olsson, Johannes W J Bijlsma, Floris P J G Lafeber, Ruth D E Fritsch-Stork
A substantial proportion of rheumatoid arthritis (RA)-patients experience an insufficient response to glucocorticoids, an important therapeutic agent in RA. The multidrug-resistance 1 (MDR1) gene product P-glycoprotein (P-gp) is an efflux pump that actively transports substrates, such as glucocorticoids, out of the cell. We investigated if the variation in response might be explained by single-nucleotide polymorphisms (SNPs) in the MDR1 gene. RA-patients treated with intravenous methylprednisolone pulses (n = 18) or oral prednisone/prednisolone (n = 22) were included in a prospective cohort, and clinical response was measured after 5 and 30 days, respectively...
January 28, 2017: Rheumatology International
https://www.readbyqxmd.com/read/28129976/evaluation-of-a-series-of-2-napthamide-derivatives-as-inhibitors-of-the-drug-efflux-pump-acrb-for-the-reversal-of-antimicrobial-resistance
#11
Yinhu Wang, Rumana Mowla, Liwei Guo, Abiodun D Ogunniyi, Taufiq Rahman, Miguel A De Barros Lopes, Shutao Ma, Henrietta Venter
Drug efflux pumps confer multidrug resistance to dangerous pathogens which makes these pumps important drug targets. We have synthesised a novel series of compounds based on a 2-naphthamide pharmacore aimed at inhibiting the efflux pumps from Gram-negative bacteria. The archeatypical transporter AcrB from Escherichia coli was used as model efflux pump as AcrB is widely conserved throughout Gram-negative organisms. The compounds were tested for their antibacterial action, ability to potentiate the action of antibiotics and for their ability to inhibit Nile Red efflux by AcrB...
January 16, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28126516/selenoesters-and-selenoanhydrides-as-novel-multidrug-resistance-reversing-agents-a-confirmation-study-in-a-colon-cancer-mdr-cell-line
#12
Márió Gajdács, Gabriella Spengler, Carmen Sanmartín, Małgorzata Anna Marć, Jadwiga Handzlik, Enrique Domínguez-Álvarez
Taking into account that multidrug resistance (MDR) is the main cause for chemotherapeutic failure in cancer treatment and as a continuation of our efforts to overcome this problem we report the evaluation of one cyclic selenoanhydride (1) and ten selenoesters (2-11) in MDR human colon adenocarcinoma Colo 320 cell line. The most potent derivatives (1, 9-11) inhibited the ABCB1 efflux pump much stronger than the reference compound verapamil. Particularly, the best one (9) was 4-fold more potent than verapamil at a 10-fold lower concentration...
January 13, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28125071/backstabbing-p-gp-side-chain-cleaved-ecdysteroid-2-3-dioxolanes-hyper-sensitize-mdr-cancer-cells-to-doxorubicin-without-efflux-inhibition
#13
Attila Hunyadi, József Csábi, Ana Martins, Joseph Molnár, Attila Balázs, Gábor Tóth
P-glycoprotein (P-gp, ABCB1) over-expression, causing a multi-drug resistant (MDR) phenotype, is a major problem in cancer chemotherapy that urgently requires novel approaches. Our previous studies showed certain ecdysteroid derivatives as promising chemo-sensitizers against MDR and non-MDR cancer cell lines while also exerting mild to moderate inhibition of P-gp function. Here we report the preparation of a set of substituted 2,3-dioxolane derivatives of poststerone, a known in vivo metabolite of 20-hydroxyecdysone (20E)...
January 25, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28120193/contribution-of-emrab-efflux-pumps-to-colistin-resistance-in-acinetobacter-baumannii
#14
Ming-Feng Lin, Yun-You Lin, Chung-Yu Lan
Efflux pumps play an important role in antimicrobial resistance for Acinetobacter baumannii. However, the function of the Emr pump system and the relationship between Emr and drug resistance has not been characterized in A. baumannii. In this study, four possible groups of emr-like genes were found by searching a genome database. Among them, A1S_1772 (emrB) and A1S_1773 (emrA) were demonstrated to be co-transcribed as a single operon. Moreover, during osmotic stress, A1S_1772 showed the largest change in gene expression compared to the other emrB-like genes, and deletion of A1S_1772 (AB ΔemrB) significantly slowed cell growth in 20% sucrose...
February 2017: Journal of Microbiology / the Microbiological Society of Korea
https://www.readbyqxmd.com/read/28119480/ceramide-1-phosphate-increases-p-glycoprotein-transport-activity-at-the-blood-brain-barrier-via-prostaglandin-e2-signaling
#15
Emily V Mesev, David S Miller, Ronald E Cannon
P-glycoprotein, an ATP-driven efflux pump, regulates permeability of the blood-brain barrier (BBB). Sphingolipids, endogenous to brain tissue, influence inflammatory responses and cell survival in vitro. Our lab has previously shown that sphingolipid signaling by sphingosine 1-phosphate decreases basal P-glycoprotein transport activity. Here, we investigated the potential for another sphingolipid, ceramide 1-phosphate (C1P), to modulate efflux pumps at the BBB. Using confocal microscopy and measuring luminal accumulation of fluorescent substrates, we assessed the transport activity of several efflux pumps in isolated rat brain capillaries...
January 24, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28117588/pharmacophore-based-repositioning-of-approved-drugs-as-novel-staphylococcus-aureus-nora-efflux-pump-inhibitors
#16
Andrea Astolfi, Tommaso Felicetti, Nunzio Iraci, Giuseppe Manfroni, Serena Massari, Donatella Pietrella, Oriana Tabarrini, Glenn W Kaatz, Maria L Barreca, Stefano Sabatini, Violetta Cecchetti
An intriguing opportunity to address antimicrobial resistance is represented by the inhibition of efflux pumps. Focusing on NorA, the most important efflux pump of Staphylococcus aureus, an efflux pump inhibitors (EPIs) library was used for ligand-based pharmacophore modeling studies. By exploitation of the obtained models, an in silico drug repositioning approach allowed for the identification of novel and potent NorA EPIs.
February 8, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28113597/on-chip-bioelectric-impedance-spectroscopy-reveals-the-effect-of-p-glycoprotein-efflux-pumps-on-the-paracellular-impedance-of-tight-junctions-at-the-blood-brain-barrier
#17
Ramsey Kraya, Alexander Komin, Peter Searson
Bioelectric impedance spectroscopy was used to elucidate the influence of P-gp efflux pumps on the kinetics of tight junction down-regulation in confluent monolayers of Madine Darby Canine Kidney Epithelial Cells (MDCK) following administration of phenylarsine oxide (PAO), a molecule that inhibits protein tyrosine phosphatases (PTP) and induces matrix metalloproteinase activity. Matrix metalloproteinases (MMPs) and phosphatase inhibitors induce modification of occludin tight junction proteins critical for the proper function of the blood-brain barrier...
August 30, 2016: IEEE Transactions on Nanobioscience
https://www.readbyqxmd.com/read/28106736/development-and-sequential-analysis-of-a-new-multi-agent-anti-acne-formulation-based-on-plant-derived-antimicrobial-and-anti-inflammatory-compounds
#18
Crina Saviuc, Bianca Ciubucă, Gabriela Dincă, Coralia Bleotu, Veronica Drumea, Mariana-Carmen Chifiriuc, Marcela Popa, Gratiela Gradisteanu Pircalabioru, Luminita Marutescu, Veronica Lazăr
The antibacterial and anti-inflammatory potential of natural, plant-derived compounds has been reported in many studies. Emerging evidence indicates that plant-derived essential oils and/or their major compounds may represent a plausible alternative treatment for acne, a prevalent skin disorder in both adolescent and adult populations. Therefore, the purpose of this study was to develop and subsequently analyze the antimicrobial activity of a new multi-agent, synergic formulation based on plant-derived antimicrobial compounds (i...
January 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28101766/crossing-the-blood-brain-barrier-recent-advances-in-drug-delivery-to-the-brain
#19
Mayur M Patel, Bhoomika M Patel
CNS disorders are on the rise despite advancements in our understanding of their pathophysiological mechanisms. A major hurdle to the treatment of these disorders is the blood-brain barrier (BBB), which serves as an arduous janitor to protect the brain. Many drugs are being discovered for CNS disorders, which, however fail to enter the market because of their inability to cross the BBB. This is a pronounced challenge for the pharmaceutical fraternity. Hence, in addition to the discovery of novel entities and drug candidates, scientists are also developing new formulations of existing drugs for brain targeting...
January 18, 2017: CNS Drugs
https://www.readbyqxmd.com/read/28098416/motuporamine-derivatives-as-antimicrobial-agents-and-antibiotic-enhancers-against-resistant-gram-negative-bacteria
#20
Diane Borselli, Marine Blanchet, Jean-Michel Bolla, Aaron Muth, Kristen Skruber, Otto Phanstiel, Jean Michel Brunel
Dihydromotuporamine C and its derivatives were evaluated for their in vitro antimicrobial activities and antibiotic enhancement properties against Gram-negative bacteria and clinical isolates. The mechanism of action of one of these derivatives, MOTU-N44, was investigated against Enterobacter aerogenes by using fluorescent dyes to evaluate outer-membrane depolarization and permeabilization. Its efficiency correlated with inhibition of dye transport, thus suggesting that these molecules inhibit drug transporters by de-energization of the efflux pump rather than by direct interaction of the molecule with the pump...
January 18, 2017: Chembiochem: a European Journal of Chemical Biology
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