efflux transport
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2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Valeria Fox ◽  
Francesco Santoro ◽  
Gianni Pozzi ◽  
Francesco Iannelli

Abstract Objectives In streptococci, the type M resistance to macrolides is due to the mef(A)–msr(D) efflux transport system of the ATP-Binding cassette (ABC) superfamily, where it is proposed that mef(A) codes for the transmembrane channel and msr(D) for the two ATP-binding domains. Phage ϕ1207.3 of Streptococcus pyogenes, carrying the mef(A)–msr(D) gene pair, is able to transfer the macrolide efflux phenotype to Streptococcus pneumoniae. Deletion of mef(A) in pneumococcal ϕ1207.3-carrying strains did not affect erythromycin efflux. In order to identify candidate genes likely involved in complementation of mef(A) deletion, the Mef(A) amino acid sequence was used as probe for database searching. Results In silico analysis identified 3 putative candidates in the S. pneumoniae R6 genome, namely spr0971, spr1023 and spr1932. Isogenic deletion mutants of each candidate gene were constructed and used in erythromycin sensitivity assays to investigate their contribution to mef(A) complementation. Since no change in erythromycin sensitivity was observed compared to the parental strain, we produced double and triple mutants to assess the potential synergic activity of the selected genes. Also these mutants did not complement the mef(A) function.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1035
Author(s):  
Sheena Sharma ◽  
Bhagwat Prasad

The oral route of drug administration is the most convenient method of drug delivery, but it is associated with variable bioavailability. Food is one of the major factors that affect oral drug absorption by influencing drug properties (e.g., solubility and dissolution rate) and physiological factors (e.g., metabolism and transport across the gastrointestinal tract). The aim of this work was to investigate the effect of food on the high-affinity intestinal efflux transporter substrate drugs. We hypothesized that transport efficiency is higher in the fed state as compared to the fasted state because of the lower intestinal lumen drug concentration due to prolonged gastric emptying time. A systematic analysis of reported clinical food-effect (FE) studies on 311 drugs was performed and the association of the efflux transport efficiency was investigated on the FE magnitude, i.e., changes in maximal plasma concentration and area under the plasma concentration–time profile curve for both solubility and permeability-limited drugs. In total, 124 and 88 drugs showed positive and negative FE, respectively, whereas 99 showed no FE. As expected, the solubility-limited drugs showed positive FE, but interestingly, drugs with a high potential for efflux transport, were associated with negative FE. Moreover, a high-fat diet was associated with a higher magnitude of negative FE for high-affinity efflux transporter substrates as compared to a low-fat diet. To account for changes in drug absorption after food intake, the prolonged gastric emptying time should be considered in the physiologically based pharmacokinetic (PBPK) modeling of orally absorbed efflux transporter substrate drugs.


2021 ◽  
pp. DMD-AR-2021-000430
Author(s):  
Feng Deng ◽  
Suvi-Kukka Tuomi ◽  
Mikko Neuvonen ◽  
Päivi Hirvensalo ◽  
Sami Kulju ◽  
...  

2021 ◽  
Vol 6 (6) ◽  
pp. 1750-1764
Author(s):  
Fuxin Jiang ◽  
Jian Ren ◽  
Yachai Gao ◽  
Jinna Wang ◽  
Yiping Zhao ◽  
...  

2020 ◽  
Author(s):  
JinHua Wen ◽  
MengHua Zhao ◽  
Ying Zhou ◽  
YanNi Lv

Abstract BackgroundThe accumulation of neurotoxic amyloid-beta (Aβ) in the brain is a characteristic of Alzheimer's disease (AD). Over the last decade, a number of reports have shown that P-glycoprotein (encoded by ABCB1) actively mediates the efflux transport of Aβ peptides. However, the mechanism by which Aβ peptides enter the cells is not clear. We found that the protein expression oforganic anion transporting Polypeptide 2 (Oatp2) in the liver tissue of mice with AD was significantly higher than that in the normal mice. In contrast, the protein expression of Oatp2 in the brain significantly decreased in mice with AD. OATP1B1, an important drug transporter might be related to the pathophysiology of AD. ResultsIn this study, we established an OATP1B1-GFP-HEK293T cell model to confirm the OATP1B1 mediated transport ofAβ1-42.Compared to the control group of GFP-HEK293Tcells, the uptake of Aβ1-42 protein in the OATP1B1-GFP-HEK293T group increased significantly with the increase in concentration of Aβ1-42, and also increased significantly with an increase in the duration of incubation. Similar results were observed in the flow cytometry experiment, and the uptake of Aβ1-42in HEK239T-OATP1B1 cells was almost twice that in the control group. These results indicate that OATP1B1 acts as an important “carrier” for the transport of Aβ1-42 from the blood to the tissues, including liver and brain. ConclusionsThis is a novel and interesting finding and OATP1B1 can be investigated as a new treatment target for AD.


Neuron ◽  
2020 ◽  
Vol 108 (5) ◽  
pp. 937-952.e7
Author(s):  
Robert S. Pulido ◽  
Roeben N. Munji ◽  
Tamara C. Chan ◽  
Clare R. Quirk ◽  
Geoffrey A. Weiner ◽  
...  

2020 ◽  
Vol 133 (1) ◽  
pp. 355-363
Author(s):  
Bujie Du ◽  
Yue Chong ◽  
Xingya Jiang ◽  
Mengxiao Yu ◽  
U‐Gling Lo ◽  
...  

2020 ◽  
Vol 60 (1) ◽  
pp. 351-359
Author(s):  
Bujie Du ◽  
Yue Chong ◽  
Xingya Jiang ◽  
Mengxiao Yu ◽  
U‐Gling Lo ◽  
...  

Xenobiotica ◽  
2020 ◽  
Vol 51 (1) ◽  
pp. 105-114
Author(s):  
Joseph Berthier ◽  
Mehdi Benmameri ◽  
François-Ludovic Sauvage ◽  
Gabin Fabre ◽  
Benjamin Chantemargue ◽  
...  

2020 ◽  
Vol 14 (2) ◽  
Author(s):  
Sonu Kumar Gupta ◽  
Priyanka Singh ◽  
Villayat Ali ◽  
Malkhey Verma

One of the major problems being faced by researchers and clinicians in leukemic treatment is the development of multidrug resistance (MDR) which restrict the action of several tyrosine kinase inhibitors (TKIs). MDR is a major obstacle to the success of cancer chemotherapy. The mechanism of MDR involves active drug efflux transport of ABC superfamily of proteins such as Pglycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) that weaken the effectiveness of chemotherapeutics and negative impact on the future of anticancer therapy. In this review, the authors aim to provide an overview of various multidrug resistance (MDR) mechanisms observed in cancer cells as well as the various strategies developed to overcome these MDR. Extensive studies have been carried out since last several years to enhance the efficacy of chemotherapy by defeating these MDR mechanisms with the use of novel anticancer drugs that could escape from the efflux reaction, MDR modulators or chemosensitizers, multifunctional nanotechnology, and RNA interference (RNAi) therapy.


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