The Pentameric Channel of COMPcc in Complex With Different Fatty Acids.

The Pentameric Channel of COMPcc in Complex with Different Fatty Acids.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(11): e48130
Macfarlane AA, Orriss G, Okun N, Meier M, Klonisch T, Khajehpour M, Stetefeld J

COMPcc forms a pentameric left-handed coiled coil that is known to bind hydrophilic signaling molecules such as vitamin D(3), and vitamin A.In an integrated approach we reveal the unique binding properties of COMPcc for saturated and unsaturated fatty acids. Our observations suggest that residues Met33 (gating pore), Thr40/Asn41 (water chamber) and Gln54 (electrostatic trap) are key elements for the binding of fatty acids by COMPcc. In addition, this work characterizes the binding of various fatty acids to COMPcc using fluorescence spectroscopy. Our findings reveal a binding trend within the hydrophobic channel of COMPcc, namely, that is driven by length of the methylene tail and incorporation of unsaturation.The unique binding properties imply that COMPcc may be involved in signalling functions in which hydrophilic ligands are involved. The pentameric channel is a unique carrier for lipophilic compounds. This opens the exciting possibility that COMPcc could be developed as a targeted drug delivery system.
HubMed – drug


The effect of chance variability in blood pressure readings on the decision making of general practitioners: an internet-based case vignette study.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(11): e46556
Mohammed MA, Marshall T, Gill P

Guidelines for the management of blood pressure (BP) in primary care generally suggest that decisions be made on the basis of specific threshold values (e.g. BP 140/90 mmHg); but this fails to adequately accommodate a common cause of variation – the play of chance.To determine the impact of chance variability in BP readings on the clinical decision making of general practitioners (GPs) regarding anti-hypertensive treatment and cardiovascular risk management.We used an internet based study design, where 109 GPs were assigned to manage one of eight case vignettes (guidelines would recommend treatment for only one of the eight) and presented with blood pressure readings that were randomly selected from an underlying population.Seventeen (15.6%, 17/109) GPs consulted the vignette for whom treatment was recommended, but only 7/17 (41.2%) GPs prescribed treatment, whereas 14/92 (15.2%) GPs prescribed medication to the other vignettes. When deciding to follow-up a vignette GPs were influenced by threshold values for systolic and diastolic BP, but not by the overall cardiovascular risk. If the first reading was a low BP (systolic <140, diastolic <90) GPs were highly likely to discharge the vignette and follow-up a high BP reading (diastolic >90 or systolic BP?140). Similar factors predicted the decision to prescribe a drug, although the vignette’s cardiovascular risk (>20%) was now statistically significant (p?=?0.03).GP decision making, whilst generally consistent with guidelines, appears to be compromised by chance variation leading to under and over treatment. Interventions to adequately accommodate chance variability into clinical decision making are required.
HubMed – drug


Transcriptional Control of the Multi-Drug Transporter ABCB1 by Transcription Factor Sp3 in Different Human Tissues.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(10): e48189
Gromnicova R, Romero I, Male D

The ATP-binding cassette (ABC) transporter ABCB1, encoded by the multidrug resistance gene MDR1, is expressed on brain microvascular endothelium and several types of epithelium, but not on endothelia outside the CNS. It is an essential component of the blood-brain barrier. The aim of this study was to identify cell-specific controls on the transcription of MDR1 in human brain endothelium. Reporter assays identified a region of 500 bp around the transcription start site that was optimally active in brain endothelium. Chromatin immunoprecipitation identified Sp3 and TFIID associated with this region and EMSA (electrophoretic mobility shift assays) confirmed that Sp3 binds preferentially to an Sp-target site (GC-box) on the MDR1 promoter in brain endothelium. This result contrasts with findings in other cell types and with the colon carcinoma line Caco-2, in which Sp1 preferentially associates with the MDR1 promoter. Differences in MDR1 transcriptional control between brain endothelium and Caco-2 could not be explained by the relative abundance of Sp1:Sp3 nor by the ratio of Sp3 variants, because activating variants of Sp3 were present in both cell types. However differential binding of other transcription factors was also detected in two additional upstream regions of the MDR1 promoter. Identification of cell-specific controls on the transcription of MDR1 indicates that it may be possible to modulate multi-drug resistance on tumours, while leaving the blood brain barrier intact.
HubMed – drug


Leukocyte ABCA1 Remains Atheroprotective in Splenectomized LDL Receptor Knockout Mice.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(10): e48080
Lammers B, Zhao Y, Foks AC, Hildebrand RB, Kuiper J, Van Berkel TJ, Van Eck M

ATP-binding cassette transporter A1 (ABCA1) is an important mediator of macrophage cholesterol efflux. It mediates the efflux of cellular cholesterol to lipid-poor apolipoprotein A-I. LDL receptor (LDLr) knockout (KO) mice deficient for leukocyte ABCA1 (ABCA1 KO?LDLr KO) show increased atherosclerosis and splenic lipid accumulation despite largely attenuated serum cholesterol levels. In the present study, we aimed to explore the importance of the spleen for the atheroprotective effects of leukocyte ABCA1.LDLr KO mice were transplanted with bone marrow from ABCA1 KO mice or wild-type (WT) controls. After 8 weeks recovery, mice were either splenectomized (SP-x) or underwent a sham operation, and were subsequently challenged with a Western-type diet (WTD).In agreement with previous studies, the atherosclerotic lesion area in ABCA1 KO?LDLr KO sham animals (655±82×10(3) µm(2)) was 1.4-fold (p?=?0.03) larger compared to sham WT?LDLr KO mice (459±33×10(3) µm(2)) after 8 weeks WTD feeding, despite 1.7-fold (p<0.001) lower serum cholesterol levels. Interestingly, deletion of ABCA1 in leukocytes led to 1.6-fold higher neutrophil content in the spleen in absence of differences in circulating neutrophils. Levels of KC, an important chemoattractant for neutrophils, in serum, however, were increased 2.9-fold (p?=?0.07) in ABCA1 KO?LDLr KO mice. SP-x induced blood neutrophilia as compared to WT?LDLr KO mice (1.9-fold; p<0.05), but did not evoke differences in serum cholesterol and anti-oxLDL antibody levels. Atherosclerotic lesion development, however, was 1.3-fold induced both in the presence and absence of leukocyte ABCA1 (WT: 614±106×10(3) µm(2), ABCA1 KO: 786±44×10(3) µm(2)). Two-way ANOVA revealed independent effects on atherosclerosis for both leukocyte ABCA1 deficiency and SP-x (p<0.05).The observed splenic alterations induced by leukocyte ABCA1 deficiency do not play a significant role in the anti-atherogenic effects of leukocyte ABCA1 on lesion development. HubMed – drug


Modeling of Tumor Progression in NSCLC and Intrinsic Resistance to TKI in Loss of PTEN Expression.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(10): e48004
Bidkhori G, Moeini A, Masoudi-Nejad A

EGFR signaling plays a very important role in NSCLC. It activates Ras/ERK, PI3K/Akt and STAT activation pathways. These are the main pathways for cell proliferation and survival. We have developed two mathematical models to relate to the different EGFR signaling in NSCLC and normal cells in the presence or absence of EGFR and PTEN mutations. The dynamics of downstream signaling pathways vary in the disease state and activation of some factors can be indicative of drug resistance. Our simulation denotes the effect of EGFR mutations and increased expression of certain factors in NSCLC EGFR signaling on each of the three pathways where levels of pERK, pSTAT and pAkt are increased. Over activation of ERK, Akt and STAT3 which are the main cell proliferation and survival factors act as promoting factors for tumor progression in NSCLC. In case of loss of PTEN, Akt activity level is considerably increased. Our simulation results show that in the presence of erlotinib, downstream factors i.e. pAkt, pSTAT3 and pERK are inhibited. However, in case of loss of PTEN expression in the presence of erlotinib, pAkt level would not decrease which demonstrates that these cells are resistant to erlotinib.
HubMed – drug



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