Evaluation of QSAR and ligand enzyme docking for the identification of ABCB1 substrates

P-glycoprotein (P-gp) is an efflux pump that belongs to ATP-binding cassette (ABC) transporter family embedded in the membrane bilayer. P-gp is a polyspecific protein that has demonstrated its function as a transporter of hydrophobic drugs as well as transporting lipids, steroids and metabolic products. Its role in multidrug resistance (MDR) and pharmacokinetic profile of clinically important drug molecules has been widely recognised. In this study, QSAR and enzyme-ligand docking methods were explored in order to classify substrates and non-substrates of P-glycoprotein. A set of 123 compounds designated as substrates (54) or non-substrates (69) by Matsson et al., 2009 was used for the investigation. For QSAR studies, molecular descriptors were calculated using ACD labs/LogD Suite and MOE (CCG Inc.). P-glycoprotein structures available in the Protein data bank were used for docking studies and determination of binding scores using MOE software. Binding sites were defined using co-crystallised ligand structures. Three classification algorithms which included classification and regression trees, boosted trees and support vector machine were examined. Models were developed using a training set of 98 compounds and were validated using the remaining compounds as the external test set. A model generated using BT was identified as the best of three models, with a prediction accuracy of 88%, Mathews correlation coefficient of 0.77 and Youden’s J index of 0.80 for the test set. Inclusion of various docking scores for different binding sites improved the models only marginally

The effect of hydro-alcoholic extract of celery (Apium graveolens) leaves on serum level of testosterone, FSH and LH in male rats

Background and Objective: Celery (Apium graveolens) is a plant from Apiaceae family with high nutritional and medicinal use.This plant has many phytoestrogens that can affect the pituitary-gonadal axis. The purpose of this study was to investigate the effect of hydro-alcoholic extract of celery leaves on serum level of testosterone, FSH and LH in male rats. Materials and Methods: In this experimental study, thirty-two male wistar rats were randomly divided into four groups of eight rats each. The control group did not receive anything. The sham group received distilled water (as a solvent), and the experimental groups received doses of 200 and 300 mg/kg/ BW of hydro-alcoholic extract of celery leaves for 20 days. The extract was gavaged once a day. One day after the last gavage, the rats were anaesthetized and blood samples were collected from the heart and then serum levels of testosterone, LH and FSH were measured. The data were analyzed using SPSS software and ANOVA test. Results: Concentration of LH in the treatment group with doses of 200 mg/kg (0.39±0.02 mIU/dl) reduced in comparison with control (0.67±0.01 mIU/dl) and sham (0.73±0.02 mIU/dl) groups (P0.05). Conclusion: The results indicated that the administration of 200 mg/kg doses of celery extract causes a significant reduction in serum LH concentration, but it has no effect on ganadotropin and testosterone hormones in highest doses used in this study. This finding may be due to the presence of flavonoid and antioxidant proporties of celery

Feasibility Study on Reducing Lead and Cadmium Absorption by Alfalfa (Medicago scutellata L.) in a Contaminated Soil Using Nano-Activated Carbon and Natural Based Nano-Zeolite

The first risk posed by heavy metal pollution in an ecosystem is metal accumulation in the biomass of growing plants, which has harmful effects on human health. Natural-based nanoparticles are efficient in remediating environmental pollutants because they have a high surface/volume ratio, high chemical activity and produce no harmful side-products. The present study investigates the capacity of natural-based nano-porous adsorbents for reducing the availability of heavy metals to annual alfalfa (Medicago scutellata L.) roots and keeps them in soil. In a factorial experiment based on a randomized design (with four replications), three nano-adsorbents (nano-activated carbon, natural nano-zeolite and modified nano-zeolite) and two heavy metals (lead and cadmium) have been tested. The results demonstrated that applying the highest rate of activated carbon and modified nano-zeolite reduced shoot Pb content by 34% and 33.2%, and shoot Cd content by 35.5% and 46.7%, respectively, compared with the adsorbent-free control

Immunologic factors in patients with chronic polypoid sinusitis

Nasal polyposis is the benign protrusion of soft tissue into the nasal cavity, with multifactorial origin. This study is designed to examine the suggested role of IgE and CD4 and CD8 lymphocytes in the pathogenesis of nasal polyposis. Blood samples were taken from 32 patients with chronic polypoid sinusitis and 32 controls. CD4 and CD8 total lymphocyte count were determined by flow cytometry and the level of serum IgE was measured by ELISA. Nasal discharge samples were also collected for determining IgE level in both patients and controls during surgery. In 68.8% of patients a history of allergy was present. The level of nasal discharge IgE was significantly higher (p 0.05). CD8 concentration and blood lymphocytes were significantly higher (

Immunologic factors in patients with chronic polypoid sinusitis

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Differential effects of the oncogenic BRAF inhibitor PLX4032 (vemurafenib) and its progenitor PLX4720 on ABCB1 function

PURPOSE: The clinically approved oncogenic BRAF inhibitor PLX4032 (vemurafenib) was shown to be a substrate of the ATP-binding cassette (ABC) transporter ABCB1. Here, we compared PLX4032 and its structurally closely related precursor compound PLX4720 for their interference with ABCB1 and the ABCB1-mediated compound transport using docking and cell culture experiments. METHODS: For the docking study of PLX4032 and PLX4720 with ABCB1, we analysed binding of both compounds to mouse Abcb1a and to human ABCB1 using a homology model of human ABCB1 based on the 3D structure of Abcb1a. Naturally ABCB1 expressing cells including V600E BRAF-mutated and BRAF wild-type melanoma cells and cells transduced with a lentiviral vector encoding for ABCB1 were used as cell culture models. ABCB1 expression and function were studied by the use of fluorescent and cytotoxic ABCB1 substrates in combination with ABCB1 inhibitors. RESULTS: Docking experiments predicted PLX4032 to interact stronger with ABCB1 than PLX4720. Experimental studies using different cellular models and structurally different ABCB1 substrates confirmed that PLX4032 interfered stronger with ABCB1 function than PLX4720. For example, PLX4032 (20μM) induced a 4-fold enhanced rhodamine 123 accumulation compared to PLX4720 (20μM) in ABCB1-transduced UKF-NB-3 cells and reduced the IC50 for the cytotoxic ABCB1 substrate vincristine in this model by 21-fold in contrast to a 9-fold decrease induced by PLX4720. CONCLUSIONS: PLX4032 exerted stronger effects on ABCB1-mediated drug transport than PLX4720. This indicates that small changes in a molecule can substantially modify its interaction with ABCB1, a promiscuous transporter that transports structurally different compounds

Improved defect detection of guided wave testing using split-spectrum processing

© 2020 by the authors. Ultrasonic guided wave (UGW) testing is widely applied in numerous industry areas for the examination of pipelines where structural integrity is of concern. Guided wave testing is capable of inspecting long lengths of pipes from a single tool location using some arrays of transducers positioned around the pipe. Due to dispersive propagation and the multimodal behavior of UGW, the received signal is usually degraded and noisy, that reduce the inspection range and sensitivity to small defects. Therefore, signal interpretation and identifying small defects is a challenging task in such systems, particularly for buried/coated pipes, in that the attenuation rates are considerably higher compared with a bare pipe. In this work, a novel solution is proposed to address this issue by employing an advanced signal processing approach called “split-spectrum processing” (SSP) to minimize the level of background noise and enhance the signal quality. The SSP technique has already shown promising results in a limited trial for a bar pipe and, in this work, the proposed technique has been experimentally compared with the traditional approach for coated pipes. The results illustrate that the proposed technique significantly increases the signal-to-noise ratio and enhances the sensitivity to small defects that are hidden below the background noise.Greenwich University (Internal funds code 13265-0641-R08584); Innovation UK fund managed by The Welding Institute (TWI) Ltd. (reference 102077, project IC0513 (TWI project 30034) in partnership of Brunel University

SURVEY IN IRAN OF CLARITHROMYCIN RESISTANCE IN HELICOBACTER PYLORI ISOLATES BY PCR-RFLP

The aims of this study were to assess primary resistance of H. pylori strains isolated from adult patients of Ilam, Iran to antibacterial agents (amoxicillin, clarithromycin, metronidazole and tetracycline) and detection of clarithromycin, azithromycin, clarithromycin, metronidazole and tetracycline resistance by disc diffusion. Fifty biopsies were taken from gastric mucosa of the antrum and body regions of adult patients by gastroscopy, and were cultured on Helicobacter pylori selective medium. The susceptibility of H. pylon strains showed that 44, 6, 6, 4 and 16 were resistance to metronidazole, amoxicillin, tetracycline, azithromycin, and clarithromycin, respectively. Polymerase chain reaction-restriction fragment length polymorphism analysis showed that all clarithromycin resistance isolates had A2143G mutation and PCR amplicons from these strains upon digestion by BsaI restriction enzyme resulted in 319 and 106 base pair fragments. Because most of physicians in Ilam do not use amoxicillin in triple therapy of H. pylon infection, isolates showed low rate of resistance to amoxicilli

Economic assessment of nature-based solutions as enablers of circularity in water systems

The transition from the current linear model of abstraction, use and discharge of water into recycle-reuse under the circular economy (CE) principles is momentous. An analysis of recent literature about the economic impact of linear to circular (L2C) transition is made. The review investigates the economic implications (i.e. cost-benefit) of deployment of enabling technologies, tools and methodologies within the circular water systems. The study is enhanced by presenting the results of our investigation into the policy impact (push-barriers) of L2C transition. As the vehicle for the L2C transition, nature-based solutions (NBS) and its economic and policy implications is discussed. A framework is proposed for the monetary assessment of the costs of investment in NBS technologies, infrastructure and education against the environmental and socio-economic benefits within the policy frameworks. This framework may build the early foundation for bridging the gap that exists for a systematic and objective economic impact (cost-benefit) analysis of L2C transition in the Water sector. This framework will lead to a generic multi-parametric cost model of NBS for Circularity Water Systems.Engineering and Physical Sciences Research Council (EPSRC); Horizon 2020 research and innovation program HYDROUS

Epidemiological alteration in pathogens found in ground meat in Iran: unexpected predominance of vancomycin-resistant Enterococcus faecalis

Colonization of the human and animal intestinal tract with potential pathogenic bacteria is correlated with the risk of contamination of food products. The current study analyzed the prevalence of Enterococcus faecalis and Escherichia coli O157H7 in ground meat in Ilam, Iran. Both index organisms were identified following standard food microbiological methods. For E. faecalis, the susceptibility to vancomycin was tested, and PCR was used to check for the vanA gene. E. faecalis was present in all 24 ground meat samples, with no E. coli O157H7 detected in samples. The analysis showed the presence of the vanA gene in 5/24 vancomycin resistant enterococci. In conclusion, this study for the first time demonstrates the presence of vancomycin-resistant enterococci in ground meat in Iran. This observation warrants further epidemiologic investigation and should be followed up in the future