Search results for "SIM"
showing 10 items of 10139 documents
Free-energy studies reveal a possible mechanism for oxidation-dependent inhibition of MGL
2016
AbstractThe function of monoacylglycerol lipase (MGL), a key actor in the hydrolytic deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2AG), is tightly controlled by the cell’s redox state: oxidative signals such as hydrogen peroxide suppress MGL activity in a reversible manner through sulfenylation of the peroxidatic cysteines, C201 and C208. Here, using as a starting point the crystal structures of human MGL (hMGL), we present evidence from molecular dynamics and metadynamics simulations along with high-resolution mass spectrometry studies indicating that sulfenylation of C201 and C208 alters the conformational equilibrium of the membrane-associated lid domain of MGL to favo…
Interference of carbidopa and other catechols with reactions catalyzed by peroxidases
2018
Abstract Background A number of compounds, including ascorbic acid, catecholamines, flavonoids, p-diphenols and hydrazine derivatives have been reported to interfere with peroxidase-based medical diagnostic tests (Trinder reaction) but the mechanisms of these effects have not been fully elucidated. Methods Reactions of bovine myeloperoxidase with o-dianisidine, bovine lactoperoxidase with ABTS and horseradish peroxidase with 4-aminoantipyrine/phenol in the presence of carbidopa, an anti-Parkinsonian drug, and other catechols, including l -dopa, were monitored spectrophotometrically and by measuring hydrogen peroxide consumption. Results Chromophore formation in all three enzyme/substrate sy…
Mathematical model of T-cell lymphoblastic lymphoma: disease, treatment, cure or relapse of a virtual cohort of patients
2017
International audience; T lymphoblastic lymphoma (T-LBL) is a rare type of lymphoma with a good prognosis with a remission rate of 85%. Patients can be completely cured or can relapse during or after a 2-year treatment. Relapses usually occur early after the remission of the acute phase. The median time of relapse is equal to 1 year, after the occurrence of complete remission (range 0.2–5.9 years) (Uyttebroeck et al., 2008). It can be assumed that patients may be treated longer than necessary with undue toxicity. The aim of our model was to investigate whether the duration of the maintenance therapy could be reduced without increasing the risk of relapses and to determine the minimum treatm…
Wavelength selection of rippling patterns in myxobacteria
2016
Rippling patterns of myxobacteria appear in starving colonies before they aggregate to form fruiting bodies. These periodic traveling cell density waves arise from the coordination of individual cell reversals, resulting from an internal clock regulating them, and from contact signaling during bacterial collisions. Here we revisit a mathematical model of rippling in myxobacteria due to Igoshin et al.\ [Proc. Natl. Acad. Sci. USA {\bf 98}, 14913 (2001) and Phys. Rev. E {\bf 70}, 041911 (2004)]. Bacteria in this model are phase oscillators with an extra internal phase through which they are coupled to a mean-field of oppositely moving bacteria. Previously, patterns for this model were obtaine…
Bioactive extracts from persimmon waste: influence of extraction conditions and ripeness
2021
In this work, a bioactive persimmon extract was produced from discarded fruits. A central composite design was used to evaluate the effect of different extraction parameters and ripeness stages of persimmon fruits on the total phenolic content and antioxidant activity of the resulting extracts. Significantly greater phenolic contents were obtained from immature persimmon (IP) fruits. The optimum IP extract with the conditions set by the experimental design was industrially up-scaled and its composition and functional properties were evaluated and compared with those obtained under lab-scale conditions. Both extracts contained significant protein (>20%) and phenolic contents (∼11–27 mg GA/g …
Pharmacogenomics of Scopoletin in Tumor Cells
2016
Drug resistance and the severe side effects of chemotherapy necessitate the development of novel anticancer drugs. Natural products are a valuable source for drug development. Scopoletin is a coumarin compound, which can be found in several Artemisia species and other plant genera. Microarray-based RNA expression profiling of the NCI cell line panel showed that cellular response of scopoletin did not correlate to the expression of ATP-binding cassette (ABC) transporters as classical drug resistance mechanisms (ABCB1, ABCB5, ABCC1, ABCG2). This was also true for the expression of the oncogene EGFR and the mutational status of the tumor suppressor gene, TP53. However, mutations in the RAS onc…
Treatment of Multidrug-Resistant Leukemia Cells by Novel Artemisinin-, Egonol-, and Thymoquinone-Derived Hybrid Compounds
2018
Two major obstacles for successful cancer treatment are the toxicity of cytostatics and the development of drug resistance in cancer cells during chemotherapy. Acquired or intrinsic drug resistance is responsible for almost 90% of treatment failure. For this reason, there is an urgent need for new anticancer drugs with improved efficacy against cancer cells, and with less toxicity on normal cells. There are impressive examples demonstrating the success of natural plant compounds to fight cancer, such as Vinca alkaloids, taxanes, and anthracyclines. Artesunic acid (ARTA), a drug for malaria treatment, also exerts cytotoxic activity towards cancer cells. Multidrug resistance often results fro…
Modeling Chronic Toxicity: A Comparison of Experimental Variability With (Q)SAR/Read-Across Predictions
2018
This study compares the accuracy of (Q)SAR/read-across predictions with the experimental variability of chronic lowest-observed-adverse-effect levels (LOAELs) from in vivo experiments. We could demonstrate that predictions of the lazy structure-activity relationships (lazar) algorithm within the applicability domain of the training data have the same variability as the experimental training data. Predictions with a lower similarity threshold (i.e., a larger distance from the applicability domain) are also significantly better than random guessing, but the errors to be expected are higher and a manual inspection of prediction results is highly recommended.
Physical mechanisms of micro- and nanodomain formation in multicomponent lipid membranes.
2016
This article summarizes a variety of physical mechanisms proposed in the literature, which can generate micro- and nanodomains in multicomponent lipid bilayers and biomembranes. It mainly focusses on lipid-driven mechanisms that do not involve direct protein-protein interactions. Specifically, it considers (i) equilibrium mechanisms based on lipid-lipid phase separation such as critical cluster formation close to critical points, and multiple domain formation in curved geometries, (ii) equilibrium mechanisms that stabilize two-dimensional microemulsions, such as the effect of linactants and the effect of curvature-composition coupling in bilayers and monolayers, and (iii) non-equilibrium me…
Intramolecular structural parameters are key modulators of the gel-liquid transition in coarse grained simulations of DPPC and DOPC lipid bilayers
2018
The capability of coarse-grained models based on the MARTINI mapping to reproduce the gel-liquid phase transition in saturated and unsaturated model lipids was investigated. We found that the model is able to reproduce a lower critical temperature for 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) with respect to 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). Nonetheless, the appearance of a gel phase for DOPC is strictly dependent on the intramolecular parameters chosen to model its molecular structure. In particular, we show that the bending angle at the coarse-grained bead corresponding to the unsaturated carbon-carbon bond acts as an order parameter determining the temperature of …