Regulation of polyisoprenylated methylated protein methyl esterase by polyunsaturated fatty acids and prostaglandins

Polyisoprenylation is a set of secondary modifications involving proteins whose aberrant activities are implicated in cancers and degenerative disorders. The last step of the pathway involves an ester‐forming polyisoprenylated protein methyl transferase‐ and hydrolytic polyisoprenylated methylated protein methyl esterase (PMPMEase)‐catalyzed reactions. Omega‐3 and omega‐6 PUFAs have been linked with antitumorigeneis and tumorigenesis, respectively. PUFAs are structurally similar to the polyisoprenyl groups and may interfere with polyisoprenylated protein metabolism. It was hypothesized that PUFAs may be more potent inhibitors of PMPMEase than their more polar oxidative metabolites, the prostaglandins. As such, the relative effects of PUFAs and prostaglandins on PMPMEase could explain the association between cyclooxygenase‐2 (COX‐2) expression in tumors, the chemopreventive effects of the non‐steroidal anti‐inflammatory (NSAIDs) COX‐2 inhibitors and PUFAs. PUFAs such as AA, EPA, and DHA inhibited PMPMEase activity with K_i values of 0.12–3.7 µM. The most potent prostaglandin was 63‐fold less potent than AA. The PUFAs were also more effective at inducing neuroblastoma cell death at physiologically equivalent concentrations. The lost PMPMEase activity in AA‐treated degenerating cells was restored by incubating the lysates with COX‐1 or COX‐2. PUFAs may thus be physiological regulators of cell growth and could owe these effects to PMPMEase inhibition. Practical applications: Some PUFAs have been widely reported to have anticancer benefits. However, the molecular mechanisms for these effects are not well understood. The findings in the current paper appear to suggest that inhibition of PMPMEase may underlie their effects. They also imply that the expression of COX‐2 in various tumors may serve to convert the PUFAs into significantly less inhibitory prostaglandins. From these findings, AA and the other PUFAs, rather than being substrates for the synthesis of tumorigenic agents may actually contribute in suppressing cell proliferation. This being congruent with the lower cancer risks associated with long term use of anti‐inflammatory agents, the practical implications will likely include the nutritional and/or therapeutic management of cancer with the goal of maintaining suitable levels of the fatty acids in tissues.     

Optimierte Beschreibung von Dispersionsschichten an einem vertikalen Abscheider

The image analysis of dispersion layers in a vertical separator is realized by the development of an evaluation routine. The influence on the dispersion layer of the volume flow and hydrostatic pressure is investigated in continuous and discontinuous settling tests. A direct relationship between volumetric flow / hydrostatic pressure and dispersion layer height can be determined. The observed properties of the dispersion layer are explained by the underlying coalescence and sedimentation processes. The modeling of the dispersion layer is analyzed using four different model approaches.     

Modelling inhaled particle deposition in the human lung—A review

Particle deposition in the human respiratory tract is determined by biological factors such as lung morphology and breathing patterns, and physical factors such as fluid dynamics, particle properties, and deposition mechanisms. Current particle deposition models may be grouped into two categories referring to the region of interest in the lung, i.e. either deposition in the whole lung (whole lung models), or deposition in a localized region of the lung (local scale models). In whole lung models, particle deposition in individual airways is computed by analytical equations for particle deposition efficiencies and specific flow conditions (analytical models). The present review focuses upon the philosophy of different conceptual whole lung models to determine deposition in bronchial and acinar airway generations, and to compare the deposition patterns predicted by these models. Since any modelling approach requires validation by comparison with the available experimental evidence, predicted deposition data are compared with published experimental data in human subjects. This comparison indicates that, at least during the writing of this review, deposition models can be validated only for total and, to some extent, for regional deposition. In local scale models, particle transport and deposition equations are solved by Computational Fluid and Particle Dynamics (CFPD) methods (numerical models), providing information on particle deposition patterns within selected structural elements of the lung, e.g. bronchial bifurcations. In this review, however, only their potential contribution to improve upon current analytical whole lung models will be considered.     

Doublecortin May Play a Role in Defining Chondrocyte Phenotype

Embryonic development of articular cartilage has not been well understood and the role of doublecortin (DCX) in determination of chondrocyte phenotype is unknown. Here, we use a DCX promoter-driven eGFP reporter mouse model to study the dynamic gene expression profiles in mouse embryonic handplates at E12.5 to E13.5 when the condensed mesenchymal cells differentiate into either endochondral chondrocytes or joint interzone cells. Illumina microarray analysis identified a variety of genes that were expressed differentially in the different regions of mouse handplate. The unique expression patterns of many genes were revealed. Cytl1 and 3110032G18RIK were highly expressed in the proximal region of E12.5 handplate and the carpal region of E13.5 handplate, whereas Olfr538, Kctd15, and Cited1 were highly expressed in the distal region of E12.5 and the metacarpal region of E13.5 handplates. There was an increasing gradient of Hrc expression in the proximal to distal direction in E13.5 handplate. Furthermore, when human DCX protein was expressed in human adipose stem cells, collagen II was decreased while aggrecan, matrilin 2, and GDF5 were increased during the 14-day pellet culture. These findings suggest that DCX may play a role in defining chondrocyte phenotype.     

An Experimental Workflow for Studying Barrier Integrity,Permeability, and Tight Junction Composition and Localization in a Single Endothelial Cell Monolayer: Proof of Concept

Endothelial and epithelial barrier function is crucial for the maintenance of physiological processes. The barrier paracellular permeability depends on the composition and spatial distribution of the cell-to-cell tight junctions (TJ). Here, we provide an experimental workflow that yields several layers of physiological data in the setting of a single endothelial cell monolayer. Human umbilical vein endothelial cells were grown on Transwell filters. Transendothelial electrical resistance (TER) and 10 kDa FITC dextran flux were measured using Alanyl-Glutamine (AlaGln) as a paracellular barrier modulator. Single monolayers were immunolabelled for Zonula Occludens-1 (ZO-1) and Claudin-5 (CLDN5) and used for automated immunofluorescence imaging. Finally, the same monolayers were used for single molecule localization microscopy (SMLM) of ZO-1 and CLDN5 at the nanoscale for spatial clustering analysis. The TER increased and the paracellular dextran flux decreased after the application of AlaGln and these functional changes of the monolayer were mediated by an increase in the ZO-1 and CLDN5 abundance in the cell–cell interface. At the nanoscale level, the functional and protein abundance data were accompanied by non-random increased clustering of CLDN5. Our experimental workflow provides multiple data from a single monolayer and has wide applicability in the setting of paracellular studies in endothelia and epithelia.     

Antivitamins for Medicinal Applications

Antivitamins represent a broad class of compounds that counteract the essential effects of vitamins. The symptoms triggered by such antinutritional factors resemble those of vitamin deficiencies, but can be successfully reversed by treating patients with the intact vitamin. Despite being undesirable for healthy organisms, the toxicities of these compounds present considerable interest for biological and medicinal purposes. Indeed, antivitamins played fundamental roles in the development of pioneering antibiotic and antiproliferative drugs, such as prontosil and aminopterin. Their development and optimisation were made possible by the study, throughout the 20th century, of the vitamins' and antivitamins' functions in metabolic processes. However, even with this thorough knowledge, commercialised antivitamin‐based drugs are still nowadays limited to antagonists of vitamins B₉ and K. The antivitamin field thus still needs to be explored more intensely, in view of the outstanding therapeutic success exhibited by several antivitamin‐based medicines. Here we summarise historical achievements and discuss critically recent developments, opportunities and potential limitations of the antivitamin approach, with a special focus on antivitamins K, B₉ and B₁₂.     

Crosslinked,biodegradable polyurethanes for precision-porous biomaterials: Synthesis and properties

Crosslinked poly(ester urethane)s and their acrylate derivatives based on trifunctional polycaprolactone and trifunctional aliphatic isocyanates were synthesized. Biodegradable scaffolds with uniform, controlled micron-scale porosity were fabricated with these materials. Mechanical and swelling properties of monolithic and microporous materials were studied. Cytotoxicity, hydrolytic, and enzymatic degradation and their effects on mechanical properties of the biodegradable scaffolds were investigated. The polymer degradation products were found not to be cytotoxic at moderate concentrations and to permit cell attachment and spreading. Degradation rates and mechanical properties could be tuned to desired performance criteria for a given application by adjusting crosslink density and the ratio of hard segment to soft segment. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48943.     

Deliberately Losing Control of C−H Activation Processes in the Design of Small-Molecule-Fragment Arrays Targeting Peroxisomal Metabolism

Combined photochemical arylation, “nuisance effect” (S_NAr) reaction sequences have been employed in the design of small arrays for immediate deployment in medium-throughput X-ray protein–ligand structure determination. Reactions were deliberately allowed to run “out of control” in terms of selectivity; for example the ortho-arylation of 2-phenylpyridine gave five products resulting from mono- and bisarylations combined with S_NAr processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified.