Synthesis and Pharmacological In Vitro Investigations of Novel Shikonin Derivatives with a Special Focus on Cyclopropane Bearing Derivatives

Melanoma is the deadliest form of skin cancer and accounts for about three quarters of all skin cancer deaths. Especially at an advanced stage, its treatment is challenging, and survival rates are very low. In previous studies, we showed that the constituents of the roots of Onosma paniculata as well as a synthetic derivative of the most active constituent showed promising results in metastatic melanoma cell lines. In the current study, we address the question whether we can generate further derivatives with optimized activity by synthesis. Therefore, we prepared 31, mainly novel shikonin derivatives and screened them in different melanoma cell lines (WM9, WM164, and MUG-Mel2 cells) using the XTT viability assay. We identified (R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl 2-cyclopropyl-2-oxoacetate as a novel derivative with even higher activity. Furthermore, pharmacological investigations including the ApoToxGlo^TM Triplex assay, LDH assay, and cell cycle measurements revealed that this compound induced apoptosis and reduced cells in the G1 phase accompanied by an increase of cells in the G2/M phase. Moreover, it showed hardly any effects on the cell membrane integrity. However, it also exhibited cytotoxicity against non-tumorigenic cells. Nevertheless, in summary, we could show that shikonin derivatives might be promising drug leads in the treatment of melanoma.     

Toughness Optimization of SBR Elastomers – Use of Fracture Mechanics Methods for Characterization

Elastomer materials are used in a wide application range and subjected to different loading from which failure of the material results. Because this failure is caused by initiation and propagation of cracks, the application of fracture mechanics methods for the assessment of the material is obvious. A short summary of the methods of technical fracture mechanics including possibilities of determination of crack resistance curves is given. Vulcanizates on the basis of SBR 1500 with various sulfur and carbon black contents were investigated. For describing the crack initiation and crack propagation behavior, several fracture mechanics examination methods were applied. Tear‐analyzer results were used to assess the crack propagation behavior under fatigue‐like loading conditions. Furthermore, for the characterization of the crack resistance of the materials under impact‐like loading conditions, instrumented tensile‐impact tests were performed. To obtain information about the initiation and propagation of a stable crack, quasi‐static fracture mechanics tests were applied. The results of the several tests are discussed in dependence on sulfur and carbon black contents. We found a non‐monotonous behavior of the toughness as a function of carbon black loading. An explanation is given in connection with a percolation‐like transition in filler morphology on larger length scales.

Schematic crack propagation curve for characterizing the fatigue behavior of the vulcanizates recorded in a TFA test.     

MALDI-TOF MS: an upcoming tool for rapid detection of antibiotic resistance in microorganisms

MALDI-TOF MS profiling for microorganism detection has already been demonstrated in the 1990s, but has evolved to the first-line identification method in many laboratories just during the past five years. While this application of MALDI-TOF MS has proven its broad applicability, accuracy, robustness, and cost-effectiveness it is of particular interest to expand the capabilities of the mass spectrometric platform. Resistance detection is the most desirable further application of MALDI-TOF MS in microbiology, but maybe also the most challenging. Different approaches have been published regarding diverse antibiotic drugs and distinct microorganism classes. The current review shall give an overview about the developments of the recent years and their potential to get transformed in clinical useful assays in the future.     

Regulation of proteins mediating neurodegeneration in experimental autoimmune encephalomyelitis and multiple sclerosis

Multiple sclerosis is characterized by inflammatory demyelination and axonal loss as pathophysiological correlates of relapsing activity and progressive development of clinical disability. The molecular processes involved in this pathogenesis are still unclear as they are quite complex and heterogeneous. In this article we present protein expression analysis of brain and spinal cord tissues from different models of murine experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model for multiple sclerosis. We observed a number of EAE-specific protein expression and PTM differences. Proteome analysis was extended to multiple sclerosis specimens in order to validate the EAE findings. Our findings suggest the regulation of a number of proteins that shed light on the molecular mechanisms of the disease processes taking place in EAE and multiple sclerosis. We found consistent modulation of proteins including serum amyloid P component, sirtuin 2, dihydropyrimidinase-related protein family proteins, stathmin 1, creatine kinase B and chloride intracellular channel protein 1. Functional classification of the proteins by database and the literature mining reveals their association with neuronal development and myelinogenesis, suggesting possible disease processes that mediate neurodegeneration.     

The Role of Polymorphisms at the Interleukin-1, Interleukin-4, GATA-3 and Cyclooxygenase-2 Genes in Non-Surgical Periodontal Therapy

Periodontitis is a multifactorial disease. The aim of this explorative study was to investigate the role of Interleukin-(IL)-1, IL-4, GATA-3 and Cyclooxygenase-(COX)-2 polymorphisms after non-surgical periodontal therapy with adjunctive systemic antibiotics (amoxicillin/metronidazole) and subsequent maintenance in a Caucasian population. Analyses were performed using blood samples from periodontitis patients of a multi-center trial (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00707369","term_id":"NCT00707369"}}NCT00707369=ABPARO-study). Polymorphisms were analyzed using quantitative real-time PCR. Clinical attachment levels (CAL), percentage of sites showing further attachment loss (PSAL) ≥1.3 mm, bleeding on probing (BOP) and plaque score were assessed. Exploratory statistical analysis was performed. A total of 209 samples were genotyped. Patients carrying heterozygous genotypes and single-nucleotide-polymorphisms (SNP) on the GATA-3-IVS4 +1468 gene locus showed less CAL loss than patients carrying wild type. Heterozygous genotypes and SNPs on the IL-1A-889, IL-1B +3954, IL-4-34, IL-4-590, GATA-3-IVS4 +1468 and COX-2-1195 gene loci did not influence CAL. In multivariate analysis, CAL was lower in patients carrying GATA-3 heterozygous genotypes and SNPs than those carrying wild-types. For the first time, effects of different genotypes were analyzed in periodontitis progression after periodontal therapy and during supportive treatment using systemic antibiotics demonstrating a slight association of GATA-3 gene locus with CAL. This result suggests that GATA-3 genotypes are a contributory but non-essential risk factor for periodontal disease progression.     

Evaluation of the Impact of Ruminant Trans Fatty Acids on Human Health: Important Aspects to Consider

The definition and evaluation of trans fatty acids (TFA) with regard to foodstuffs and health hazard are not consistent. Based on the current situation, the term should be restricted only to TFA with isolated double bonds in trans-configuration. Conjugated linoleic acids (CLA) should be separately assessed. Ideally, the origin of the consumed fat should be declared, i.e., ruminant TFA (R-TFA) and industrial TFA (non-ruminant; I-TFA). In ruminant fat, more than 50% of R-TFA consists of vaccenic acid (C18:1 t11). In addition, natural CLA, i.e., c9,t11 CLA is also present. Both are elevated in products from organic farming. In contrast to elaidic acid (t9) and t10, which occur mainly in partially hydrogenated industrial fat, t11 is partially metabolized into c9,t11 CLA via Δ9-desaturation. This is the major metabolic criterion used to differentiate between t11 and other trans C18:1. t11 indicates health beneficial effects in several studies. Moreover, CLA in milk fat is associated with the prevention of allergy and asthma. An analysis of the few studies relating to R-TFA alone makes clear that no convincing adverse physiological effect can be attributed to R-TFA. Only extremely high R-TFA intakes cause negative change in blood lipids. In conclusion, in most European countries, the intake of R-TFA is assessed as being low to moderate. Restriction of R-TFA would unjustifiably represent a disadvantage for organic farming of milk.     

The influence of user expertise and prototype fidelity in usability tests

An empirical study examined the impact of user expertise and prototype fidelity on the outcomes of a usability test. User expertise (expert vs. novice) and prototype fidelity (paper prototype, 3D mock-up, and fully operational appliance) were manipulated as independent variables in a 2 × 3 between-subjects design. Employing a floor scrubber as a model product, 48 users carried out several cleaning tasks. Usability problems identified by participants were recorded. Furthermore, performance, system management strategies and perceived usability were measured. The results showed that experts reported more usability problems than novices but these were considered to be less severe than those reported by novices. Reduced fidelity prototypes were generally suitable to predict product usability of the real appliance. The implications for the running of usability tests are specific to the fidelity of the prototype.     

Filler Wetting in Miscible ESBR/SSBR Blends and Its Effect on Mechanical Properties

The selective wetting behavior of silica in emulsion styrene butadiene rubber (ESBR)/solution styrene butadiene rubber (SSBR) blends is characterized by the wetting concept, which is further developed for filled blends based on miscible rubbers. It is found that not only the chemical rubber–filler affinity but also the topology of the filler surface significantly influences the selective filler wetting in rubber blends. The nanopore structure of the silica surface has been recognized as the main reason for the difference in the wetting behavior of the branched ESBR molecules and linear SSBR molecules. However, the effect of nanopore structure becomes more significant in the presence of silane. It is discussed that the adsorption of silane on silica surface constricts the nanopore to some extent that hinders effectively the space filling of the nanopores by the branched ESBR molecules but not by the linear SSBR molecules. As a result, in silanized ESBR/SSBR blends the dominant wetting of silica surface by the tightly bonded layer of SSBR molecules causes a low‐energy dissipation in the rubber–filler interphase. That imparts the low rolling resistance to the blends similar to that of a silica‐filled SSBR compound, while the ESBR‐rich matrix warrants the good tensile behavior, i.e., good abrasion and wear resistance of the blends.

     

Rather the Rule than the Exception: Non-Convex Pareto Sets and their Navigation in Distillation Processes

Novel algorithms for adaptive approximation and interactive navigation of Pareto sets are applied to various homogeneous distillation processes with recycle streams within an industrial flowsheet simulator. The adaptive approximation scheme shows that the Pareto set consists of both convex and non-convex regions when the product purities are maximised while minimising the total heat duties. It is illustrated how such Pareto sets can be navigated interactively using a ray tracing technique. Our results suggest that the occurrence of non-convex regions in the Pareto sets is due to recycle streams in the flowsheets and is therefore the rule rather than the exception in multi-objective optimisation of flowsheet simulations in chemical engineering.