Anti-Adhesive Surfaces Inspired by Bee Mandible Surfaces.

Propolis, a naturally sticky substance used by bees to secure their hives and protect the colony from pathogens, presents a fascinating challenge. Despite its adhesive nature, honeybees adeptly handle propolis with their mandibles. Previous research has shown a combination of an anti-adhesive fluid layer and scale-like microstructures on the inner surface of bee mandibles. Our aim was to deepen our understanding of how surface energy and microstructure influence the reduction in adhesion for challenging substances like propolis. To achieve this, we devised surfaces inspired by the intricate microstructure of bee mandibles, employing diverse techniques including roughening steel surfaces, creating lacquer structures using Bénard cells, and moulding resin surfaces with hexagonal patterns. These approaches generated patterns that mimicked the bee mandible structure to varying degrees. Subsequently, we assessed the adhesion of propolis on these bioinspired structured substrates. Our findings revealed that on rough steel and resin surfaces structured with hexagonal dimples, propolis adhesion was significantly reduced by over 40% compared to unstructured control surfaces. However, in the case of the lacquer surface patterned with Bénard cells, we did not observe a significant reduction in adhesion.

Interaction between honeybee mandibles and propolis.

In a biomimetic top-down process, challenging the problem of resin deposition on woodworking machine tools, an adequate biological model was sought, which hypothetically could have developed evolutionary anti-adhesive strategies. The honeybee (Apis mellifera) was identified as an analogue model since it collects and processes propolis, which largely consists of collected tree resin. Propolis is a sticky substance used by bees to seal their hive and protect the colony against pathogens. In spite of its stickiness, honeybees are able to handle and manipulate propolis with their mandibles. We wanted to know if beneficial anti-adhesive properties of bee mandibles reduce propolis adhesion. The anatomy of bee mandibles was studied in a (cryo-)scanning electron microscope. Adhesion experiments were performed with propolis on bee mandibles to find out if bee mandibles have anti-adhesive properties that enable bees to handle the sticky material. A scale-like pattern was found on the inside of the mandible. Fresh mandibles were covered with a seemingly fluid substance that was at least partially removed during the washing process. Propolis adhesion on bee mandibles was measured to be 1 J/m2 and was indeed significantly lower compared to five technical materials. Propolis adhesion was higher on mandibles that were washed compared to fresh, unwashed mandibles. Results indicate that the medial surface of the mandible is covered with a fluid substance that reduces propolis adhesion. First results suggested that the surface pattern does do not have a direct effect on propolis adhesion.

Truxillic acid derivatives act as peroxisome proliferator-activated receptor gamma activators.

In previous studies, we identified a truxillic acid derivative as selective activator of the peroxisome proliferator-activated receptor gamma, which is a member of the nuclear receptor family and acts as ligand-activated transcription factor of genes involved in glucose metabolism. Herein we present the structure-activity relationships of 16 truxillic acid derivatives, investigated by a cell-based reporter gene assay guided by molecular docking analysis.

Natural products in parallel chemistry--novel 5-lipoxygenase inhibitors from BIOS-based libraries starting from alpha-santonin.

Recently, we developed a concept known as biology-oriented synthesis (BIOS), which targets the design and synthesis of small- to medium-sized compound libraries on the basis of genuine natural product templates to provide screening compounds with high biological relevance. We herein describe the parallel solution phase synthesis of two BIOS-based libraries starting from alpha-santonin (1). Modification of the sesquiterpene lactone 1 by introduction of a thiazole moiety followed by a Lewis-acid-mediated lactone opening yielded a first library of natural product analogues. An acid-mediated dienone-phenol rearrangement of 1 and a subsequent etherification/amidation sequence led to a second natural product-based library. After application of a fingerprint-based virtual screening on these compounds, the biological screening of 23 selected library members against 5-lipoxygenase resulted in the discovery of four potent novel inhibitors of this enzyme.

Who cares for patients with attention-deficit/hyperactivity disorder (ADHD)? Insights from Nordbaden (Germany) on administrative prevalence and physician involvement in health care provision.

OBJECTIVE: To determine age and gender specific administrative prevalence of ADHD (hyperkinetic disorder, HKD, and hyperkinetic conduct disorder, HKCD, according to ICD-10-based coding) in Germany in 2003, and to assess physician involvement in medical care. METHOD: Retrospective claims database analysis covering the insured population of Nordbaden, Germany (n = 2.238 million). RESULTS: A total of 11,875 subjects with a diagnosis of HKD/HKCD were identified (overall 12-month prevalence rate 0.53%). Prevalence was highest among children age 7-12 years (5.0%; boys, 7.2%; girls, 2.7%). Among adults age 20 years and higher, prevalence was 0.04% (males, 0.04%; females, 0.03%). 36.0% (13.0%) of children and adolescents and 33.5% (12.5%) of adults with a diagnosis of ADHD were seen by a specialized physician at least once (four times) during the year. Physician involvement by discipline was highly skewed. CONCLUSION: Diagnosis rates in children and adolescents exceeded those expected according to ICD-10 criteria, but matched DSM-IV-based estimates. In the adult population, ADHD was rarely detected. Most patients were not seen by a mental health specialist, and physician involvement was highly concentrated. Potential policy implications include a high need for expertise among pediatricians and general practitioners. The data indicate an urgent need for further research into health care utilization and quality.

Identification of natural-product-derived inhibitors of 5-lipoxygenase activity by ligand-based virtual screening.

A natural product collection and natural-product-derived combinatorial libraries were virtually screened for potential inhibitors of human 5-lipoxygenase (5-LO) activity. We followed a sequential ligand-based approach in two steps. First, similarity searching with a topological pharmacophore descriptor (CATS 2D method) was performed to enable scaffold-hopping. Eighteen compounds were selected from a virtual hit list of 430 substances, which had mutual pharmacophore features with at least one of 43 known 5-LO inhibitors that served as query structures. Two new chemotypes exhibited significant activity in a cell-based 5-LO activity assay. The two most potent molecules served as seed structures for a second virtual screening round. This time, a focused natural-product-derived combinatorial library was analyzed by different ligand-based virtual screening methods. The best molecules from the final set of screening candidates potently suppressed 5-LO activity in intact cells and may represent a novel class of 5-LO inhibitors. The results demonstrate the potential of natural-product-derived screening libraries for hit and lead structure identification.

Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis.

Protein phosphatases have very recently emerged as important targets for chemical biology and medicinal chemistry research, and new phosphatase inhibitor classes are in high demand. The underlying frameworks of natural products represent the evolutionarily selected fractions of chemical space explored by nature so far and meet the criteria of relevance to nature and biological prevalidation most crucial to inhibitor development. We refer to synthesis efforts and compound collection development based on these criteria as biology-oriented synthesis. For the discovery of phosphatase inhibitor classes by means of this approach, four natural product-derived or -inspired medium-sized compound collections were synthesized and investigated for inhibition of the tyrosine phosphatases VE-PTP, Shp-2, PTP1B, MptpA, and MptpB and the dual-specificity phosphatases Cdc25A and VHR. The screen yielded four unprecedented and selective phosphatase inhibitor classes for four phosphatases with high hit rates. For VE-PTP and MptpB the first inhibitors were discovered. These results demonstrate that biology-oriented synthesis is an efficient approach to the discovery of new compound classes for medicinal chemistry and chemical biology research that opens up new opportunities for the study of phosphatases, which may lead to the development of new drug candidates.

Natural products in combinatorial chemistry: an andrographolide-based library.

The generation of a natural-product-based library starting from andrographolide is described. Utilizing andrographolide itself in parallel solution-phase synthesis leads to a 360-membered library. The initial transformation of the starting material via ozonolysis is followed by the conversion into a suitable template by introduction of a thiazole moiety. Subsequent decoration at two points of diversity yields the desired natural product derivatives. The selection of actually synthesized compounds is based on a virtually generated library and the assessment of its members with respect to physicochemical parameters, thus ensuring pharmacological relevance of the compounds.