Elastin is an essential vertebrate protein responsible for the elasticity of force-bearing tissues such as those of the lungs, blood vessels, and skin. One of the key features required for the exceptional properties of this durable biopolymer is the extensive covalent cross-linking between domains of its monomer molecule tropoelastin. To date, elastin's exact molecular assembly and mechanical properties are poorly understood. Here, using bovine elastin, we investigated the different types of cross-links in mature elastin to gain insight into its structure. We purified and proteolytically cleaved elastin from a single tissue sample into soluble cross-linked and noncross-linked peptides that we studied by high-resolution MS. This analysis enabled the elucidation of cross-links and other elastin modifications. We found that the lysine residues within the tropoelastin sequence were simultaneously unmodified and involved in various types of cross-links with different other domains. The Lys-Pro domains were almost exclusively linked via lysinonorleucine, whereas Lys-Ala domains were found to be cross-linked via lysinonorleucine, allysine aldol, and desmosine. Unexpectedly, we identified a high number of intramolecular cross-links between lysine residues in close proximity. In summary, we show on the molecular level that elastin formation involves random cross-linking of tropoelastin monomers resulting in an unordered network, an unexpected finding compared with previous assumptions of an overall beaded structure.

Natural products have been used for the treatment of human diseases since ancient history. Over time, due to the lack of precise tools and techniques for the separation, purification, and structural elucidation of active constituents in natural resources there has been a decline in financial support and efforts in characterization of natural products. Advances in the design of chemical compounds and the understanding of their functions is of pharmacological importance for the biomedical field. However, natural products regained attention as sources of novel drug candidates upon recent developments and progress in technology. Natural compounds were shown to bear an inherent ability to bind to biomacromolecules and cover an unparalleled chemical space in comparison to most libraries used for high-throughput screening. Thus, natural products hold a great potential for the drug discovery of new scaffolds for therapeutic targets such as sirtuins. Sirtuins are Class III histone deacetylases that have been linked to many diseases such as Parkinson`s disease, Alzheimer’s disease, type II diabetes, and cancer linked to aging. In this review, we examine the revitalization of interest in natural products for drug discovery and discuss natural product modulators of sirtuins that could serve as a starting point for the development of isoform selective and highly potent drug-like compounds, as well as the potential application of naturally occurring sirtuin inhibitors in human health and those in clinical trials.

Chemical toxins pose a great threat to honey bee health because they affect memory and cognition, diminish immunity, and increase susceptibility to infection, resulting in decreased colony performance, reproduction, and survival. Although the behavioral effects of sub-lethal chemical exposure on honey bees have been intensively studied, how xenobiotics affect olfaction, at the molecular level, still needs to be elucidated. In the present work, in silico tools, such as molecular docking, binding free energy calculations, and molecular dynamics simulations are used to predict if environmental chemicals have stronger binding affinities to honey bee antennal odorant-binding protein 14 (OBP14) than the representative floral odors citralva, eugenol, and the fluorescent probe 1-N-phenylnaphthylamine. Based on structural analysis, 21 chemicals from crop pesticides, household appliances, cosmetics, food, public health-related products, and other sources, many of which are pervasive in the hive environment, have higher binding affinities than the floral odors. These results suggest that chemical exposures are likely to interfere with the honey bee's sense of smell and this disruptive mechanism may be responsible for the lower associative learning and memory based on olfaction found in bees exposed to pesticides. Moreover, bees mainly rely on olfactory cues to perceive their environment and orient themselves as well as to discriminate and identify their food, predators, nestmates, and diseased individuals that need to be removed with hygienic behavior. In summary, sub-lethal exposure to environmental toxins can contribute to colony collapse in several ways from the disruption of proper olfaction functioning.binding free energy calculation, chemical toxin, honey bee, molecular docking, molecular dynamics, odorant binding protein, olfaction, pesticide | INTRODUCTIONRecently, honey bee health is in decline on a global scale and three main stressors have emerged as the potential cause of the decline, which include the loss of foraging habitat, diseases, and exposure to sub-lethal levels of pesticides. 1 The ever-increasing use of pesticides in not only the agricultural landscape but also in urban and suburban areas has led to the honey bee being exposed to a wide array of them, regularly, at sub-lethal concentrations. 2,3 Not all bee pesticide toxicity is known to behave in a dose-dependent manner resulting in low doses having a surprisingly damaging effect on bee health. 4 These sub-lethal exposures are known to have a number of negative effects on honey bees such as increased susceptibility to infection, 5 higher mortality when combined with an infection, 6 disruption of metabolic pathways, 7 homing and navigational deficiencies, 8 lower fertility and reproductive output, 9,10 and a loss of associative learning and memory based on both olfactory and visual cues. 11,12