Design, synthesis and evaluation of side-chain hydroxylated derivatives of lithocholic acid as potent agonists of the vitamin D receptor (VDR).

A high number of biologically active and low-calcemic secosteroidal ligands of the vitamin D receptor (VDR) have been developed, some of which are already used clinically although with limited success in the treatment of hyperproliferative diseases because the required pharmaceutical dosages induce toxicity. We describe here the in silico design, synthesis, structural analysis and biological evaluation of two novel active lithocholic acid derivatives hydroxylated at the side chain as highly potent inhibitors of atopic dermatitis-relevant keratinocyte inflammation of potential therapeutic interest.

Assessing Specialized Metabolite Diversity in the Cosmopolitan Plant Genus L.

Coevolutionary theory suggests that an arms race between plants and herbivores yields increased plant specialized metabolite diversity and the geographic mosaic theory of coevolution predicts that coevolutionary interactions vary across geographic scales. Consequently, plant specialized metabolite diversity is expected to be highest in coevolutionary hotspots, geographic regions, which exhibit strong reciprocal selection on the interacting species. Despite being well-established theoretical frameworks, technical limitations have precluded rigorous hypothesis testing.

Unlocking the full potential of open innovation in the life sciences through a classification system.

A common understanding of expectations and requirements is critical for boosting research-driven business opportunities in open innovation (OI) settings. Transparent communication requires common definitions and standards for OI to align the expectations of both parties. Here, we suggest a five-level classification system for OI models, reflecting the degree of openness.

Classification complexity in myoelectric pattern recognition.

Background: Limb prosthetics, exoskeletons, and neurorehabilitation devices can be intuitively controlled using myoelectric pattern recognition (MPR) to decode the subject's intended movement. In conventional MPR, descriptive electromyography (EMG) features representing the intended movement are fed into a classification algorithm. The separability of the different movements in the feature space significantly affects the classification complexity.

The design, synthesis, and anti-inflammatory evaluation of a drug-like library based on the natural product valerenic acid.

The plant natural product, valerenic acid (1) was chosen as a desirable scaffold for the generation of a novel screening library due to its drug-like physicochemical parameters (such as LogP, hydrogen bond donor/acceptor counts, and molecular weight). An 11-membered amide library (2-12) was subsequently generated using parallel solution-phase synthesis and Ghosez's reagent. The chemical structures of all semi-synthetic analogues (2-12) were elucidated following analysis of the NMR, MS, UV and IR data.

Evolutionary prediction of medicinal properties in the genus Euphorbia L.

The current decrease of new drugs brought to the market has fostered renewed interest in plant-based drug discovery. Given the alarming rate of biodiversity loss, systematic methodologies in finding new plant-derived drugs are urgently needed. Medicinal uses of plants were proposed as proxy for bioactivity, and phylogenetic patterns in medicinal plant uses have suggested that phylogeny can be used as predictive tool.

Global medicinal uses of Euphorbia L. (Euphorbiaceae).

Ethnopharmacological Relevance: The genus Euphorbia (spurges, Euphorbiaceae) is the third largest genus of flowering plants, with almost 2000 species. Its exceptional diversity of growth forms and near-cosmopolitan distribution have attracted human interest since ancient times. For instance in Australia, topical application of latex of Euphorbia peplus L.

Lysophosphatidic acid binds to and activates GPR92, a G protein-coupled receptor highly expressed in gastrointestinal lymphocytes.

Here, the ligand binding, activation, and tissue distribution of the orphan G protein-coupled receptor (GPCR) GPR92 were studied. GPR92 binds and is activated by compounds based on the lysophosphatidic acid (LPA) backbone. The binding of LPA to GPR92 was of high affinity (K(D) = 6.

Reverse pharmacology and the de-orphanization of 7TM receptors.

Approximately 800 genes coding for seven-transmembrane, G-protein-coupled receptors have so far been recognized. In spite of this, many of these receptors are defined by their sequence only, and are therefore classified as orphan receptors. Without knowing what their endogenous ligands are, we lack the information needed to understand their physiological role and hence cannot make use of them as drug targets.

Progress in methodology. Improved reporter gene assays used to identify ligands acting on orphan seven-transmembrane receptors.

Seven-transmembrane G-protein-coupled receptors play a central role in physiology by facilitating cell communication through recognition of a wide range of ligands. Even more important, they represent important drug targets. Unfortunately, for many of these receptors the endogenous ligands, and hence their functions, remain to be identified.

Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids.

Short-chain fatty acids (SCFAs) have long been known to exert cellular effects on blood leukocytes. Acetate, propionate, and butyrate represent the most capable SCFA, inducing calcium mobilization which subsequently regulates leukocyte function in the immune system. We have cloned the previously described putative orphan G-protein coupled receptor, GPR43, and have functionally identified SCFA as the activating ligands.

A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs.

Fatty acids, which are essential nutritional components, are also involved in cardiovascular and metabolic diseases. Here we report a human cell surface receptor that we name free fatty acid receptor (FFAR), because it is specifically activated by medium to long-chain free fatty acids. The receptor belongs to the class of seven-transmembrane, G-protein coupled receptors (GPCRs) and also mediates responses to antidiabetic drugs of the thiazolidinedione type.