Background: Biased agonism is an incompletely understood phenomenon describing the unequal activation of different signal transduction pathways by a G protein-coupled receptor (GPCR). Results: A cell-free approach using GPCR-transducer fusion proteins (G-protein or ␤-arrestin) quantifies signaling in vitro to elucidate the molecular basis of biased agonism. Conclusion: Differences in ligand-receptor-transducer coupling account for biased agonism in cells. Significance: Biased agonism is a bona fide molecular property of GPCR ligands.

A prospective, large library virtual screen against an activated β2-adrenergic receptor (β2AR) structure returned potent agonists to the exclusion of inverse-agonists, providing the first complement to the previous virtual screening campaigns against inverse-agonist-bound G protein coupled receptor (GPCR) structures, which predicted only inverse-agonists. In addition, two hits recapitulated the signaling profile of the co-crystal ligand with respect to the G protein and arrestin mediated signaling. This functional fidelity has important implications in drug design, as the ability to predict ligands with predefined signaling properties is highly desirable. However, the agonist-bound state provides an uncertain template for modeling the activated conformation of other GPCRs, as a dopamine D2 receptor (DRD2) activated model templated on the activated β2AR structure returned few hits of only marginal potency.

Food effect, also known as food-drug interactions, is a common phenomenon associated with orally administered medications and can be defined as changes in absorption rate or absorption extent. The mechanisms of food effect and their consequences can involve multiple factors, including human post-prandial physiology, properties of the drug, and how the drug is administered. Therefore, it is essential to have a thorough understanding of these mechanisms when recommending whether a specific drug should be taken with or without food. Food-drug interactions can be clinically relevant, especially when they must be avoided to prevent undesirable effects or exploited to optimize medication therapy. This review conducts a literature search that examined studies on food effect. We summarized the literature and identified and discussed common food effect mechanisms. Furthermore, we highlighted drugs that have a clinically significant food effect and discussed the corresponding mechanisms. In addition, this review analyzes the effects of high-fat food or standard meals on the oral drug absorption rate and absorption extent for 229 drugs based on the Biopharmaceutics Drug Disposition Classification System and demonstrates an association between Biopharmaceutics Drug Disposition Classification System class and food effect.

Periostin (POSTN), a recently characterised matricellular protein, is frequently dysregulated in various malignant cancers and promotes tumor metastatic growth. POSTN plays a critical role in the crosstalk between murine breast cancer stem cells (CSCs) and their niche to permit metastatic colonization. However, whether pro-metastatic capability of POSTN is associated with multipotent potentials of mesenchymal stem cells (MSCs) has not been documented. Here we demonstrate that POSTN promotes a stem cell-like trait and a mesenchymal phenotype in human mammary epithelial cells and breast cancer cells. Interestingly, ectopic overexpression of POSTN or recombinant POSTN treatment can induce human mammary epithelial cells and breast cancer cells differentiation into multiple cell lineages that recapitulate part of the multilineage differentiation potentials of MSCs. Moreover, POSTN is highly expressed in bone marrow-derived MSCs and their derived adipocytes, chondrocytes, and osteoblasts in vitro. Furthermore, POSTN promotes the growth of xenograft tumors in vivo. POSTN-overexpressing human mammary epithelial cells enhance breast tumor growth and metastasis. These data thus provide evidence of a new role for POSTN in mammary epithelial neoplasia and metastasis, suggesting that epithelial cancer cells might acquire CSC-like traits and a mesenchymal phenotype, as well as the multipotent potentials of MSCs to promote tumorigenesis and metastasis. Therefore, targeting POSTN and other extracellular matrix components of tumor microenvironment may help to develop new therapeutical strategies to inhibit tumor metastasis.

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A novel pH activatable near-infrared fluorescence probe was developed, which successfully visualized acidosis in tumors. This probe holds promise to non-invasively predict the tumor metastasis potential and evaluate the therapeutic response.

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Background and Purpose Receptor internalisation is by nature kinetic. Application of a standard equilibrium dose response model to describe the properties of a ligand inducing internalisation, while commonly used, are therefore problematic. Here, we propose two quantitative approaches to address this issue—(a) a model‐free method and (b) a kinetic modelling approach—and systematically evaluate the performance of these methods against traditional equilibrium methods to characterise the internalisation profiles of cannabinoid CB1 receptor agonists. Experimental Approach Kinetic internalisation assays were conducted using a concentration series of six CB1 receptor ligands. Internalisation rate analysis and snapshot equilibrium analysis were performed. A model‐free method was developed based on the mean residence time of internalisation. A kinetic internalisation model was developed under the quasi‐steady state assumption. Key Results Rates of receptor internalisation depended on both agonist and concentration. Agonist potencies from snapshot equilibrium analysis increased with stimulation time, and there was no single time point at which internalisation profiles could infer agonist properties in a comparative manner. The model‐free method yielded a time‐invariant measure of potency/efficacy for internalisation. The kinetic model adequately described the internalisation of CB1 receptors over time and provided robust estimates of both potency and efficacy. Conclusion and Implications Applying equilibrium analysis to a non‐equilibrium pathway cannot provide a reliable estimate of agonist potency. Both the model‐free and kinetic modelling approaches characterised the internalisation profiles of CB1 receptor agonists. The kinetic model provides additional advantages as a method to capture changes in receptor number during other functional assays.