Background: The endocannabinoid system functions through two well characterized receptor systems, the CB 1 and CB 2 receptors. Work by a number of groups in recent years has provided evidence that the system is more complicated and additional receptor types should exist to explain ligand activity in a number of physiological processes. Experimental approach: Cells transfected with the human cDNA for GPR55 were tested for their ability to bind and to mediate GTPgS binding by cannabinoid ligands. Using an antibody and peptide blocking approach, the nature of the Gprotein coupling was determined and further demonstrated by measuring activity of downstream signalling pathways.Key results: We demonstrate that GPR55 binds to and is activated by the cannabinoid ligand CP55940. In addition endocannabinoids including anandamide and virodhamine activate GTPgS binding via GPR55 with nM potencies. Ligands such as cannabidiol and abnormal cannabidiol which exhibit no CB 1 or CB 2 activity and are believed to function at a novel cannabinoid receptor, also showed activity at GPR55. GPR55 couples to Ga13 and can mediate activation of rhoA, cdc42 and rac1. Conclusions: These data suggest that GPR55 is a novel cannabinoid receptor, and its ligand profile with respect to CB 1 and CB 2 described here will permit delineation of its physiological function(s).

The application of nanomaterials (NMs) in biomedicine is increasing rapidly and offers excellent prospects for the development of new non-invasive strategies for the diagnosis and treatment of cancer. In this review, we provide a brief description of cancer pathology and the characteristics that are important for tumor-targeted NM design, followed by an overview of the different types of NMs explored to date, covering synthetic aspects and approaches explored for their application in unimodal and multimodal imaging, diagnosis and therapy. Significant synthetic advances now allow for the preparation of NMs with highly controlled geometry, surface charge, physicochemical properties, and the decoration of their surfaces with polymers and bioactive molecules in order to improve biocompatibility and to achieve active targeting. This is stimulating the development of a diverse range of nanometer-sized objects that can recognize cancer tissue, enabling visualization of tumors, delivery of anti-cancer drugs and/or the destruction of tumors by different therapeutic techniques.

Nanoparticles represent highly promising platforms for the development of imaging and therapeutic agents, including those that can either be detected via more than one imaging technique (multi-modal imaging agents) or used for both diagnosis and therapy (theranostics). A major obstacle to their medical application and translation to the clinic, however, is the fact that many accumulate in the liver and spleen as a result of opsonization and scavenging by the mononuclear phagocyte system. This focused review summarizes recent efforts to develop zwitterionic-coatings to counter this issue and render nanoparticles more biocompatible. Such coatings have been found to greatly reduce the rate and/or extent of non-specific adsorption of proteins and lipids to the nanoparticle surface, thereby inhibiting production of the "biomolecular corona" that is proposed to be a universal feature of nanoparticles within a biological environment. Additionally, in vivo studies have demonstrated that larger-sized nanoparticles with a zwitterionic coating have extended circulatory lifetimes, while those with hydrodynamic diameters of ≤5 nm exhibit small-molecule-like pharmacokinetics, remaining sufficiently small to pass through the fenestrae and slit pores during glomerular filtration within the kidneys, and enabling efficient excretion via the urine. The larger particles represent ideal candidates for use as blood pool imaging agents, whilst the small ones provide a highly promising platform for the future development of theranostics with reduced side effect profiles and superior dose delivery and image contrast capabilities.

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SUMMARY:The 26S proteasome constitutes the central proteolytic machinery of the highly conserved ubiquitin/proteasome system, the cell's major tool for extralysosomal protein degradation. Recently, a plethora of cell proteins implicated in the regulation of basic cellular processes, such as proliferation, differentiation, cell cycling, and apoptosis have been discovered to undergo processing and functional limitation by entering the ubiquitin/proteasome pathway with the final destination to be proteolytically degraded by the 26S proteasome. Because both negative and positive regulators of proliferation and apoptosis undergo proteasomal degradation in a tightly regulated and temporally controlled fashion, the 26S proteasome can play opposite roles in the regulation of proliferation and apoptosis. These roles are apparently defined by the cell's environment and proliferative state. Finally, proteasomal protein degradation is deregulated in a number of human diseases, including cancer and neurodegenerative and myodegenerative diseases, which all exhibit an imbalance of proliferation and apoptosis. An improved understanding of the modes of proteasomal action should lead to the development of beneficial therapeutic and diagnostic strategies in the future. (Lab Invest 2002, 82:965-980).