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The synthesis and characterization of a gadolinium-based contrast agent conjugated to 3-phosphoglycerate (Gd-3PG) are reported. The synthetic steps are optimized to incorporate a selective deprotection strategy for a primary tert-butyl dimethyl silyl (TBS) hydroxyl over a secondary one. The relaxivity of Gd-3PG shows characteristic improvement, likely due to secondary sphere effects and/or an increase in molecular weight (5.39 ± 0.14 mM−1 s−1 at 1.4 T and 37 °C). Michaelis–Menten enzymatic kinetics was measured on the modified 3PG-arm and it showed similar activity to the native 3PG metabolite, Km = 240 ± 30 μM. This agent and future versions of this type of GBCA, which are conjugated to glycolytic metabolites, were designed to monitor in vivo allosteric regulatory events in glycolytic processes. [ABSTRACT FROM AUTHOR]

Senescent cells play a vital role in the pathogenesis of musculoskeletal (MSK) diseases, such as chronic inflammatory joint disorders, rheumatoid arthritis (RA), and osteoarthritis (OA). Cellular senescence in articular joints represents a response of local cells to persistent stress that leads to cell-cycle arrest and enhanced production of inflammatory cytokines, which in turn perpetuates joint damage and leads to significant morbidities in afflicted patients. It has been recently discovered that clearance of senescent cells by novel "senolytic" therapies can attenuate the chronic inflammatory microenvironment of RA and OA, preventing further disease progression and supporting healing processes. To identify patients who might benefit from these new senolytic therapies and monitor therapy response, there is an unmet need to identify and map senescent cells in articular joints and related musculoskeletal tissues. To fill this gap, new imaging biomarkers are being developed to detect and characterize senescent cells in human joints and musculoskeletal tissues. This review article will provide an overview of these efforts. New imaging biomarkers for senescence cells are expected to significantly improve the specificity of state-of-the-art imaging technologies for diagnosing musculoskeletal disorders. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) play key roles in diverse biological processes, transport biomolecules between cells and have been engineered for therapeutic applications. A useful EV bioengineering strategy is to express engineered proteins on the EV surface to confer targeting, bioactivity and other properties. Measuring how incorporation varies across a population of EVs is important for characterising such materials and understanding their function, yet it remains challenging to quantitatively characterise the absolute number of engineered proteins incorporated at single‐EV resolution. To address these needs, we developed a HaloTag‐based characterisation platform in which dyes or other synthetic species can be covalently and stoichiometrically attached to engineered proteins on the EV surface. To evaluate this system, we employed several orthogonal quantification methods, including flow cytometry and fluorescence microscopy, and found that HaloTag‐mediated quantification is generally robust across EV analysis methods. We compared HaloTag‐labelling to antibody‐labelling of EVs using single vesicle flow cytometry, enabling us to measure the substantial degree to which antibody labelling can underestimate proteins present on an EV. Finally, we demonstrate the use of HaloTag to compare between protein designs for EV bioengineering. Overall, the HaloTag system is a useful EV characterisation tool which complements and expands existing methods. [ABSTRACT FROM AUTHOR]

Basal Cell Carcinoma (BCC) is the most commonly diagnosed cancer worldwide. While the survivability of BCC is high, many patients are excluded from clinically available treatments due to health risks or personal choice. Further, patients with advanced or metastatic disease have severely limited treatment options. The dysregulation of the Hedgehog (Hh) signaling cascade drives onset and progression of BCC. As such, the modulation of this pathway has driven advancements in BCC research. In this review, we focus firstly on inhibitors that target the Hh pathway as chemotherapeutics against BCC. Two therapies targeting Hh signaling have been made clinically available for BCC patients, but these treatments suffer from limited initial efficacy and a high rate of chemoresistant tumor recurrence. Herein, we describe more recent developments of chemical scaffolds that have been designed to hopefully improve upon the available therapeutics. We secondly discuss the history and recent efforts involving modulation of the Hh genome as a method of producing in vivo models of BCC for preclinical research. While there are many advancements left to be made towards improving patient outcomes with BCC, it is clear that targeting the Hh pathway will remain at the forefront of research efforts in designing more effective chemotherapeutics as well as relevant preclinical models. [ABSTRACT FROM AUTHOR]

A new class of magnetic resonance (MR) contrast agents that uses a self-immolative mechanism for activation in the presence of an enzyme is reported. A Gd(III) agent that is activated by the oncologically significant beta-glucuronidase is synthesized in nine steps.

Research has been conducted on the intracellular Ca (super)2+ and its regulation in living animals. The use of the MRI contrast agent where the complex relaxivity is controlled by the absence or presence of the divalent ion Ca (super)2+ is described.

The detection of a point mutation using dual-signaling probes on CMS-DNA arrays coupled to an electrochemical reader is described. The results show that rapid and accurate detection of a single-base mismatch is achieved by using these dual-signaling probes on CMS-DNA chips.

Metal complexes that bind to an enzyme's active site could be used to inhibit the enzyme if excess enzymatic activity is causing disease. However, the metal complex must be specific to that enzyme, must be stable, non-toxic, and bioavailable, and must produce no compensatory effects.

Axial ligation X affects reduction potentials more than equatorial substituents B and A in a study of the electrochemical properties of cobalt(III) derivatives of acacen (H2acacen = bis(acetylacetone) ethylenediimine). The lowest pi-pi* intraligand charge-transfer transition is responsible for the absorption between 340-378 nm in CoIII(acacen) spectra. A study is presented of Co(III) interactions with nucleic acids and proteins, with some cobalt(III) Schiff base complexes known to be antiviral agents.

The first steroid conjugated hormone magnetic resonance (MR) contrast agent is synthesized to track cell signaling processes upon binding to a transcriptional system. By combining a transcriptional system and a noninvasive imaging technology, the compound successfully crossed cell membranes and modulated gene transcription.