Abstract Imaging contrast agents are widely investigated in preclinical and clinical studies, among which biogenic imaging contrast agents (BICAs) are developing rapidly and playing an increasingly i Show more
Abstract Imaging contrast agents are widely investigated in preclinical and clinical studies, among which biogenic imaging contrast agents (BICAs) are developing rapidly and playing an increasingly important role in biomedical research ranging from subcellular level to individual level. The unique properties of BICAs, including expression by cells as reporters and specific genetic modification, facilitate various in vitro and in vivo studies, such as quantification of gene expression, observation of protein interactions, visualization of cellular proliferation, monitoring of metabolism, and detection of dysfunctions. Furthermore, in human body, BICAs are remarkably helpful for disease diagnosis when the dysregulation of these agents occurs and can be detected through imaging techniques. There are various BICAs matched with a set of imaging techniques, including fluorescent proteins for fluorescence imaging, gas vesicles for ultrasound imaging, and ferritin for magnetic resonance imaging. In addition, bimodal and multimodal imaging can be realized through combining the functions of different BICAs, which helps overcome the limitations of monomodal imaging. In this review, the focus is on the properties, mechanisms, applications, and future directions of BICAs. Show less
The properties of small molecule Pt(II) compounds that drive specific cellular responses are of interest due to their broad clinical use as chemotherapeutics as well as to provide a better mechanistic Show more
The properties of small molecule Pt(II) compounds that drive specific cellular responses are of interest due to their broad clinical use as chemotherapeutics as well as to provide a better mechanistic understanding of bioinorganic processes. The chemotherapeutic compound cisplatin causes cell death through DNA damage, while oxaliplatin may induce cell death through inhibition of ribosome biogenesis, also referred to as nucleolar stress induction. Previous work has found a subset of oxaliplatin derivatives that cause nucleolar stress at 24 h drug treatment. Here we report that these different Pt(II) derivatives exhibit a range of rates and degrees of global nucleolar stress induction as well as inhibition of rRNA transcription. Potential explanations for these variations include both the ring size and stereochemistry of the non-aquation-labile ligand. We observe that Pt(II) compounds containing a 6-membered ring show faster onset and a higher overall degree of nucleolar stress than those containing a 5-membered ring, and that compounds having the 1R,2R-stereoisomeric conformation show faster onset and a higher overall degree of stress than those having the 1S,2S-conformation. Pt(II) cellular accumulation and cellular Pt(II)-DNA adduct formation did not correlate with nucleolar stress induction, indicating that the effect is not due to global interactions. Together these results suggest that Pt(II) compounds induce nucleolar stress through a mechanism that likely involves one or a few key intermolecular interactions. Show less
In addition to serving as respiratory electron shuttle, ferri-cytochrome c (cyt c) acts as a peroxidase; i.e., it catalyzes the oxidation of organic substrates by H2O2. This peroxidase function plays Show more
In addition to serving as respiratory electron shuttle, ferri-cytochrome c (cyt c) acts as a peroxidase; i.e., it catalyzes the oxidation of organic substrates by H2O2. This peroxidase function plays a key role during apoptosis. Typical peroxidases have a five-coordinate heme with a vacant distal coordination site that permits the iron center to interact with H2O2. In contrast, native cyt c is six-coordinate, as the distal coordination site is occupied by Met80. It thus seems counterintuitive that native cyt c would exhibit peroxidase activity. The current work scrutinizes the origin of this structure-function mismatch. Cyt c-catalyzed peroxidase reactions show an initial lag phase that is consistent with the in situ conversion of a precatalyst to an active peroxidase. Using mass spectrometry, we demonstrate the occurrence of cyt c self-oxidation in the presence of H2O2. The newly generated oxidized proteoforms are shown to possess significantly enhanced peroxidase activity. H2O2-induced modifications commence with oxidation of Tyr67, followed by permanent displacement of Met80 from the heme iron. The actual peroxidase activation step corresponds to subsequent side chain carbonylation, likely at Lys72/73. The Tyr67-oxidized/carbonylated protein has a vacant distal ligation site, and it represents the true peroxidase-active structure of cyt c. Subsequent self-oxidation eventually causes deactivation. It appears that this is the first report that identifies H2O2-induced covalent modifications as an essential component for the peroxidase activity of "native" cyt c. Show less