👤 F. F. Li

Methylation of Lys and Arg residues on non-histone proteins has emerged as a prevalent post-translational modification and as an important regulator of cellular signal transduction mediated by the MAPK, WNT, BMP, Hippo and JAK-STAT signalling pathways. Crosstalk between methylation and other types of post-translational modifications, and between histone and non-histone protein methylation frequently occurs and affects cellular functions such as chromatin remodelling, gene transcription, protein synthesis, signal transduction and DNA repair. With recent advances in proteomic techniques, in particular mass spectrometry, the stage is now set to decode the methylproteome and define its functions in health and disease. Show less

AbstractNew iridium tetrazolate complexes containing o‐, m‐, or p‐carboranyl substitution in different positions of a phenylpyridine ligand have been prepared. The carborane isomers and the effect of their substitution position in the tuning of optical properties have been examined. The neutral complexes with the carboranyl substituent on the phenyl ring in meta position relative to the metal exhibit redshifted emission bands in contrast to blueshifts for those with carboranyl in para position. All cationic complexes display evidently blueshifted dual‐peak emission compared with the carborane‐free complex (c‐TZ) with a broad single‐peak emission. Introduction of carborane leads to a blueshift over 70 nm relative to c‐TZ. Carboranes also significantly improve phosphorescence efficiency (ΦP) and lifetime (τ), that is, ΦP=0.64 versus 0.21 (c‐TZ) and τ=880 ns versus 241 ns (c‐TZ). The unique hydrophilic nido‐carborane‐based IrIII complex nido‐o‐1 shows the largest phosphorescence efficiency (abs ΦP=0.57) among known water‐soluble iridium complexes, long emission lifetime (τ=4.38 μs), as well as varying emission efficiency and lifetime with O2 content in aqueous solution. Therefore, nido‐o‐1 has been used as an excellent oxygen‐sensitive phosphor for intracellular O2 sensing and hypoxia imaging. Show less

Current precious-metal-containing anticancer agents are mostly chelated with N-containing ligands and function by interacting with DNA. In the present study, Pd(acac)2, a Pd(II) complex containing four O-donor ligands, has been evaluated as an active anticancer agent. Pd(acac)2 showed no interaction with N-ligand-containing DNA and the S-ligand-containing DMSO, probably because of the two six-member chelate rings that limit the release of the central Pd nuclei to bind to other ligands. Importantly, we found that Pd(acac)2 exhibited better growth inhibitory effects than cisplatin in several cancer cells. Treatment with Pd(acac)2 significantly induced apoptosis in H460 cells. Mechanistically, Pd(acac)2 induced the activation of a series of key components in ER stress-mediated apoptotic pathway, followed by caspase cleavage and activation, while cisplatin showed no similar effects. CHOP knockdown by specific siRNA significantly attenuated Pd(acac)2-induced cell apoptosis. Finally, Pd(acac)2 significantly inhibits H460 cell growth in xenograft mouse models. Taken together, these mechanistic insights on Pd(acac)2 provide us with a novel mechanism and strategy for the development of precious-metal-based anticancer drugs. Show less

AbstractFormation and repair of platinum (Pt)‐induced DNA adducts is a critical step in Pt drug‐mediated cytotoxicity. Measurement of Pt–DNA adduct kinetics in tumors may be useful for better understanding chemoresistance and therapeutic response. However, this concept has yet to be rigorously tested because of technical challenges in measuring the adducts at low concentrations and consistent access to sufficient tumor biopsy material. Ultrasensitive accelerator mass spectrometry was used to detect [14C]carboplatin–DNA monoadducts at the attomole level, which are the precursors to Pt–DNA crosslink formation, in six cancer cell lines as a proof‐of‐concept. The most resistant cells had the lowest monoadduct levels at all time points over 24 hr. [14C]Carboplatin “microdoses” (1/100th the pharmacologically effective concentration) had nearly identical adduct formation and repair kinetics compared to therapeutically relevant doses, suggesting that the microdosing approach can potentially be used to determine the pharmacological effects of therapeutic treatment. Some of the possible chemoresistance mechanisms were also studied, such as drug uptake/efflux, intracellular inactivation and DNA repair in selected cell lines. Intracellular inactivation and efficient DNA repair each contributed significantly to the suppression of DNA monoadduct formation in the most resistant cell line compared to the most sensitive cell line studied (p < 0.001). Nucleotide excision repair (NER)‐deficient and ‐proficient cells showed substantial differences in carboplatin monoadduct concentrations over 24 hr that likely contributed to chemoresistance. The data support the utility of carboplatin microdosing as a translatable approach for defining carboplatin–DNA monoadduct formation and repair, possibly by NER, which may be useful for characterizing chemoresistance in vivo. Show less

The condensation of DNA is essential for biological processes such as DNA transcription and replication, and its study receives additional impetus from an interest in gene therapy. Although many efficacious condensing agents have been discovered and investigated, little is known about the conversation of condensation-release under suitable conditions. A novel class of DNA condensing agents based on small azaheterocyclic metal-binding molecules has been discovered and described. Both linear and plasmid DNA can be condensed to nanoparticles by the title compounds with 50 °C incubation, especially in the presence of divalent metal ions. Importantly, this condensation may be released to original forms with little or no damage to the DNA under incubation at physiological temperatures. These changes in DNA morphology over time have been analyzed by gel electrophoresis, circular dichroism (CD), and atomic force microscopy (AFM). The present work might help to develop strategies for the design and synthesis of controllable condensing agents, which may also be applied to control gene expression and delivery. Show less