The versatility of cellular response arises from the communication, or crosstalk, of signaling pathways in a complex network of signaling and transcriptional regulatory interactions. Understanding the Show more
The versatility of cellular response arises from the communication, or crosstalk, of signaling pathways in a complex network of signaling and transcriptional regulatory interactions. Understanding the various mechanisms underlying crosstalk on a global scale requires untargeted computational approaches. We present a network-based statistical approach, MuXTalk, that uses high-dimensional edges called multilinks to model the unique ways in which signaling and regulatory interactions can interface. We demonstrate that the signaling-regulatory interface is located primarily in the intermediary region between signaling pathways where crosstalk occurs, and that multilinks can differentiate between distinct signaling-transcriptional mechanisms. Using statistically over-represented multilinks as proxies of crosstalk, we infer crosstalk among 60 signaling pathways, expanding currently available crosstalk databases by more than five-fold. MuXTalk surpasses existing methods in terms of model performance metrics, identifies additions to manual curation efforts, and pinpoints potential mediators of crosstalk. Moreover, it accommodates the inherent context-dependence of crosstalk, allowing future applications to cell type- and disease-specific crosstalk. Show less
Organoiridium picolinamidate complexes are promising for intracellular applications because of their biocompatibility, activity in living systems, and ease of derivatization. To shield their metal cen Show more
Organoiridium picolinamidate complexes are promising for intracellular applications because of their biocompatibility, activity in living systems, and ease of derivatization. To shield their metal centers from inhibition by biological nucleophiles (e.g., glutathione), attempts were made to increase the steric bulk of the supporting N-(2,6-R2-phenyl)picolinamidate ligand. It was found that when R = H (Ir1) or methyl (Ir2), the ligand adopts N,N'-coordination to iridium, whereas when R = isopropyl (Ir3) or phenyl (Ir4), N,O-coordination was observed. Based on experimental measurements and density functional theory calculations, it was revealed that the carbon chemical shift of the C(O)NR group can be used as a diagnostic handle to distinguish between the N,N'- and N,O-isomers in solution. Computational studies indicate that the former is favored thermodynamically but the latter is preferred when the R group is overly bulky. Complexes Ir1-Ir4 exhibit differences in lipophilicity, cellular uptake, cytotoxicity, and the propensity to generate reactive oxygen species in living cells. Reaction studies showed that Ir1/Ir2 are more efficient than Ir3/Ir4 in promoting the reduction of aldehydes to alcohols via transfer hydrogenation but both isomer types were susceptible to catalyst poisoning by glutathione. This work has led to new insights into structural isomerism in organoiridium picolinamidate complexes and suggests that steric tuning alone is insufficient to protect the Ir center from poisoning by biological nucleophiles. Show less
To study the antitumor activity and action mechanism of Ru(II) polypyridyl plumbagin (PLN) complexes, four complexes [Ru(PLN)(DMSO)2]Cl (Ru1), [Ru(bpy)2(PLN)](PF6) (bp Show more
To study the antitumor activity and action mechanism of Ru(II) polypyridyl plumbagin (PLN) complexes, four complexes [Ru(PLN)(DMSO)2]Cl (Ru1), [Ru(bpy)2(PLN)](PF6) (bpy is bipyridine) (Ru2), [Ru(phen)2(PLN)](PF6) (phen is 1,10-phenanthroline) (Ru3), and [Ru(DIP)2(PLN)](PF6) (DIP is 4,7-diphenyl-1,10-phenanthroline) (Ru4) were obtained and fully characterized. Lipophilicity, cellular uptake and cytotoxicity of these Ru(II) complexes are in the order of: Ru1Show less
The chemical structures of Ru (II) complexes are known to affect their cellular behavior and toxicity. In this study, three new luminescent Ru (II) complexes, [Ru(bpy)2(HIPMP)](ClO4Show more
The chemical structures of Ru (II) complexes are known to affect their cellular behavior and toxicity. In this study, three new luminescent Ru (II) complexes, [Ru(bpy)2(HIPMP)](ClO4)2 (Ru1, bpy = 2,2'-bipyridine, HIPMP = 2-(1H-imidazo-[4,5-f] [1,10] phenanthrolin-2-yl)-4-methylphenol), [Ru(phen)2(HIPMP)](ClO4)2 (Ru2, phen = 1,10-phenanthroline), [Ru(dmb)2(HIPMP)](ClO4)2 (Ru3, dmb = 4,4'-dimethyl-2,2'-bipyridine), were synthesized, and their anticancer activities were examined. All three complexes displayed anticancer activities against various cancer cells, with Ru2 exhibiting the highest cytotoxic activities. Ru2 was shown to accumulate specifically in the endoplasmic reticulum (ER) and induce ER stress-mediated apoptosis. In addition, Ru2 could generate reactive oxygen species (ROS) and trigger mitochondrial membrane potential depolarization. These results demonstrated that Ru2 induced apoptosis in HeLa cells through ER stress and ROS production. Show less