BODIPY nanoparticles functionalized with lactose for cancer-targeted and fluorescence imaging-guided photodynamic therapy.

A series of four lactose-modified BODIPY photosensitizers (PSs) with different substituents (-I, -H, -OCH3, and -NO2) in the para-phenyl moiety attached to the meso-position of the BODIPY core were synthesized; the photophysical properties and photodynamic anticancer activities of these sensitizers were investigated, focusing on the electronic properties of the different substituent groups. Compared to parent BODIPY H, iodine substitution (BODIPY I) enhanced the intersystem crossing (ISC) to produce singlet oxygen (1O2) due to the heavy atom effect, and maintained a high fluorescence quantum yield (ΦF) of 0.45. Substitution with the electron-donating methoxy group (BODIPY OMe) results in a significant perturbation of occupied frontier molecular orbitals and consequently achieves higher 1O2 generation capability with a high ΦF of 0.49, while substitution with the electron-withdrawing nitro group (BODIPY NO2) led a perturbation of unoccupied frontier molecular orbitals and induces a forbidden dark S1 state, which is negative for both fluorescence and 1O2 generation efficiencies. The BODIPY PSs formed water-soluble nanoparticles (NPs) functionalized with lactose as liver cancer-targeting ligands. BODIPY I and OMe NPs showed good fluorescence imaging and PDT activity against various tumor cells (HeLa and Huh-7 cells). Collectively, the BODIPY NPs demonstrated high 1O2 generation capability and ΦF may create a new opportunity to develop useful imaging-guided PDT agents for tumor cells.

Dihydrocapsaicin induces translational repression and stress granule through HRI-eIF2α phosphorylation axis.

Stress granules (SGs) are cytoplasmic biomolecular condensates that are formed against a variety of stress conditions when translation initiation is perturbed. SGs form through the weak protein-protein, protein-RNA, and RNA-RNA interactions, as well as through the intrinsically disordered domains and post-translation modifications within RNA binding proteins (RBPs). SGs are known to contribute to cell survivability by minimizing the stress-induced damage to the cells by delaying the activation of apoptosis. Here, we find that dihydrocapsaicin (DHC), an analogue of capsaicin, is a SG inducer that promotes polysome disassembly and reduces global protein translation via phosphorylation of eIF2α. DHC-mediated SG assembly is controlled by the phosphorylation of eIF2α at serine 51 position and is controlled by all four eIF2α stress kinases (i.e., HRI, PKR, PERK, and GCN2) with HRI showing maximal effect. We demonstrate that DHC is a bonafide compound that induces SG assembly, disassembles polysome, phosphorylates eIF2α in an HRI dependent manner, and thereby arrest global translation. Together, our results suggest that DHC is a novel SG inducer and an alternate to sodium arsenite to study SG dynamics.

Loss of MeCP2 causes subtle alteration in dendritic arborization of retinal ganglion cells.

Methyl-CpG-binding protein (MeCP2) is highly expressed in neurons. It plays an important role in the development of synapses and the formation of circuits in the central nervous system (CNS). Mutations in MECP2 cause neurodevelopmental disorders and mental retardation in humans. Therefore, it has become important to determine the distribution and function of MeCP2 in vivo. The retina consists of three nuclear cell layers and two layers of synapses; neurons in each layer are connected to form fine circuits necessary for visual signal transduction. Using immunohistochemical analysis, we found that MeCP2 was expressed in all nuclear cell layers, with differences in the levels of MeCP2 expression observed among the layers. To understand the structural defects in the retina due to the loss of MeCP2, we sought to elucidate the organization of the retinal structure in the Mecp2 knockout (KO) mouse. Overall, we found a normal retinal structure in Mecp2 KO mice. However, because Mecp2 mutations have a highly variable effect on neuronal architecture, we analyzed morphological changes in a subset of retinal ganglion cells of Mecp2 KO mice. In Thy1-GFP mice crossed with Mecp2 mutant mice, Sholl intersections analyses showed a subtle increase in number of intersections due to increased branching proximal to the soma in Mecp2 KO mice. Our results demonstrate that the expression of MeCP2 and the effects of Mecp2 mutations are highly specific to tissue and cell types.