Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition

Hedgehog signaling drives oncogenesis in several cancers and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened. However, resistance to Smoothened inhibitors occurs via genetic changes of Smoothened or other downstream Hedgehog components. Here, we overcome these resistance mechanisms by modulating GLI transcription via inhibition of BET bromodomain proteins. We show the BET bromodomain protein, BRD4, regulates GLI transcription downstream of SMO and SUFU and chromatin immunoprecipitation studies reveal BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites upon treatment with JQ1, a small molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid/rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists

Gadolinium functionalized carbon dots for fluorescence/magnetic resonance dual-modality imaging of mesenchymal stem cells

The development of multimodal nanoprobes is of great importance in nanomedicine because it integrates the advantages of each imaging modality and offers a significantly enhanced diagnostic effect. In this work, gadolinium(III) functionalized fluorescent carbon dots (Gd-CDs) are synthesized by means of a one-step hydrothermal approach. As a fluorescent nanomaterial, the obtained Gd-CDs exhibit strong and stable fluorescence with excitation-independent emission behavior. Moreover, as an MRI contrast agent, the Gd-CDs exhibited a longitudinal relaxation rate of 6.06 mM(-1) s(-1), which is significantly higher than that of the commercially available MRI agent Gadovist (4.24 mM(-1) s(-1)). In addition, the cellular experiment reveals that Gd-CDs promote the proliferation of human mesenchymal stem cells (hMSCs), which is tracked by the fluorescence/Magnetic Resonance dual-modality imaging of hMSCs by the Gd-CDs

Restriction of Access to Dark State: A New Mechanistic Model for Heteroatom-Containing AIE Systems

Aggregation-induced emission (AIE) is an unusual photophysical phenomenon and provides an effective and advantageous strategy for the design of highly emissive materials in versatile applications such as sensing, imaging, and theragnosis. "Restriction of intramolecular motion" is the well-recognized working mechanism of AIE and have guided the molecular design of most AIE materials. However, it sometimes fails to be workable to some heteroatom-containing systems. Herein, in this work, we take more than one excited state into account and specify a mechanism –"restriction of access to dark state (RADS)" – to explain the AIE effect of heteroatom-containing molecules. An anthracene-based zinc ion probe named APA is chosen as the model compound, whose weak fluorescence in solution is ascribed to the easy access from the bright (π,π*) state to the closelying dark (n,π*) state caused by the strong vibronic coupling of the two excited states. By either metal complexation or aggregation, the dark state is less accessible due to the restriction of the molecular motion leading to the dark state and elevation of the dark state energy, thus the emission of the bright state is restored. RADS is found to be powerful in elucidating the photophysics of AIE materials with excited states which favor non-radiative decay, including overlap-forbidden states such as (n,π*) and CT states, spin-forbidden triplet states, which commonly exist in heteroatom-containing molecules

Regulating the proximity effect of heterocycle-containing AIEgens

Abstract Proximity effect, which refers to the low-lying (n,π*) and (π,π*) states with close energy levels, usually plays a negative role in the luminescent behaviors of heterocyclic luminogens. However, no systematic study attempts to reveal and manipulate proximity effect on luminescent properties. Here, we report a series of methylquinoxaline derivatives with different electron-donating groups, which show different photophysical properties and aggregation-induced emission behaviors. Experimental results and theoretical calculation reveal the gradually changed energy levels and different coupling effects of the closely related (n,π*) and (π,π*) states, which intrinsically regulate proximity effect and aggregation-induced emission behaviors of these luminogens. With the intrinsic nature of heterocycle-containing compounds, they are utilized for sensors and information encryption with dynamic responses to acid/base stimuli. This work reveals both positive and negative impacts of proximity effect in heterocyclic aggregation-induced emission systems and provides a perspective to develop functional and responsive luminogens with aggregation-induced emission properties

An Intelligent AIEgen with Nonmonotonic Multi-Responses to Multi-Stimuli

Intelligent stimulus-response (S/R) systems are the basis of natural process and machine control, and have been intensively explored in biomimetic design, analytical chemistry and biological applications. However, nonmonotonic multi-S/R systems are still rarely studied so far. Now, we propose a rational design strategy to achieve such a unique S/R system by integrating opposite luminescence behaviors in one molecule. When solvent polarity increases, many heterocycles often become more emissive due to the suppression of the proximity effect. However, molecules with donor-acceptor (D-A) structures tend to be less emissive because of the twisted intramolecular charge transfer. Meanwhile, protonation on D/A moieties will weaken/strengthen the D-A interaction to result in blue/red-shifted emissions. By combining a protonatable heterocyclic acceptor and a protonatable donor together in one molecule, we can easily achieve nonmonotonic brightness responses to polarity stimuli and nonmonotonic color responses to pH stimuli. In this work, a simple molecule, namely ASQ is chosen as the model compound to verify the design strategy feasibility. It successfully shows two opposite trends of responses to polarity and pH stimuli, and aggregation-induced emission (AIE) with a nonmonotonic AIE curve. Moreover, the acidified ASQ solution is also a pure organic up-conversion and white-light-emitting system. A new mechanistic viewpoint is established to explain its unique anti-Stokes emission. Besides, ASQ shows multivalent functionalities including albumin protein sensing, ratiometric pH sensing, and amine gas sensing, etc. Therefore, ASQ is proved to be a fundamentally important and versatile functional “intelligent” AIE luminogen with nonmonotonic multi-responses to multi-stimuli. </p