To maximize both the activatable singlet oxygen (1O2) production and fluorescence of theranostic photodynamic (PDT) reagents, herein we propose a modularized molecular structural profile, i.e. the intersystem crossing (ISC) and fluorescence functionalities were accomplished with different modules in a dyad, thus enabling the activated 1O2 production yield (ΦΔ, PDT) and the fluorescence yield (ΦF) to both approach 100%. The PDT and the fluorescence were caged with a thiol-cleavable disulfide bond (–S–S–) linker and an electron trap (2,4-dinitrobenzenesulfide, DNBS). This new molecular structural profile is different from that of conventional theranostic PDT reagents, which are based on a single chromophore for both PDT and fluorescence; thus, the limitation of ΦΔ + ΦF = 100% exists for only half of our new molecular profile. To this end, six Bodipy dyads were prepared. The photophysical properties of the dyads were studied with steady state absorption, fluorescence and nanosecond transient absorption spectroscopy. The dyads show weak PDT and luminescence, due to the caging effect. In the presence of thiols (GSH or Cys), cleavage of the disulfide linker and DNBS occurs, and the PDT and fluorescence modules are activated simultaneously (ΦF: 1.3% → 47.6%; ΦΔ: 16.7% → 71.5%). These results are useful in designing activatable PDT/fluorescence imaging theranostic reagents.

Breast cancer that is accompanied by a high level of cyclin E expression usually exhibits poor prognosis and clinical outcome. Several factors are known to regulate the level of cyclin E during the cell cycle progression. The transcription factor DEC1 (also known as STRA13 and SHARP2) plays an important role in cell proliferation and apoptosis. Nevertheless, the mechanism of its role in cell proliferation is poorly understood. In this study, using the breast cancer cell lines MCF-7 and T47D, we showed that DEC1 could inhibit the cell cycle progression of breast cancer cells independently of its transcriptional activity. The cell cycle-dependent timing of DEC1 overexpression could affect the progression of the cell cycle through regulating the level of cyclin E protein. DEC1 stabilized cyclin E at the protein level by interacting with cyclin E. Overexpression of DEC1 repressed the interaction between cyclin E and its E3 ligase Fbw7α, consequently reducing the level of polyunbiquitinated cyclin E and increased the accumulation of non-ubiquitinated cyclin E. Furthermore, DEC1 also promoted the nuclear accumulation of Cdk2 and the formation of cyclin E/Cdk2 complex, as well as upregulating the activity of the cyclin E/Cdk2 complex, which inhibited the subsequent association of cyclin A with Cdk2. This had the effect of prolonging the S phase and suppressing the growth of breast cancers in a mouse xenograft model. These events probably constitute the essential steps in DEC1-regulated cell proliferation, thus opening up the possibility of a protein-based molecular strategy for eliminating cancer cells that manifest a high-level expression of cyclin E.

The regulation of cardiac differentiation is critical for maintaining normal cardiac development and function. The precise mechanisms whereby cardiac differentiation is regulated remain uncertain. Here, we have identified a GATA-4 target, EGF, which is essential for cardiogenesis and regulates cardiac differentiation in a dose- and time-dependent manner. Moreover, EGF demonstrates functional interaction with GATA-4 in inducing the cardiac differentiation of P19CL6 cells in a time- and dose-dependent manner. Biochemically, GATA-4 forms a complex with STAT3 to bind to the EGF promoter in response to EGF stimulation and cooperatively activate the EGF promoter. Functionally, the cooperation during EGF activation results in the subsequent activation of cyclin D1 expression, which partly accounts for the lack of additional induction of cardiac differentiation by the GATA-4/STAT3 complex. Thus, we propose a model in which the regulatory cascade of cardiac differentiation involves GATA-4, EGF, and cyclin D1.

Epithelial–mesenchymal transition (EMT) has a major role in cancer progression and metastasis. However, the specific mechanism of transcriptional repression involved in this process remains largely unknown. Dachshund homologue 1 (DACH1) expression is lost in invasive breast cancer with poor prognosis, and the role of DACH1 in regulating breast cancer metastasis is poorly understood. In this study, significant correlation between the expression of DACH1 and the morphology of breast cancer cells was observed. Subsequent investigation into the relationship between DACH1 and EMT showed that overexpression of DACH1 in ZR-75-30 cells induced a shift towards epithelial morphology and cell–cell adhesion, as well as increased the expression of the epithelial marker E-cadherin and suppressed cell migration and invasion. In contrast, silencing DACH1 in MCF-7 and T47D cells disrupted the epithelial morphology and cell–cell contact, reduced the expression of E-cadherin, and induced cell migration and invasion. DACH1 also specifically interacted with SNAI1, but not SNAI2, to form a complex, which could bind to the E-box on the E-cadherin promoter in an SNAI1-dependent manner. DACH1 inhibited the transcriptional activity of SNAI1, leading to the activation of E-cadherin in breast cancer cells. Furthermore, the level of DACH1 also correlated with the extent of metastasis in a mouse model. DACH1 overexpression significantly decreased the metastasis and growth of 4T1/Luc cells in BALB/c mice. Analysis of tissue samples taken from human breast cancers showed a significant correlation between the expression of DACH1 and E-cadherin in SNAI1-positive breast cancer. Collectively, our data identified a new mechanistic pathway for the regulation of EMT and metastasis of breast cancer cells, one that is based on the regulation of E-cadherin expression by direct DACH1–SNAI1 interaction.

To maximize both the activatable singlet oxygen (1O2) production and fluorescence of theranostic photodynamic (PDT) reagents, herein we propose a modularized molecular structural profile, i.e. the intersystem crossing (ISC) and fluorescence functionalities were accomplished with different modules in a dyad, thus enabling the activated 1O2 production yield (ΦΔ, PDT) and the fluorescence yield (ΦF) to both approach 100%. The PDT and the fluorescence were caged with a thiol-cleavable disulfide bond (–S–S–) linker and an electron trap (2,4-dinitrobenzenesulfide, DNBS). This new molecular structural profile is different from that of conventional theranostic PDT reagents, which are based on a single chromophore for both PDT and fluorescence; thus, the limitation of ΦΔ + ΦF = 100% exists for only half of our new molecular profile. To this end, six Bodipy dyads were prepared. The photophysical properties of the dyads were studied with steady state absorption, fluorescence and nanosecond transient absorption spectroscopy. The dyads show weak PDT and luminescence, due to the caging effect. In the presence of thiols (GSH or Cys), cleavage of the disulfide linker and DNBS occurs, and the PDT and fluorescence modules are activated simultaneously (ΦF: 1.3% → 47.6%; ΦΔ: 16.7% → 71.5%). These results are useful in designing activatable PDT/fluorescence imaging theranostic reagents.