DNAzyme-Derived Aptamer Reversely Regulates the Two Types of Enzymatic Activities of Covalent-Organic Frameworks for the Colorimetric Analysis of Uranium.

Nanozymes are nanomaterials with enzyme-mimetic activity. It is known that DNA can interact with various nanozymes in different ways, enhancing or inhibiting the activity of nanozymes, which can be used to develop various biosensors. In this work, we synthesized a photosensitive covalent-organic framework (Tph-BT) as a nanozyme, and its oxidase and peroxidase activities could be reversely regulated by surface modification of single-stranded DNA (ssDNA) for the colorimetric detection of UO22+. Tph-BT exhibits excellent oxidase activity and weak peroxidase activity, and it is surprising to find that the UO22+-specific DNA aptamer can significantly inhibit the oxidase activity while greatly enhancing the peroxidase activity. The present UO22+ interacts with the DNA aptamer to form secondary structures and detaches from the surface of Tph-BT, thereby restoring the enzymatic activity of Tph-BT. Based on the reversed regulation effects of the DNA aptamer on the two types of enzymatic activities of Tph-BT, a novel "off-on" and "on-off" sensing platform can be constructed for the colorimetric analysis of UO22+. This research demonstrates that ssDNA can effectively regulate the different types of enzymatic activities of single COFs and achieve the sensitive and selective colorimetric analysis of radionuclides by the naked eye.

Reversed Regulation Effects of ssDNA on the Mimetic Oxidase and Peroxidase Activities of Covalent Organic Frameworks.

Nanomaterials with enzyme mimetic activity have attracted extensive attention, especially in the regulation of their catalytic activities by biomolecules or other polymers. Here, a covalent organic framework (Tph-BT COF) with excellent photocatalytic activity is constructed by Schiff base reaction, and its mimetic oxidase activity and peroxidase activity is inversely regulated via single-stranded DNA (ssDNA). Under light-emitting diode (LED) light irradiation, Tph-BT exhibited outstanding oxidase activity, which efficiently catalyzed oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) to produce blue oxTMB, and ssDNA, especially those with poly-thymidine (T) sequences, can significantly inhibit its oxidase activity. On the contrary, Tph-BT showed weak peroxidase activity, and the presence of ssDNA, particularly poly-cytosine (C) sequences, can remarkably enhance the peroxidase activity. The influence of base type, base length, and other factors on the activities of two enzymes is also studied, and the results reveal that the adsorption of ssDNA on the surface of Tph-BT prevented intersystem crossing (ISC) and energy transfer processes to reduce 1 O2 generation, while the electrostatic interaction between ssDNA and TMB enhanced Tph-BT's affinity for TMB to facilitate the electron transfer from TMB to • OH. This study investigates multitype mimetic enzyme activities of nonmetallic D-A conjugated COFs and demonstrates their feasibility of regulation by ssDNA.

Discovery of Simple Diacylhydrazine-Functionalized Cinnamic Acid Derivatives as Potential Microtubule Stabilizers.

To develop novel microtubule-binding agents for cancer therapy, an array of N-cinnamoyl-N'-(substituted)acryloyl hydrazide derivatives were facilely synthesized through a two-step process. Initially, the antiproliferative activity of these title compounds was explored against A549, 98 PC-3 and HepG2 cancer cell lines. Notably, compound I23 exhibited the best antiproliferative activity against three cancer lines with IC50 values ranging from 3.36 to 5.99 µM and concurrently afforded a lower cytotoxicity towards the NRK-52E cells. Anticancer mechanism investigations suggested that the highly bioactive compound I23 could potentially promote the protofilament assembly of tubulin, thus eventually leading to the stagnation of the G2/M phase cell cycle of HepG2 cells. Moreover, compound I23 also disrupted cancer cell migration and significantly induced HepG2 cells apoptosis in a dosage-dependent manner. Additionally, the in silico analysis indicated that compound I23 exhibited an acceptable pharmacokinetic profile. Overall, these easily prepared N-cinnamoyl-N'-(substituted)acryloyl hydrazide derivatives could serve as potential microtubule-interacting agents, probably as novel microtubule-stabilizers.

Facile Construction of Covalent Organic Framework Nanozyme for Colorimetric Detection of Uranium.

2D covalent organic frameworks (2D COFs) have been recognized as a novel class of photoactive materials owing to their extended π-electron conjugation and high chemical stabilities. Herein, a new covalent organic framework (Tph-BDP) is facilely synthesized by using a porphyrin derivative and an organic dye BODIPY derivative (5,5-difluoro-2,8-diformyl-1,3,7,9-tetramethyl-10-phenyl-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazabori-nin-4-ium-5-uide) as monomers for the first time, and their unique photosensitive properties endow them excellent simulated oxidase activity under 635 nm laser irradiation that can catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB). Further findings demonstrate that the presence of uranium (UO22+ ) can coordinate with imines of the oxidation products of TMB, thus modulating the charge transfer process of the colored products accompanied with intensive aggregation and remarkable color fading. This research provides a preparation strategy for COFs with excellent photocatalytic properties and nanozyme activity, and broadens the applications of the simple colorimetric methods for sensitive and selective radionuclide detection.

CHD1L promotes EOC cell invasiveness and metastasis via the regulation of METAP2.

Chromodomain helicase DNA binding protein 1-like (CHD1L) gene has been proposed to play an oncogenic role in human hepatocellular carcinoma. Previously we reported that CHD1L overexpression is significantly associated with the metastasis proceeding of epithelial ovarian cancer (EOC), and may predict a poor prognosis in EOC patients. However, the potential oncogenic mechanisms by which CHD1L acts in EOC remain unclear. To elucidate the oncogenic function of CHD1L, we carried out a series of in vitro assays, with effects of CHD1L ectogenic overexpression and silencing being determined in EOC cell lines (HO8910, A2780 and ES2). Real-time PCR and Western blotting analyses were used to identify potential downstream targets of CHD1L in the process of EOC invasion and metastasis. In ovarian carcinoma HO8910 cell lines, ectopic overexpression of CHD1L substantially induced the invasive and metastasis ability of the cancer cells in vitro. In contrast, knockdown of CHD1L using shRNA inhibited cell invasion in vitro in ovarian carcinoma A2780 and ES2 cell lines. We also demonstrated that methionyl aminopeptidase 2 (METAP2) was a downstream target of CHD1L in EOC, and we found a significant, positive correlation between the expression of CHD1L and METAP2 in EOC tissues (P<0.05). Our findings indicate that CHD1L plays a potential role in the inducement of EOC cancer cell invasion and/or metastasis via the regulation of METAP2 expression and suggests that CHD1L inhibition may provide a potential target for therapeutic intervention in human EOC.

Overexpression of SLC12A5 is associated with tumor progression and poor survival in ovarian carcinoma.

INTRODUCTION: The solute carrier family 12 member 5 (SLC12A5) gene is playing a putative oncogenic role in colorectal carcinoma. However, the status of SLC12A5 amplification and expression in ovarian carcinoma and its potential clinical and/or prognostic significance has not yet been investigated. METHODS: In the present study, semi-quantitative staining and fluorescence in situ hybridization were used to investigate SLC12A5 protein expression and gene amplification levels. Samples were obtained from archival, formalin-fixed, paraffin-embedded pathological specimens consisting of 30 normal ovaries, 30 ovarian cystadenomas, 30 borderline ovarian tumors, and 147 invasive ovarian carcinomas. SLC12A5 immunohistochemical staining results, pathological parameters, and patient prognosis were then evaluated using various statistical models. Patient survival rate was also assessed using receiver-operator curve analysis. RESULTS: Our results revealed no SLC12A5 protein overexpression in normal ovaries. However, 7% of cystadenomas had SLC12A5 protein overexpression along with 17% of borderline tumors and 37% of ovarian carcinomas (P<0.01). Amplification of SLC12A5 was detected in 10.3% of ovarian carcinomas. Further correlational analyses showed that SLC12A5 protein overexpression in ovarian carcinomas was significantly associated with ascending histological grade, pT/pN/pM status, as well as FIGO stage (P<0.05). A subsequent univariate survival analysis of our ovarian carcinoma cohorts resulted in a significant association between SLC12A5 protein overexpression and decreased patient survival (44.3 and 85.9 months for high and low SLC12A5 protein expression, respectively; P<0.001). Importantly, additional multivariate analysis revealed that SLC12A5 protein expression was a significant, independent prognostic factor for overall survival in ovarian carcinoma patients (P=0.003). CONCLUSIONS: Collectively, these findings support the conclusion that SLC12A5 protein overexpression could indicate an invasive and/or aggressive phenotype of ovarian carcinoma. Future work will need to investigate whether SLC12A5 protein can serve as an independent prognostic molecular marker in patients with ovarian carcinoma.

An in-situ strategy to construct uracil-conjugated covalent organic frameworks with tunable fluorescence/recognition characteristics for sensitive and selective Mercury(II) detection.

Previous researches of covalent organic frameworks (COFs) have shown their potential as fluorescent probes, but the regulation of their optical properties and recognition characteristics still remains a challenge, and most of reports required complicated post-decoration to improve the sensing performance. In this context, we propose a novel in-situ strategy to construct uracil-conjugated COFs and modulate their fluorescence properties for sensitive and selective mercury(II) detection. By using 1,3,6,8-tetrakis(4-formylphenyl)pyrene (TFPPy) and 1,3,6,8-tetrakis(4-aminophenyl)pyrene (TAPPy) as fundamental blocks and 5-aminouraci (5-AU) as the functional monomer, a series of COFs (Py-COFs and Py-U-COFs-1 to Py-U-COFs-5) with tunable fluorescence were solvothermally synthesized through an in-situ Schiff base reaction. The π-conjugated framework serves as a signal reporter, the evenly and densely distributed uracil acts as a mercury(II) receptor, and the regular pores (channels) make the rapid and sensitive detection of the mercury(II) possible. In this research, we manage to regulate the crystalline structure, the fluorescence properties, and the sensing performance of COFs by simply changing the molar ratio of precursors. We expect this research to open up a new strategy for effective and controllable construction of functionalized COFs for environmental analysis.

Maelstrom promotes tumor metastasis through regulation of FGFR4 and epithelial-mesenchymal transition in epithelial ovarian cancer.

BACKGROUND: Increasing evidence has indicated that Maelstrom (MAEL) plays an oncogenic role in various human carcinomas. However, the exact function and mechanisms by which MAEL acts in epithelial ovarian cancer (EOC) remain unclear. RESULTS: This study demonstrated that MAEL was frequently overexpressed in EOC tissues and cell lines. Overexpression of MAEL was positively correlated with the histological grade of tumors, FIGO stage, and pT/pN/pM status (p < 0.05), and it also acted as an independent predictor of poor patient survival (p < 0.001). Ectopic overexpression of MAEL substantially promoted invasiveness/metastasis and induced epithelial-mesenchymal transition (EMT), whereas silencing MAEL by short hairpin RNA effectively inhibited its oncogenic function and attenuated EMT. Further study demonstrated that fibroblast growth factor receptor 4 (FGFR4) was a critical downstream target of MAEL in EOC, and the expression levels of FGFR4 were significantly associated with MAEL. (P < 0.05). CONCLUSION: Our findings suggest that overexpression of MAEL plays a crucial oncogenic role in the development and progression of EOC through the upregulation of FGFR4 and subsequent induction of EMT, and also provide new insights on its potential as a therapeutic target for EOC.

Construction of D-A-Conjugated Covalent Organic Frameworks with Enhanced Photodynamic, Photothermal, and Nanozymatic Activities for Efficient Bacterial Inhibition.

Bacterial infection causes serious threats to human life, especially with the appearance of antibiotic-resistant bacteria. Phototherapeutic approaches have become promising due to their noninvasiveness, few adverse effects, and high efficiency. Herein, a covalent organic framework (TAPP-BDP) with a conjugated donor-acceptor (D-A) structure has been constructed for efficient photoinduced bacteriostasis. Under the irradiation with a single near-infrared (NIR) light (λ = 808 nm), TAPP-BDP alone involves triple and synergistic bacterial inhibition based on the integration of photodynamic, photothermal, and peroxidase-like enzymatic activities. The unique D-A structure endows TAPP-BDP with a narrow energy band gap, improving its photodynamic and nanozyme activities to generate reactive oxygen species (ROS) to realize the broad-spectrum bactericidal activity. The extended π-conjugated skeleton of TAPP-BDP results in enhanced absorption in NIR, and the remarkable photothermal activity can increase the temperature up to 65 °C to cause efficient bacterial degeneration. TAPP-BDP shows excellent antibacterial efficiency against both Gram-negative and Gram-positive bacteria. Animal experiments further suggest that TAPP-BDP can effectively heal wounds infected with Staphylococcus aureus in living systems.

Accelerated cardiomyopathy in mice with overexpression of cardiac G(s)alpha and a missense mutation in the alpha-myosin heavy chain.

BACKGROUND: To understand further the pathogenesis of familial hypertrophic cardiomyopathy, we determined how the cardiomyopathy induced by an Arg403-->Gln missense mutation in the alpha-myosin heavy chain (403) is affected by chronically enhancing sympathetic drive by mating the mice with those overexpressing G(s)alpha (G(s)alpha x403). METHODS AND RESULTS: Heart rate in 3-month-old conscious mice was elevated similarly (P<0.05) in mice overexpressing G(s)alpha (G(s)alpha mice; 746 +/- 14 bpm) and G(s)alpha x403 mice (718+/- 19 bpm) compared with littermate wild-type mice (WT; 623+/- 18 bpm) and 403 mice (594+/- 16 bpm). Left ventricular ejection fraction (LVEF), as determined by echocardiography, was enhanced in G(s)alpha x403 mice (88+/- 1%, P<0.001) compared with WT (69+/- 1%), 403 (75+/- 1%), and G(s)alpha (69 +/- 2%) mice. Isolated cardiomyocytes from G(s)alpha x403 mice also exhibited higher (P<0.001) baseline percent contraction (11.9+/- 0.5%) than WT (7.0+/- 0.5%), 403 (5.5+/- 0.5%), and G(s)alpha (7.8+/- 0.3%) cardiomyocytes. Relaxation of myocytes was impaired in 403 mice compared with WT but enhanced in G(s)alpha and normalized in G(s)alpha x403 mice. This was also observed in vivo. In vivo isoproterenol (0.1 microgram . kg(-1) . min(-1)) increased LVEF to maximal levels in G(s)alpha x403 and G(s)alpha, whereas in 403, the response was attenuated compared with WT. At 10 months of age, G(s)alpha x403 had significantly depressed LVEF (57 +/- 4%). Histopathological examination demonstrated that myocyte hypertrophy and fibrosis were already present in young G(s)alpha x403 mice and that old animals had severe cardiomyopathy. By 15 months of age, the survival of G(s)alpha x403 was 0% compared with 100% for WT, 71% for G(s)alpha, and 100% for 403 mice (P<0.05). CONCLUSIONS: These results show that the cardiomyopathy developed by G(s)alpha x403 mice is synergistic rather than additive, most likely owing to the elevated baseline function combined with enhanced responsiveness to sympathetic stimulation.