Hongjuan Zeng

Folate-Functionalized Magnetic-Mesoporous Silica Nanoparticles for Drug/Gene Codelivery To Potentiate the Antitumor Efficacy

An appropriate codelivery system for chemotherapeutic agents and nucleic acid drugs will provide a more efficacious approach for the treatment of cancer. Combining gene therapy with chemotherapeutics in a single delivery system is more effective than individual delivery systems carrying either gene or drug. In this work, we developed folate (FA) receptor targeted magnetic-mesoporous silica nanoparticles for the codelivery of VEGF shRNA and doxorubicin (DOX) (denoted as M-MSN(DOX)/PEI-FA/VEGF shRNA). Our data showed that M-MSN(DOX)/PEI-FA could strongly condense VEGF shRNA at weight ratios of 30:1, and possesses higher stability against DNase I digestion and sodium heparin. In vitro antitumor activity assays revealed that HeLa cell growth was significantly inhibited. The intracellular accumulation of DOX by confocal microscopy and fluorescence spectrophotometry showed that M-MSN(DOX)/PEI-FA were more easily taken up than nontargeted M-MSN(DOX). Quantitative PCR and ELISA data revealed that M-MSN/PEI-FA/VEGF shRNA induced a significant decrease in VEGF expression as compared to cells treated with either the control or other complexes. The invasion and migration phenotypes of the HUVECs were significantly decrease after coculture with MSN/PEI-FA/VEGF shRNA nanocomplexes-treated HeLa cells. The approach provides a potential strategy to treat cancer by a singular nanoparticle delivery system.

Mechanosensitive caveolin-1 activation-induced PI3K/Akt/mTOR signaling pathway promotes breast cancer motility, invadopodia formation and metastasis in vivo

Cancer cells are subjected to fluid shear stress during passage through the venous and lymphatic system. Caveolin-1 (Cav-1), a principal structural component of caveolar membrane domains, contributes to cancer development but its mechanobiological roles under low shear stress (LSS) conditions remain largely unknown. Here, we identified Cav-1 is mechanosensitive to LSS exposure, and its activation-induced PI3K/Akt/mTOR signaling promotes motility, invadopodia formation and metastasis of breast carcinoma MDA-MB-231 cells. Application of LSS (1.8 and 4.0 dynes/cm2) to MDA-MB-231 cells significantly increased the cell motility, invadopodia formation, MT1-MMP expression, ECM degradation, and also induced a sustained activation of Cav-1 and PI3K/Akt/mTOR signaling cascades. Methyl-β-cyclodextrin-caused caveolae destruction markedly decreased LSS-induced activation of both Cav-1 and PI3K/Akt/mTOR, leading to suppress MT1-MMP expression, inhibit invadopodia formation and ECM degradation, suggesting that caveolae integrity also involved in metastasis. Immunocytochemical assay showed that LSS induces the Cav-1 clustering in lipid rafts and co-localization of Cav-1 and MT1-MMP on invadopodia. Immunofluorescence confocal analysis demonstrated that Cav-1 activation were required for the acquisition of a polarized phenotype in MDA-MB-231 cells. Finally, Cav-1 knockdown significantly suppressed tumor colonization in the lungs and distant metastases in animal models. Our findings highlight the importance of Cav-1 in hematogenous metastasis, and provide new insights into the underlying mechanisms of mechanotransduction induced by LSS.

MCP-1-induced ERK/GSK-3β/Snail signaling facilitates the epithelial–mesenchymal transition and promotes the migration of MCF-7 human breast carcinoma cells

Monocyte chemoattractant protein-1 (MCP-1) is a chemotactic cytokine that can bind to its receptor cysteine–cysteine chemokine receptor 2 (CCR2) and plays an important role in breast cancer cell metastasis. However, the molecular mechanisms underlying MCP-1-induced alterations in cellular functions during tumor progression are poorly understood. Here, we showed that MCP-1 stimulated the epithelial–mesenchymal transition (EMT) and induced the tumorigenesis of breast cancer cells by downregulating E-cadherin, upregulating vimentin and fibronectin, activating matrix metallopeptidase-2 (MMP-2), and promoting migration and invasion. Moreover, MCP-1 treatment reduced glycogen synthase kinase-3β (GSK-3β) activity via the MEK/ERK-mediated phosphorylation of serine-9 in MCF-7 cells. The inhibition of MEK/ERK by U0126 attenuated the MCP-1-induced phosphorylation of GSK-3β and decreased the expression of Snail, an EMT-related transcription factor, leading to the inhibition of MCF-7 cell migration and invasion. Inactivation of GSK-3β by LiCl (lithium chloride) treatment notably increased MMP-2 activity, vascular endothelial growth factor expression and EMT of MCF-7 cells. These findings revealed that MCP-1-induced EMT and migration are mediated by the ERK/GSK-3β/Snail pathway, and identified a potential novel target for therapeutic intervention in breast cancer.

MCP-1-triggered ERK/GSK-3beta/Snail pathway facilitates epithelial- mesenchymal transition and promotes cell migration of human breast carcinoma MCF-7 cells

Monocyte chemoattractant protein-1 (MCP-1) is a chemotactic cytokine that can bind to its receptor cysteine–cysteine chemokine receptor 2 (CCR2) and plays an important role in breast cancer cell metastasis. However, the molecular mechanisms underlying MCP-1-induced alterations in cellular functions during tumor progression are poorly understood. Here, we showed that MCP-1 stimulated the epithelial–mesenchymal transition (EMT) and induced the tumorigenesis of breast cancer cells by downregulating E-cadherin, upregulating vimentin and fibronectin, activating matrix metallopeptidase-2 (MMP-2), and promoting migration and invasion. Moreover, MCP-1 treatment reduced glycogen synthase kinase-3β (GSK-3β) activity via the MEK/ERK-mediated phosphorylation of serine-9 in MCF-7 cells. The inhibition of MEK/ERK by U0126 attenuated the MCP-1-induced phosphorylation of GSK-3β and decreased the expression of Snail, an EMT-related transcription factor, leading to the inhibition of MCF-7 cell migration and invasion. Inactivation of GSK-3β by LiCl (lithium chloride) treatment notably increased MMP-2 activity, vascular endothelial growth factor expression and EMT of MCF-7 cells. These findings revealed that MCP-1-induced EMT and migration are mediated by the ERK/GSK-3β/Snail pathway, and identified a potential novel target for therapeutic intervention in breast cancer.

Growth and humidity-dependent electrical properties of bulk-like MoS2 thin films on Si

Bulk-like molybdenum disulfide (MoS2) thin films were deposited on Si substrates using a dc magnetron sputtering technique and n-MoS2/p-Si junctions were fabricated at room temperature (RT) and 400 °C, respectively. The typical oscillating modes of E12g and A1g were shown in the Raman spectra of the as-grown MoS2 films. Atomic force microscopy illustrated that the surfaces of the films were composed of dense nanoscale grains and scanning electron microscopy revealed the existence of large quantities of pores in the surface. The current–voltage curves of the junctions showed obvious rectifying characteristics due to the energy-band bending near the interface of MoS2/Si. The fabricated junctions exhibited humidity-dependent electrical properties. Compared with the one with the MoS2 film deposited at RT, the junction fabricated at 400 °C showed much more obvious sensing properties to humid gas. In particular, the sensitivity of the device could be tuned by external electrical fields. In the forward voltage range, the currents increased significantly after the junction was exposed to humid conditions. The response increased with increasing voltage and reached a saturated value after V = 1.9 V. The sensing performance featured high sensitivity, fast response and recovery. The junction current in the reverse voltage range decreased under the humid condition. This was contrary to that in the forward voltage range. We also studied the dependence of the sensing response on humidity levels. An almost linear correlation was obtained in the measured range of humidity levels. The sensing mechanisms of the MoS2/Si heterojunction were proposed.

Source/drain electrodes contact effect on the stability of bottom-contact pentacene field-effect transistors

Bottom-contact pentacene field-effect transistors were fabricated with a PMMA dielectric layer, and the air stability of the transistors was investigated. To characterize the device stability, the field-effect transistors were exposed to ambient conditions for 30 days and subsequently characterized. The degradation of electrical performance was traced to study the variation of field-effect mobility, saturation current and off-state current. By investigating the morphology variance of the pentacene film at the channel and source/drain (S/D) contact regions by atomic force microscopy, it was clear that the morphology of the pentacene film adhered to the S/D degenerated dramatically. Moreover, by studying the variation of contact resistance in detail, it was found that the S/D contact effect was the main reason for the degradation in performance.

Complex thiolated mannose/quinone film modified on EQCM/Au electrode for recognizing specific carbohydrate–proteins

A complex thiolated mannose (TM)/quinone functionalised polythiophene (QFPT) thin film was modified on EQCM/Au electrode for recognition of specific carbohydrate-proteins. Different lectins such as those from Sambucus nigra (elder berry), Arachis hypogaea (peanut), Ulex europaeus (gorse, furze), Triticum vulgaris and Concanavalin A (ConA) was used for probes to evaluate bio-sensing performance of the TM/QFPT film. A specific response was observed for ConA from lectins when using the TM/QFPT film as sensing material and employing either elelctrochemical or the QCM method. No response was detected between thiolated mannose and other lectins. The linear relationship between current and ConA concentration is in the range of 0.5-17.5 nM by the elelctrochemical method and the linear relationship between frequency change and ConA concentration is in the range of 0.5-4.5 nM by the QCM method. This shows that the TM/QFPT-modified EQCM biosensor presents a paralleled determination by using electrochemical and the QCM method. The elelctrochemical method of the biosensor can be applicable in a large concentration range and its frequency change can be more precise.

Notch-1 signaling activates NF-κB in human breast carcinoma MDA-MB-231 cells via PP2A-dependent AKT pathway

Abstract Breast cancer has a high incidence in the world and is becoming a leading cause of death in female patients due to its high metastatic ability. High expression of Notch-1 and its ligand Jagged-1 correlates with poor prognosis in breast cancer. Our previous work has shown that Notch-1 signaling pathway upregulates NF-κB transcriptional activity and induces the adhesion, migration and invasion of human breast cancer cell line MDA-MB-231. However, the role of Notch-1 in NF-κB activation is still poorly understood. Here, we aim to understand the exact mechanism that Notch-1 regulates NF-κB activity. In MDA-MB-231 cells where Notch-1 is constitutively activated, the phosphorylation of p85 and AKT (Tyr308/Ser473) is upregulated, indicating PI3K/AKT pathway is activated. Notch-1 activation caused the increase of PP2A phosphorylation at Tyr307, indicating Notch-1 inhibits PP2A activity. NF-κB transcriptional activity was evaluated by dual-luciferase reporter assay, and the results showed that, while silencing of Notch-1, PP2A activity was upregulated and NF-κB activity was downregulated, whereas PP2A inhibitor okadaic acid (OA) restored NF-κB activity. Immunofluorescence and Western blots showed that OA treatment antagonized the decrease of p65 nuclear translocation caused by Notch-1 silencing. Moreover, OA treatment also upregulated MMP-2, MMP-9 and VEGF mRNA expression levels, indicating OA rescues Notch-1 silencing that caused low cell invasion. Taken together, our results suggest that Notch-1-activating PI3K/AKT/NF-κB pathway is PP2A dependent; PP2A may be a potential therapeutic target in breast cancer.

Photosensitizer-assembled PEGylated graphene-copper sulfide nanohybrids as a synergistic near-infrared phototherapeutic agent

Objectives: Stimulative nanostructures play a crucial role in developing the smart nanomedicine for high therapeutic efficacy with minimum adverse effects. Herein, a near-infrared (NIR) light-responsive nanohybrids p-nanographene oxide (GO)-copper sulfide (CuS)/indocyanine green (ICG) comprised of GO, CuS nanoparticles and photosensitizer ICG was fabricated to couple the photothermal property of CuS and photodynamic effect of ICG in one system in order to achieve the synergistic phototherapy. Methods: pGO-CuS/ICG was constructed by self-assembling ICG on pGO-CuS nanostructure. Its physicochemical, photothermal and photodynamic properties were studied by spectroscopic methods. The in vitro cellular uptake, cytotoxicity, the single/combined photothermal therapeutic (PTT) and photodynamic therapeutic (PDT) effects were investigated with biological techniques. Results: pGO-CuS/ICG exhibited high efficacy of photothermal conversation and singlet oxygen generation under NIR laser excitation. It entered into the target cancer cells probably via passive transmembrane pathway and exerted obvious PTT and PDT effect against the tumor cells upon irradiation with the respective 940 and 808 nm lasers. In particular, the tremendous synergistic efficacy of PDT and PTT had been demonstrated by tuning the NIR laser combined irradiation. Conclusions: This study promises the future applications of pGO-CuS/ICG as a NIR light activable theranostic nanodrug for deep-seated cancer noninvasive phototherapy.

Novel Piezoelectric DDVP Sensor Based on Self‐Assembly Method

Abstract A novel piezoelectric sensor was fabricated by depositing the films of polyvinyl pyrrolindone (PVP) and PVP with butyl cholinesterase (BuChE) (BuChE‐PVP), respectively, on the surface of quartz crystal microbalance (QCM) using self‐assembly method. The sensitive films were characterized with online examination and XPS technique. The obtained sensors were applied to measure o,o‐dimethyl‐o‐2,2‐dichlorovinyl phosphate (DDVP) pesticide concentration. It shows that BuChE‐PVP sensor has higher sensitivity than PVP sensor. There is a linear relationship between the shift of frequency and the concentration of DDVP in a range from 4.25 to 21.25 ppm. This highly sensitive sensor has also been shown to determine DDVP concentration in several samples, and the relative standard error is less than 3%. It also shows that CO, NO2, H2S, and SO2 with 10 times the concentration of DDVP have no interference with DDVP detection in the tested concentration range.