Mesoporous polydopamine delivery system for intelligent drug release and photothermal-enhanced chemodynamic therapy using MnO2 as gatekeeper.

The non-specific leakage of drugs from nanocarriers seriously weakened the safety and efficacy of chemotherapy, and it was very critical of constructing tumor microenvironment (TME)-responsive delivery nanocarriers, achieving the modulation release of drugs. Herein, using manganese dioxide (MnO2) as gatekeeper, an intelligent nanoplatform based on mesoporous polydopamine (MPDA) was developed to deliver doxorubicin (DOX), by which the DOX release was precisely controlled, and simultaneously the photothermal therapy (PTT) and chemodynamic therapy (CDT) were realized. In normal physiological environment, the stable MnO2 shell effectively avoided the leakage of DOX. However, in TME, the overexpressed glutathione (GSH) degraded MnO2 shell, which caused the DOX release. Moreover, the photothermal effect of MPDA and the Fenton-like reaction of the generated Mn2+ further accelerated the cell death. Thus, the developed MPDA-DOX@MnO2 nanoplatform can intelligently modulate the release of DOX, and the combined CDT/PTT/chemotherapy possessed high-safety and high-efficacy against tumors.

Ultrasmall gold decorated bimetallic metal-organic framework based nanoprobes for enhanced chemodynamic therapy with triple amplification.

Chemodynamic therapy (CDT) has shown potential for important applications in tumor precision therapy, but insufficient endogenous hydrogen peroxide (H2O2), overexpressed glutathione (GSH) and a weak Fenton-reaction rate greatly reduced the efficacy of CDT. Herein, a metal-organic framework (MOF) based bimetallic nanoprobe with self-supplying H2O2 was developed for enhancing CDT with triple amplification, in which ultrasmall gold nanoparticles (AuNPs) were deposited on Co-based MOFs (ZIF-67), and manganese dioxide (MnO2) nanoshells were coated to form a ZIF-67@AuNPs@MnO2 nanoprobe. In the tumor microenvironment, MnO2 depleted overexpressed GSH to produce Mn2+, and the bimetallic Co2+/Mn2+ nanoprobe accelerated the Fenton-like reaction rate. Moreover, by catalyzing glucose via ultrasmall AuNPs, the self-supplying H2O2 further promoted hydroxyl radical (˙OH) generation. Compared with those of ZIF-67 and ZIF-67@AuNPs, the ˙OH yield of ZIF-67@AuNPs@MnO2 obviously increased, due to which the cell viability decreased to 9.3%, and the tumor completely disappeared, indicating the enhanced CDT performance of the ZIF-67@AuNPs@MnO2 nanoprobe.

Ultrasmall Gold-Coated Mesoporous Polydopamine Nanoprobe to Enhance Chemodynamic Therapy by Self-Supplying H2O2 and Photothermal Stimulation.

Tumor microenvironment (TME) responsive chemodynamic therapy (CDT) showed an important application in inhibiting tumor growth by producing the highly toxic hydroxyl radical (·OH), but insufficient hydrogen peroxide (H2O2) and overexpressed glutathione (GSH) limited its application. Herein, by integrating photothermal therapy (PTT) and CDT, a new kind of mesoporous polydopamine (MPDA)-based cascade-reaction nanoplatform (MPDA@AuNPs-Cu) was designed for enhanced antitumor therapy, in which ultrasmall gold nanoparticles (AuNPs) with glucose oxidase (GOx)-like activity were deposited on MPDA for providing H2O2, and Cu2+ was chelated for GSH-responsive Fenton-like reaction. It was demonstrated that the MPDA@AuNPs-Cu nanoprobe showed high photothermal conversion efficiency and excellent biocompatibility. Moreover, the MPDA@AuNPs-Cu nanoprobe exhibited strong ·OH generation because of H2O2 self-generation and photothermal stimulation. Importantly, compared with MPDA-Cu, MPDA@AuNPs-Cu exhibited enhanced in vitro and in vivo CDT/PTT performance, by which the tumor growth was completely inhibited, achieving TME-responsive antitumor efficacy.

Endo/exo-genous dual-stimuli responsive gold nanotetrapod-based nanoprobe for magnetic resonance imaging and enhanced multimodal therapeutics by amplifying·OH generation.

Tumor microenvironment (TME) responsive chemodynamic therapy (CDT) can produce high-toxic hydroxyl radicals (·OH) to kill cancer cells, but the limited concentration of endogenous hydrogen peroxide (H2O2) seriously restricted its application. Herein, using endo/exo-genous dual-stimuli, a novel nanoprobe with enhanced ·OH generation was developed for magnetic resonance (MR) imaging and multimodal therapeutics, in which gold nanotetrapod (AuNTP) with photothermal therapy (PTT) performance was coated with mesoporous silica (mSiO2) and loaded with cisplatin (CDDP), then a thin layer of manganese dioxide (MnO2) was deposited to construct AuNTP@mSiO2@CDDP@MnO2 nanoprobes. In TME, endogenous H2O2, CDDP-triggered self-supplying H2O2 produced via cascade reaction and the exogenous photothermal effect of AuNTPs together enhanced the ·OH generation of Mn2+ induced by glutathione (GSH) responsive degradation of MnO2. The prepared AuNTP@mSiO2@CDDP@MnO2 nanoprobes possessed perfect core@shell structure, good biocompatibility and GSH-dependent MR performance, in which the relaxation rates increased from 0.717 mM-1·s-1 to 8.12 mM-1·s-1. Under the multimodal therapeutics of CDT/PTT/chemotherapy, the developed AuNTP@mSiO2@CDDP@MnO2 nanoprobes demonstrated good antitumor efficacy. Our work provided a promising strategy for constructing TME-responsive nanoprobes with endo/exo-genous stimuli, achieving enhanced visualized theranostics of tumors. STATEMENT OF SIGNIFICANCE: Tumor microenvironment (TME) responsive chemodynamic therapy (CDT) can produce high-toxic hydroxyl radicals (·OH) to kill cancer cells, but the limited concentration of endogenous hydrogen peroxide (H2O2) seriously restricted its application. Using endo/exo-genous dual-stimuli, AuNTP@mSiO2@CDDP@MnO2 (AMCM) nanoprobe was constructed, in which endogenous H2O2, CDDP-triggered self-supplying H2O2 and the exogenous photothermal effect of AuNTPs together enhanced the ·OH generation. Under the multimodal therapeutics of CDT/PTT/chemotherapy, the developed AuNTP@mSiO2@CDDP@MnO2 nanoprobe demonstrated good antitumor efficacy, and provided a promising strategy for constructing TME-responsive nanoprobes with endo/exo-genous stimuli, achieving enhanced CDT of tumors.

[Application of Wechat public platform in teaching reform of prosthodontics].

PURPOSE: To explore the law of development and existing problems in prosthodontics teaching in the new era, through flipped classroom teaching based on WeChat public platform. METHODS: WeChat public number was applied and WeChat groups were set up among the students of grade 2013, and 93 students were divided into 20 WeChat groups, with 4 to 5 students in each group. The main platform on reform of prosthodontics teaching was WeChat app, supplemented by platforms of Lediaocha and Youkaoshi. Teachers published courseware and learning resources with WeChat public number and WeChat groups. Two-dimensional codes on questionnaires and tests which were generated by Lediaocha and Youkaoshi could be published with WeChat and the final learning effectiveness was compared using SPSS 19.0 software package for t test. RESULTS: The results showed that 59.1% students admitted WeChat teaching effective, only 5.4% students believed ineffective. Based upon partial chapters of prosthodontics, the score of classroom test (91.35±4.45) was significantly higher than that of pre-class test(90.14±5.03, P＜0.05). CONCLUSIONS: The reform of flipped classroom based on WeChat platform in prosthodontics have some advantages, such as more flexibility in teaching form and time arrangement, promoting students' learner autonomy, and increasing students' motivation and effects of learning prosthodontics.

Advanced glycation end products increased placental vascular permeability of human BeWo cells via RAGE/NF-kB signaling pathway.

OBJECTIVE: This study aimed to investigate the mechanisms of advanced glycation end products (AGEs) on cell tight conjunction and placental vascular permeability in BeWo cells. STUDY DESIGN: Monolayer permeability assay and transmission electron microscopy were employed to reveal the transformation of the placental vascular permeability and cell tight conjunction. Immunofluorescence, western blot and RT-qPCR were adopted to determine the protein and mRNA levels. Anti-RAGE and NF-kB inhibitor (PDTC) were used to inactivate the RAGE/NF-kB signaling pathway. RESULTS: AGEs significantly decreased trans-epithelial electrical resistance (TEER), while increased paracellular permeability (P < 0.05). TEM showed that AGEs made cell junction loose. AGEs inhibited ZO-1 and Occludin expressions, while anti-RAGE or PDTC partially restored their levels. AGEs also significantly increased mRNA RAGE and NF-kB expressions in BeWo cells (P < 0.05), and their expressions were inhibited by anti-RAGEy or PDTC. CONCLUSION: AGEs could reduce the expressions of ZO-1 and Occludin by activating RAGE/NF-kB signaling pathway, thus increasing placental vascular permeability.

Low molecular weight heparin (nadroparin) improves placental permeability in rats with gestational diabetes mellitus via reduction of tight junction factors.

Placental structural abnormalities and dysfunction in those with gestational diabetes mellitus (GDM) can lead to increased placental permeability, which is in turn related to a poorer maternal and fetal prognosis. The present study sought to assess whether increased placental permeability in rats with GDM was accompanied by alterations in tight junction (TJ) factors and to evaluate the impact of low molecular weight heparin (LMWH) on these factors. The present study was conducted using pregnant female rats that were randomized into control, GDM and GDM + LMWH groups. Diabetes was induced via intraperitoneal administration of streptozotocin to rats in the GDM and GDM + LMWH groups, whereas rats in the GDM + LMWH group received daily subcutaneous LMWH starting on day 5 of pregnancy. On gestational day 16, all rats were sacrificed and Evans Blue (EB) assay was used to gauge vascular permeability based on EB dye leakage. Transmission electron microscopy was further used to assess TJ structures, and the TJ proteins zonular occludens­1 (ZO­1) and occludin (OCLN) were assessed using immunohistochemistry and western blotting. Blood samples were obtained from the abdominal aorta for ELISA measurements of advanced glycation end products (AGEs) concentrations, and placental receptor for AGEs (RAGE) and vascular endothelial growth factor (VEGF) expression was assessed using reverse transcription­quantitative PCR. In addition, western blotting was used to measure placental NF­κB. Compared with in the control group, EB leakage was markedly increased in GDM group rats; this was associated with reduced ZO­1 and OCLN expression. Conversely, LMWH attenuated this increase in placental permeability in rats with GDM and also mediated a partial recovery of ZO­1 and OCLN expression. Blood glucose and serum AGEs concentrations did not differ between the GDM and GDM + LMWH groups. Furthermore, LMWH treatment resulted in decreases in RAGE and VEGF mRNA expression levels, which were upregulated in the GDM group, whereas it had the opposite effect on the expression of NF­κB. In conclusion, GDM was associated with increased placental permeability and this may be linked with changes in TJs. LMWH intervention mediated protection against this GDM­associated shift in placental permeability via the RAGE/NF­κB pathway.

Effect of Platelet-rich Plasma on Implant Bone Defects in Rabbits Through the FAK/PI3K/AKT Signaling Pathway.

Platelet-rich plasma (PRP) has been shown to be a beneficial growth factor for bone tissue healing and is used in implantology. The aim of this study was to investigate the effects of PRP on bone defects in rabbits. Twenty rabbits were used to establish the implant bone defect model in this study. An intrabony defect (5mm × 5mm × 3mm) was created in alveolar bone in the lower jar of each rabbit. The wound was treated with PRP. The expression of platelet-derived growth factor BB (PDGFBB) was assessed by enzyme-linked immunosorbent assay (ELISA). Focal adhesion kinase (FAK) and related phosphatidylinositol 3-kinase (PI3K)/AKT (protein kinase B) levels were measured by Western blot. The results show that PRP could significantly improve the bone healing process when compared with control, and 10% PRP could markedly increase fibroblast proliferation 48-h post treatment. PDGFBB was higher in the PRP group than that in the control group. PRP treatment also could elevate the phosphorylation of FAK and PI3K/AKT, although the inhibitor of PDGFR could reverse this trend. These results suggest that PRP treatment improves the bone healing process through the FAK/PI3K/AKT pathway.

Octreotide enhances the sensitivity of the SKOV3/DDP ovarian cancer cell line to cisplatin chemotherapy in vitro.

The present study aimed to investigate the effects of octreotide (OCT) on the reversal of resistance of cisplatin-resistant cancer cells and on enhancement of the cisplatin sensitivity of cancer cells. The 3-(4,5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide method and flow cytometry were used to investigate the effect of cisplatin, OCT or the combination of these two compounds on the proliferation and apoptosis of SKOV3/DDP cells. Real-time, quantitative RT-PCR was used to detect the mRNA expression of SSTR2, MDR1, MRP2, GST-π and EGFR in SKOV3/DDP cells following OCT treatment. At the concentration of 2.5-20 µg/ml, OCT significantly reduced the IC(50) value (P<0.05) and promoted apoptosis (P<0.05) in the SKOV3/DDP cells in response to cisplatin. The synergistic effect of OCT and cisplatin on SKOV3/DDP cell proliferation was observed. SSTR2 was expressed on the SKOV3/DDP cell surface. OCT increased GST-π expression (P<0.05) and reduced MRP2 and EGFR expression (P<0.05) in a dose-dependent manner. However, it had no effect on the expression of MDR1 (P>0.05). It is suggested that OCT inhibits ovarian cancer proliferation and promotes apoptosis, via the cell surface expression of SSRT2, and reverses cisplatin resistance through the inhibition of MRP2 and EGFR expression.