Calcium-enriched carbon nanoparticles loaded with indocyanine green for near-infrared fluorescence imaging-guided synergistic calcium overload, photothermal therapy, and glutathione-depletion-enhanced photodynamic therapy.

Combining phototherapy with other treatments has significantly advanced cancer therapy. Here, we designed and fabricated calcium-enriched carbon nanoparticles (Ca-CNPs) that could effectively deplete glutathione (GSH) and release calcium ions in tumors, thereby enhancing the efficacy of photodynamic therapy (PDT) and the calcium overload effect that leads to mitochondrial dysfunction. Due to the electrostatic interaction, π-π stacking interaction, multiple hydrogen bonds, and microporous structures, indocyanine green (ICG) was loaded onto the surface of Ca-CNPs with a high loading efficiency of 44.7 wt%. The obtained Ca-CNPs@ICG can effectively improve the photostability of ICG while retaining its ability to generate singlet oxygen (1O2) and undergo photothermal conversion (Ca-CNPs@ICG vs. ICG, 45.1% vs. 39.5%). In vitro and in vivo experiments demonstrated that Ca-CNPs@ICG could be used for near-infrared fluorescence imaging-guided synergistic calcium overload, photothermal therapy, and GSH depletion-enhanced PDT. This study sheds light on the improvement of 1O2 utilization efficiency and calcium overload-induced mitochondrial membrane potential imbalance in tumor cells.

Catalase-like pleated niobium carbide MXene loaded with polythiophene for oxygenated sonodynamic therapy in solid tumor.

Sonodynamic therapy (SDT), an emerging treatment for solid tumors, has the advantages of deep tissue penetration, non-invasiveness, low side effects, and negligible drug resistance. However, the hypoxic environment of deep solid tumors can discount the efficacy of oxygenated dependent SDT. Here, we synthesized a polythiophene-based sonosensitizer (PT2) and a two-dimensional pleated niobium carbide (Nb2C) Mxene. PT2 was loaded onto the surface of poly(vinylpyrrolidone) (PVP)-coated Nb2C MXene through electrostatic interaction to obtain Nb2C-PVP-PT2 nanosheets (NSs) with a high loading efficiency of 153.7%. Nb2C MXene exhibited catalase-like activity, which could catalyze hydrogen peroxide (H2O2) to produce O2, in turn alleviating tumor hypoxia and enhancing the efficacy of SDT. The depletion of H2O2 further results in abnormal cellular H2O2 levels and reduced tumor cell activity. Moreover, the decomposed NSs led to the release of the sonosensitizer PT2 that can efficiently generate both singlet oxygen and superoxide anions under ultrasound irradiation. These events led to the inhibition of DNA replication of tumor cells, causing tumor cell death, allowing for enhanced SDT efficacy.

Dissolved organic matter heightens the toxicity of tetrabromobisphenol A to aquatic organisms.

Tetrabromobisphenol A (TBBPA) is a new type of persistent organic pollutant, which causes environmental pollution and health problems, and has attracted the attention of the international research community. Once released into the environment, TBBPA can interact with dissolved organic matter (DOM), which affects its behavior. However, the effect of DOM on the biological toxicity of TBBPA remains unclear. The toxic effects of TBBPA on three model aquatic organisms (Chlorella pyrenoidosa, Daphnia magna, and Danio rerio), in the absence and presence of DOM were investigated. The order of acute toxicity of TBBPA to the three aquatic organisms was D. magna > D. rerio > C. pyrenoidosa. In the presence of DOM the median effect/lethal concentrations values of TBBPA to the three aquatic organisms decreased by at least 32 (C. pyrenoidosa), 52 (D. magna), and 6.6% (D. rerio), implying that DOM enhanced the acute toxicity of TBBPA to all the organisms. Moreover, the higher the concentration of DOM, the higher the acute toxicity of TBBPA. Furthermore, the presence of DOM increased total reactive oxygen species (ROS) induced by TBBPA in a concentration-dependent manner. A tracking analysis of total ROS in the three aquatic organisms also showed that the presence of DOM aggravated the accumulation of total ROS induced by TBBPA, indicating that oxidative stress is a characteristic mechanism of toxicity of TBBPA to aquatic organisms when DOM is present. In addition, the evaluated risk quotient indicated that the ecological risk of TBBPA to aquatic organisms can increase in environments rich in DOM.

NF-κB-mediated miR-650 plays oncogenic roles and activates AKT/ERK/NF-κB pathways by targeting RERG in glioma cells.

PURPOSE: Glioma is the most common cancer in the central nervous system and has a high mortality rate. Despite advances that have been made in the treatment of glioma, its prognosis still remains poor. Dysregulation of miRNAs has been reported in many cancers, including glioma. Here, we set out to assess the role of miR-650 in glioma, including its diagnostic and therapeutic potential. METHODS: miR-650 and RAS-like estrogen-regulated growth inhibitor (RERG) expression levels were analyzed using qRT-PCR in primary glioma tissues and cell lines. Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, colony formation, Western blotting, scratch wound healing, Transwell, adhesion, autophagy, immunofluorescence, luciferase reporter, electrophoretic mobility shift, tumor xenograft and flow cytometry assays were employed to investigate the mechanisms underlying the effect of miR-650 and RERG on glioma development. RESULTS: miR-650 was found to be up-regulated in glioma tissues and cell lines compared to non-cancerous brain tissues and neural progenitor cells, respectively. We also found that miR-650 promoted cell proliferation, migration and invasion in glioma cells, and enhanced glioma tumor formation and growth in vivo. We identified and validated RERG as a direct target of miR-650. RERG was shown to act as a tumor suppressor in glioma cells, and its suppressor roles were rescued by miR-650. We found that nuclear factor (NF)-κB bound to the promoter of miR-650 and enhanced its expression. PH domain and leucine rich repeat protein phosphatase 2 (PHLPP2), as a co-factor of the RERG/PHLPP2 complex, mediated miR-650-induced activation of the protein kinase B/extracellular-signal-regulated kinase/NF-κB signaling pathways. CONCLUSIONS: Our data revealed novel functional roles for miR-650 in glioma development and may provide new avenues for future clinical applications.

Correction: The involvement of Bcl-2 family proteins in AKT-regulated cell survival in cisplatin resistant epithelial ovarian cancer.

[This corrects the article DOI: 10.18632/oncotarget.13817.].

Combined Toxicity of TiO2 Nanospherical Particles and TiO2 Nanotubes to Two Microalgae with Different Morphology.

The joint activity of multiple engineered nanoparticles (ENPs) has attracted much attention in recent years. Many previous studies have focused on the combined toxicity of different ENPs with nanostructures of the same dimension. However, the mixture toxicity of multiple ENPs with different dimensions is much less understood. Herein, we investigated the toxicity of the binary mixture of TiO2 nanospherical particles (NPs) and TiO2 nanotubes (NTs) to two freshwater algae with different morphology, namely, Scenedesmus obliquus and Chlorella pyrenoidosa. The physicochemical properties, dispersion stability, and the generation of reactive oxygen species (ROS) were determined in the single and binary systems. Classical approaches to assessing mixture toxicity were applied to evaluate and predict the toxicity of the binary mixtures. The results show that the combined toxicity of TiO2 NPs and NTs to S. obliquus was between the single toxicity of TiO2 NTs and NPs, while the combined toxicity to C. pyrenoidosa was higher than their single toxicity. Moreover, the toxicity of the binary mixtures to C. pyrenoidosa was higher than that to S. obliquus. A toxic unit assessment showed that the effects of TiO2 NPs and NTs were additive to the algae. The combined toxicity to S. obliquus and C. pyrenoidosa can be effectively predicted by the concentration addition model and the independent action model, respectively. The mechanism of the toxicity caused by the binary mixtures of TiO2 NPs and NTs may be associated with the dispersion stability of the nanoparticles in aquatic media and the ROS-induced oxidative stress effects. Our results may offer a new insight into evaluating and predicting the combined toxicological effects of ENPs with different dimensions and of probing the mechanisms involved in their joint toxicity.

The involvement of Bcl-2 family proteins in AKT-regulated cell survival in cisplatin resistant epithelial ovarian cancer.

Many studies involving patients with cisplatin-resistant ovarian cancer have shown that AKT activation leads to inhibition of apoptosis. The aim of this study was to examine the potential involvement of the Bcl-2 family proteins in AKT-regulated cell survival in response to cisplatin treatment. Cisplatin-sensitive (PEO1) and cisplatin-resistant (PEO4) cells were taken from ascites of patients with ovarian cancer before cisplatin treatment and after development of chemoresistance. It was found that cisplatin treatment activated the AKT signaling pathway and promoted cell proliferation in cisplatin-resistant EOC cells. When AKT was transfected into nucleus of cisplatin-resistant ovarian cancer cells, DNA-PK was phosphorylated at S473. The activated AKT (pAKT-S473) in these cells inhibited the death signal induced by cisplatin thereby inhibiting cisplatin-mediated apoptosis. Results from this study showed that the combination of cisplatin, DNA-PK inhibitor NU7441, and AKT inhibitor TCN can overcome drug resistance, increase apoptosis, and re-sensitize PEO4 cells to cisplatin treatment. A decrease in apoptotic activity was seen in PEO4 cells when Bad was downregulated by siRNA, which indicated that Bad promotes apoptosis in PEO4 cells. Use of the Bcl-2 inhibitor ABT-737 showed that ABT-737 binds to Bcl-2 but not Mcl-1 and releases Bax/Bak which leads to cell apoptosis. The combination of ABT-737 and cisplatin leads to a significant increase in the death of PEO1 and PEO4 cells. All together, these results indicate that Bcl-2 family proteins are regulators of drug resistance. The combination of cisplatin and Bcl-2 family protein inhibitor could be a strategy for the treatment of cisplatin-resistant ovarian cancer.

MicroRNA-544 inhibits glioma proliferation, invasion and migration but induces cell apoptosis by targeting PARK7.

Glioma is a common type of primary brain tumor. The survival rate in people with malignant gliomas is extremely low associated with the lack of effective treatment. Here, we firstly observed that miR-544 expression is downregulated in glioma tissues and its overexpression in glioma cell line dramatically reduces cell proliferation, migration and invasion. In addition, we found that the tumor growth in nude mouse was as well inhibited by miR-544 overexpressed in glioma cell. Our further investigation showed that the inhibitor role of miR-544 in tumor development was related to the downregulated expression of Park7 gene which has been demonstrated as a functional downstream target of miR-544. Thus, our discovery suggested that miR-544 might used as a therapeutic reagent for the treatment of glioma in the future.

Chitosan oligosaccharide decreases very-low-density lipoprotein triglyceride and increases high-density lipoprotein cholesterol in high-fat-diet-fed rats.

It is well known that chitosan has beneficial lipid-regulating effects, but it remains unknown whether chitosan oligosaccharide (COS), the chitosan degradation product, has the same lipid benefits. High-fat-diet-fed Wistar rats were administrated with COS by gastric gavage for three weeks. The effects of COS on lipids, lipoprotein components and lipid metabolism related protein activities were investigated. Plasma lipids level assays by an enzyme method showed that COS decreased triglyceride (TG) by 29-31%, and increased high-density lipoprotein (HDL) cholesterol by 8-11%, but did not affect low-density lipoprotein (LDL) cholesterol. Lipid distribution analysis through fast protein liquid chromatography indicated that COS significantly decreased TG content distributed in very-low-density lipoprotein (VLDL)/LDL fractions but increased cholesterol content in HDL fractions. Apolipoprotein analysis through plasma ultracentrifugation and sodium dodecyl sulfate polyacrylamide gel electrophoresis displayed that COS decreased apolipoprotein B-100 of LDL and increased apolipoprotein E of LDL and apolipoprotein B-100 of VLDL, but did not change apoA-I content of HDL particles. Lipoprotein formation associated protein determination showed that COS also increased plasma activity of lecithin cholesterol acyl transferase but not phospholipid transfer protein. The present study suggests that COS may play a beneficial role in plasma lipid regulation of rats with dyslipidemia induced by high-fat diet. The COS-decreased VLDL/LDL TG and -enhanced HDL cholesterol may be related to the upregulated activity of lecithin cholesterol acyl transferase.

Study on chitosan/polycaprolactone blending vascular scaffolds by electrospinning.

The chitosan/polycaprolactone (CS/PCL) vascular scaffolds were prepared by electrospinning in order to combine the advantage of CS and PCL into the vascular scaffolds. The obtained CS/PCL vascular scaffolds were dried with ethanol, and then characterized by SEM and electronic universal testing machine. The endothelial progenitor cells (EPCs) were implanted in the scaffolds with various mass ratios of CS to PCL. The vascular scaffolds were examined by adhesion rate in different culturing times and the cells growth was observed. Micro/nano structured surface of CS/PCL vascular scaffolds are more stable after dealing with ethanol. The obtained CS/PCL vascular scaffolds showed porous, micro/nano structured surfaces which were similar to natural extracellular matrix. When the mass ratio of CS to PCL is 0.5, the breaking elongation of CS/PCL vascular scaffolds was 31.64%, and the curves of stress-strain indicate that the obtained vascular scaffolds possess good elastic deformation. The adhesion rates of EPCs on CS/PCL vascular scaffolds increase to 95.1% in 24 h, the observation of EPCs labeled with CM-Dil (chlormethylbenzamido-1,1dioctadecyl-3,3,3',3'-tetramethylindocarbocyamine) after culturing 72 h by fluorescence microscopy also illustrates that CS/PCL vascular scaffolds are beneficial to cell growth and cell adhesion.

High entrapment efficiency of chitosan/polylactic acid/tripolyphotspate nanosized microcapsules for rapamycin by an emulsion-evaporation approach.

Chitosan (CS)/polylactic acid (PLA)/tripolyphotspate (TPP) nanosized microcapsules were prepared by emulsion-evaporation. The average diameter of the obtained nanosized microcapsules was around 100-300 nm, and a homogeneous size distribution and good dispersion were observed. The entrapment efficiency of the nanosized CS/PLA/TPP microcapsules for rapamycin was increased with the increase in amount of PLA. When the ratio of CS to PLA was 80 to 20, the entrapment efficiency of CS/PLA/TPP nanosized microcapsules for rapamycin reached the highest (89.8 +/- 1.72%). It was also observed that The RAPA entrapment efficiency reached its highest at 20% of addition dosage of RAPA.