Enhanced Sensitivity of A549 Cells to Doxorubicin with WS2 and WSe2 Nanosheets via the Induction of Autophagy.

The excellent physicochemical properties of two-dimensional transition-metal dichalcogenides (2D TMDCs) such as WS2 and WSe2 provide potential benefits for biomedical applications, such as drug delivery, photothermal therapy, and bioimaging. WS2 and WSe2 have recently been used as chemosensitizers; however, the detailed molecular basis underlying WS2- and WSe2-induced sensitization remains elusive. Our recent findings showed that 2D TMDCs with different thicknesses and different element compositions induced autophagy in normal human bronchial epithelial cells and mouse alveolar macrophages at sublethal concentrations. Here, we explored the mechanism by which WS2 and WSe2 act as sensitizers to increase lung cancer cell susceptibility to chemotherapeutic agents. The results showed that WS2 and WSe2 enhanced autophagy flux in A549 lung cancer cells at sublethal concentrations without causing significant cell death. Through the autophagy-specific RT2 Profiler PCR Array, we identified the genes significantly affected by WS2 and WSe2 treatment. Furthermore, the key genes that play central roles in regulating autophagy were identified by constructing a molecular interaction network. A mechanism investigation uncovered that WS2 and WSe2 activated autophagy-related signaling pathways by interacting with different cell surface proteins or cytoplasmic proteins. By utilizing this mechanism, the efficacy of the chemotherapeutic agent doxorubicin was enhanced by WS2 and WSe2 pre-treatment in A549 lung cancer cells. This study revealed a feature of WS2 and WSe2 in cancer therapy, in which they eliminate the resistance of A549 lung cancer cells against doxorubicin, at least partially, by inducing autophagy.

Iron-modified biochar boosts anaerobic digestion of sulfamethoxazole pharmaceutical wastewater: Performance and microbial mechanism.

The accumulation of volatile fatty acids (VFAs) caused by antibiotic inhibition significantly reduces the treatment efficiency of sulfamethoxazole (SMX) wastewater. Few studies have been conducted to study the VFAs gradient metabolism of extracellular respiratory bacteria (ERB) and hydrogenotrophic methanogen (HM) under high-concentration sulfonamide antibiotics (SAs). And the effects of iron-modified biochar on antibiotics are unknown. Here, the iron-modified biochar was added to an anaerobic baffled reactor (ABR) to intensify the anaerobic digestion of SMX pharmaceutical wastewater. The results demonstrated that ERB and HM were developed after adding iron-modified biochar, promoting the degradation of butyric, propionic and acetic acids. The content of VFAs reduced from 1166.0 mg L-1 to 291.5 mg L-1. Therefore, chemical oxygen demand (COD) and SMX removal efficiency were improved by 22.76% and 36.51%, and methane production was enhanced by 6.19 times. Furthermore, the antibiotic resistance genes (ARGs) such as sul1, sul2, intl1 in effluent were decreased by 39.31%, 43.33%, 44.11%. AUTHM297 (18.07%), Methanobacterium (16.05%), Geobacter (6.05%) were enriched after enhancement. The net energy after enhancement was 0.7122 kWh m-3. These results confirmed that ERB and HM were enriched via iron-modified biochar to achieve high efficiency of SMX wastewater treatment.

Sequential exposures of single walled carbon nanotubes and heavy metal ions to macrophages induce different cytotoxicity.

The probability of occupational exposure rises with the increasing production and biomedical application of carbon nanotubes (CNTs). Thus, the risk of co-exposure of nanomaterials with environmental pollutants is also increasing. Although many studies have focused on the combined toxicity of nanomaterials and pollutants, more attention has been paid to the toxicity of nanomaterials after adsorbing pollutants or the toxicity of nanomaterials and pollutants exposed simultaneously. Few studies have been conducted on the toxicity and toxicity mechanisms of nanomaterials and environmental pollutants following sequential exposure. In this study, we employed THP-1 cells to investigate how pristine single walled CNTs (p-SWCNTs) and oxidized single walled CNTs (SWCNT-COOHs) pretreatments at a non-lethal dose of 10 µg/mL affect cell responses to metal ions (i. e., Pb2+, Cu2+, and Cr(VI)). We found that p-SWCNTs caused more significant damage to cell membrane integrity than SWCNT-COOHs, which led to higher metallothionein (MT) levels and increased transport of metal ions into cells. Pretreatment of p-SWCNTs in cells significantly increased the cytotoxicity of Pb2+, Cu2+, and Cr(VI) by 2-4-fold, whereas SWCNT-COOHs pretreated cells showed no noteworthy changes in response to heavy metals, which were further confirmed by the cellular reactive oxygen species (ROS) assays. These findings indicate that understanding the effects of the exposure sequence of engineered nanomaterials and environmental pollutants on their toxicity provides an excellent complement to combined toxicity evaluation.

Zn2+ loading as a critical contributor to the circ_0008553-mediated oxidative stress and inflammation in response to PM2.5 exposures.

Inflammation is a major adverse outcome induced by inhaled particulate matter with a diameter of ≤ 2.5 µm (PM2.5), and a critical trigger of most PM2.5 exposure-associated diseases. However, the key molecular events regulating the PM2.5-induced airway inflammation are yet to be elucidated. Considering the critical role of circular RNAs (circRNAs) in regulating inflammation, we predicted 11 circRNAs that may be involved in the PM2.5-induced airway inflammation using three previously reported miRNAs through the starBase website. A novel circRNA circ_0008553 was identified to be responsible for the PM2.5-activated inflammatory response in human bronchial epithelial cells (16HBE) via inducing oxidative stress. Using a combinatorial model PM2.5 library, we found that the synergistic effect of the insoluble core and loaded Zn2+ ions at environmentally relevant concentrations was the major contributor to the upregulation of circ_0008553 and subsequent induction of oxidative stress and inflammation in response to PM2.5 exposures. Our findings provided new insight into the intervention of PM2.5-induced adverse outcomes.

H2O2/DEM-Promoted Maft Promoter Demethylation Drives Nrf2/ARE Activation in Zebrafish.

The Nrf2/ARE signaling pathway is a cell survival response pathway in response to environmental stresses. The Nrf2/ARE signaling pathway can be activated by stimulating cysteine residues at different positions in the Keap1. However, the epigenetic mechanisms of the Nrf2/ARE pathway under different stimuli are still poorly understood. In this study, we found that both hydrogen peroxide (H2O2) and Diethyl Maleate (DEM) activated the Nrf2/ARE signaling pathway at 120 hpf in zebrafish. H2O2 regulated the demethylation of the maft promoter by inhibiting the expression of methyltransferase. This promotes the mRNA expression of the Nrf2 binding factor maft, thereby promoting the downstream antioxidant genes. The methylation of the Nrf2/ARE signaling pathway was not significantly regulated by DEM. However, under oxidative stress, the methyltransferase inhibitors (decitabine and azacitidine) demethylated the promoter region of maft. It activated the expression of the maft, further improving the Nrf2/ARE signal pathway. At last, antioxidant target genes were activated. It was shown that H2O2 and DEM cooperated with methyltransferase inhibitors, providing an important reference for the treatment of oxidative stress-related diseases and breaking new ground for the study of the mechanism of methyltransferase inhibitors in the process of tumor chemotherapy.

Ring-Pins combined with cable cerclage for the fixation of displaced inferior patellar pole fractures.

Objective: The study aimed to present the clinical results and complication rates of ring-pins with cable cerclage for treating the inferior pole of patella fracture. Method: A study that retrospectively reviewed consecutive patients of the displaced inferior pole of patella fracture (AO/OTA 34-A1) operated with a ring-pin tension band using cable cerclage between October 2015 and October 2017 was performed. The duration of surgery, motion range of the knee, function outcomes, and complications were recorded. Results: The average follow-up of 31 patients was 21 months. The mean operation time was 50 min. Fractures in all 31 patients healed at a mean duration of 8 weeks. There was no infection, no withdrawing of ring-pins, no implant breakage, and no loss of fracture reduction. The mean range of motion was 120°, and no patient complained of implant irritation at the final follow-up. The average Bostman score was 29.0 points, and 28 patients graded clinical outcomes excellent and 3 patients graded clinical outcomes good at the last follow-up. Conclusions: Ring-pin combined with cable cerclage for treating the displaced inferior pole of patellar fracture is simple, and the postoperative internal fixation-related complication rate is low. It is a good choice for treating the displaced inferior pole of the patellar fracture.

Intracellular Exposure Dose-Associated Susceptibility of Steatotic Hepatocytes to Metallic Nanoparticles.

Non-alcoholic fatty liver disease (NAFLD), mainly characterized by the accumulation of excess fat in hepatocytes, is the most prevalent liver disorder afflicting ~25% of adults worldwide. In vivo studies have shown that adult rodents with NAFLD were more sensitive to metallic nanoparticles (MNPs) than healthy MNPs. However, due to the complex interactions between various cell types in a fatty liver, it has become a major challenge to reveal the toxic effects of MNPs to specific types of liver cells such as steatotic hepatocytes. In this study, we reported the susceptibility of steatotic hepatocytes in cytotoxicity and the induction of oxidative stress to direct exposures to MNPs with different components (silver, ZrO2, and TiO2 NPs) and sizes (20-30 nm and 125 nm) in an oleic acid (OA) -induced steatotic HepG2 (sHepG2) cell model. Furthermore, the inhibitory potential of MNPs against the process of fatty acid oxidation (FAO) were obvious in sHepG2 cells, even at extremely low doses of 2 or 4 µg/mL, which was not observed in non-steatotic HepG2 (nHepG2) cells. Further experiments on the differential cell uptake of MNPs in nHepG2 and sHepG2 cells demonstrated that the susceptibility of steatotic hepatocytes to MNP exposures was in association with the higher cellular accumulation of MNPs. Overall, our study demonstrated that it is necessary and urgent to take the intracellular exposure dose into consideration when assessing the potential toxicity of environmentally exposed MNPs.

Recent advances in covalent organic frameworks for cancer diagnosis and therapy.

In recent years, the number of patients diagnosed with cancer has been soaring. Therefore, the design, development, and implementation of new approaches for the diagnosis and therapy of different types of cancers have attracted an increasing amount of attention. To date, different methods have been used for cancer diagnosis and therapy with main drawbacks in terms of severe side effects, e.g., damage to healthy cells, development of drug resistance and tumor recurrence. Therefore, there is an urgent need for the introduction and application of innovative methods. Covalent organic frameworks (COFs) are versatile materials with excellent properties in terms of biocompatibility, porous and crystalline structure, and easy functionalization. The porous structure and organic monomers in COFs allow them to load different therapeutic drugs and/or functional species efficiently. These promising properties make COFs ideal candidates for medical application, especially in cancer diagnosis and therapy. To date, many studies have focused on the design and synthesis of novel COFs while their application as diagnostic and therapeutic materials remains less understood. In this review, different synthesis and functionalization approaches of COFs were summarized. In particular, cancer diagnosis and therapy based on COFs were investigated and the advantages and limitations of each method were discussed. Most importantly, the mechanism for cancer therapy of COFs and fundamental challenges and perspectives for the application of COFs in cancer theranostics were assessed.

Biotransformation and detoxification of the neonicotinoid insecticides nitenpyram and dinotefuran by Phanerochaete sordida YK-624.

Neonicotinoid insecticides have been widely used throughout the world over the last two decades. In the present study, we investigated the degradation of neonicotinoid insecticides nitenpyram (NIT) and dinotefuran (DIN) by the white-rot fungus Phanerochaete sordida YK-624. While NIT was completely degraded by P. sordida YK-624 under ligninolytic conditions, only a 20% decrease was observed under nonligninolytic conditions. On the other hand, P. sordida YK-624 degraded 31% of DIN under ligninolytic conditions after a 20-day incubation, while it did not degrade DIN under nonligninolytic conditions. We found that cytochromes P450 played a key role in the biotransformation of NIT and DIN by P. sordida YK-624. A novel NIT metabolite (E)-N-((6-chloropyridin-3-yl)methyl)-N-ethyl-N'-hydroxy acetimidamide (CPMHA) and a novel DIN metabolite N-((4aS,7aS,E)-1-methylhexahydrofuro[2,3-d]pyrimidin-2(1H)-ylidene)nitramide (PHPF) were identified in this study. In addition, to evaluate neurotoxicity, the effects of NIT, DIN and their metabolites on the viability of human neuroblastoma cells SH-SY5Y were determined. PHPF showed higher neurological toxicity than DIN, whereas the metabolite of NIT, CPMHA, showed no toxic effect. Our results indicated that the neurological toxicity of NIT could be effectively removed by P. sordida YK-624.

Remote Induction of Cell Autophagy by 2D MoS2 Nanosheets via Perturbing Cell Surface Receptors and mTOR Pathway from Outside of Cells.

The ability of nanoparticles to induce adverse consequences in human cells relies on their physical shapes. In this aspect, how two-dimensional nanoparticles differ from three-dimensional nanoparticles is not well-known. To elucidate this difference, combined experimental and theoretical approaches are employed to compare MoS2 nanosheets with 5-layer and 40-layer thicknesses for their cellular effects and the associated molecular events. At a concentration as defined by the nanosheet surface areas (10 cm2/mL), 40-layer nanosheets are internalized by cells, whereas 5-layer nanosheets mostly bind to the cell surface without internalization. Although they alter different autophagy-related genes, a common mechanism is that they both perturb cell surface protein amyloid precursor proteins and activate the mTOR signaling pathway. Our findings prove that the perturbation of cellular function without nanoparticle internalization has significant nanomedicinal and nanotoxicological significances.

miR-21 and miR-19b delivered by hMSC-derived EVs regulate the apoptosis and differentiation of neurons in patients with spinal cord injury.

BACKGROUND: In this study, we aimed to evaluate the therapeutic effects of extracellular vesicles (EVs), which were collected from differentiated PC12 cells and mesenchymal cells (MSCs), on the treatment of spinal cord injury (SCI). In addition, we aimed to identify miRNAs related to the inhibitory effect of EVs against cell apoptosis. METHODS: Electron microscopy was used to observe the distributions of EVs in the samples. Real-time PCR, western blot, thiazolyl blue tetrazolium bromide (MTT) assay, and flow cytometry were performed to establish the molecular signaling pathway underlying the effect of EVs in SCI. In addition, a Basso-Beattie-Bresnahan (BBB) score system, Nissl staining, immunohistochemistry assay, and TdT-mediated dUTP nick-end labeling (TUNEL) assay were conducted to validate the molecular signaling pathway established above. RESULTS: The expression of miR-21 and miR-19b was upregulated in EVs isolated from induced PC12 cells and MSCs, along with decreased expression of phosphatase and tensin homolog (PTEN) messenger RNA (mRNA)/protein and a lower level of cell apoptosis. The transfection of miR-21/miR-19b precursors into the cells also exhibited an inhibitory effect on cell apoptosis. In addition, in-silicon analysis and luciferase assays validated the role of PTEN as a virtual target of miR-21/miR-19b. Finally, the BBB scores and Nissl staining also validated the therapeutic effects of EVs derived from differentiated P12 cells/MSCs in SCI rats. Accordingly, the negative correlations between miR-21/miR-19b and PTEN mRNA/protein were implicated in the post-SCI recovery. CONCLUSIONS: The increased levels of miR-21/miR-19b in the EVs derived from differentiated PC12 cells and MSCs suppresses the apoptosis of neuron cells by downregulating the expression of PTEN.

Interactions Between Nanoparticles and Dendritic Cells: From the Perspective of Cancer Immunotherapy.

Dendritic cells (DCs) are the primary antigen-presenting cells and play key roles in the orchestration of the innate and adaptive immune system. Targeting DCs by nanotechnology stands as a promising strategy for cancer immunotherapy. The physicochemical properties of nanoparticles (NPs) influence their interactions with DCs, thus altering the immune outcome of DCs by changing their functions in the processes of maturation, homing, antigen processing and antigen presentation. In this review, we summarize the recent progress in targeting DCs using NPs as a drug delivery carrier in cancer immunotherapy, the recognition of NPs by DCs, and the ways the physicochemical properties of NPs affect DCs' functions. Finally, the molecular pathways in DCs that are affected by NPs are also discussed.

Green Preparation of High Yield Fluorescent Graphene Quantum Dots from Coal-Tar-Pitch by Mild Oxidation.

Coal tar pitch (CTP), a by-product of coking industry, has a unique molecule structure comprising an aromatic nucleus and several side chains bonding on this graphene-like nucleus, which is very similar to the structure of graphene quantum dots (GQDs). Based on this perception, we develop a facile approach to convert CTP to GQDs only by oxidation with hydrogen peroxide under mild conditions. One to three graphene layers, monodisperse GQDs with a narrow size distribution of 1.7 ± 0.4 nm, are obtained at high yield (more than 80 wt. %) from CTP. The as-produced GQDs are highly soluble and strongly fluorescent in aqueous solution. This simple strategy provides a feasible route towards the commercial synthesis of GQDs for its cheap material source, green reagent, mild condition, and high yield.

Knockdown of PAICS inhibits malignant proliferation of human breast cancer cell lines.

BACKGROUND: Phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), an enzyme required for de novo purine biosynthesis, is associated with and involved in tumorigenesis. This study aimed to evaluate the role of PAICS in human breast cancer, which remains the most frequently diagnosed cancer and the leading cause of cancer-related death among women in less developed countries. RESULTS: Lentivirus-based short hairpin RNA targeting PAICS specifically depleted its endogenous expression in ZR-75-30 and MDA-MB-231 breast cancer cells. Depletion of PAICS led to a significant decrease in cell viability and proliferation. To ascertain the mechanisms through which PAICS modulates cell proliferation, flow cytometry was performed, and it was confirmed that G1-S transition was blocked in ZR-75-30 cells through PAICS knockdown. This might have occurred partly through the suppression of Cyclin E and the upregulation of Cyclin D1, P21, and CDK4. Moreover, PAICS knockdown obviously promoted cell apoptosis in ZR-75-30 cells through the activation of PARP and caspase 3 and downregulation of Bcl-2 and Bcl-xl expression in ZR-75-30 cells. CONCLUSIONS: These findings demonstrate that PAICS plays an essential role in breast cancer proliferation in vitro, which provides a new opportunity for discovering and identifying novel effective treatment strategies.

Knockdown of PAICS inhibits malignant proliferation of human breast cancer cell lines

BACKGROUND: Phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), an enzyme required for de novo purine biosynthesis, is associated with and involved in tumorigenesis. This study aimed to evaluate the role of PAICS in human breast cancer, which remains the most frequently diagnosed cancer and the leading cause of cancer-related death among women in less developed countries. RESULTS: Lentivirus-based short hairpin RNA targeting PAICS specifically depleted its endogenous expression in ZR-75-30 and MDA-MB-231 breast cancer cells. Depletion of PAICS led to a significant decrease in cell viability and proliferation. To ascertain the mechanisms through which PAICS modulates cell proliferation, flow cytometry was performed, and it was confirmed that G1-S transition was blocked in ZR-75-30 cells through PAICS knockdown. This might have occurred partly through the suppression of Cyclin E and the upregulation of Cyclin D1, P21, and CDK4. Moreover, PAICS knockdown obviously promoted cell apoptosis in ZR-75-30 cells through the activation of PARP and caspase 3 and downregulation of Bcl-2 and Bcl-xl expression in ZR-75-30 cells. CONCLUSIONS: These findings demonstrate that PAICS plays an essential role in breast cancer proliferation in vitro, which provides a new opportunity for discovering and identifying novel effective treatment strategies.

Initiation of Targeted Nanodrug Delivery in Vivo by a Multifunctional Magnetic Implant.

Implant-mediated targeted drug delivery without an external magnetic field is very challenging. In this work, we report targeted nanodrug delivery initiated by a Fe3O4/poly(lactic-co-glycolic acid) implant scaffold with high magnetism. The implant scaffold is biocompatible and durable. It effectively attracts nanodrugs to its surface, thus killing cancer cells. These findings provide a proof of concept for the magnetic implant-directed nanodrug targeting without the need for an external magnetic field. This approach may further facilitate more precise medical treatments.

Reducing Both Pgp Overexpression and Drug Efflux with Anti-Cancer Gold-Paclitaxel Nanoconjugates.

Repeated administrations of anti-cancer drugs to patients often induce drug resistance. P-glycoprotein (Pgp) facilitates an efficient drug efflux, preventing cellular accumulation of drugs and causing multi-drug resistance (MDR). In this study, we developed a gold-paclitaxel nanoconjugate system to overcome MDR. Gold nanoparticles (GNPs) were conjugated with ß-cyclodextrin enclosing paclitaxel (PTX) molecules and PEG molecules. GNP conjugates were effectively endocytosed by both drug-sensitive human lung cancer H460 cells and Pgp-overexpressed drug-resistant H460PTX cells. Compared with PTX, PGNPs did not induce the Pgp overexpression in drug-sensitive H460 cells after long-term treatment and also avoided being pumped out of cells by overexpressed Pgp molecules in H460PTX with a 17-fold lower EC50 compared to PTX. Fluorescent microscopy and flow cytometry further confirmed that fluorescent labeled PGNPs (f-PGNPs) maintained a high cellular PTX level in both H460 and H460PTX cells. These results demonstrated that nano-drug conjugates were able to avoid the development of drug resistance in sensitive cells and evade Pgp-mediated drug resistance and to maintain a high cytotoxicity in drug-resistant cancer cells. These findings exemplify a powerful nanotechnological approach to the long-lasting issue of chemotherapy-induced drug resistance.

Safety Profile of TiO2-Based Photocatalytic Nanofabrics for Indoor Formaldehyde Degradation.

Anatase TiO2 nanoparticles (TNPs) are synthesized using the sol-gel method and loaded onto the surface of polyester-cotton (65/35) fabrics. The nanofabrics degrade formaldehyde at an efficiency of 77% in eight hours with visible light irradiation or 97% with UV light. The loaded TNPs display very little release from nanofabrics (~0.0%) during a standard fastness to rubbing test. Assuming TNPs may fall off nanofabrics during their life cycles, we also examine the possible toxicity of TNPs to human cells. We found that up to a concentration of 220 µg/mL, they do not affect viability of human acute monocytic leukemia cell line THP-1 macrophages and human liver and kidney cells.

Pokemon siRNA Delivery Mediated by RGD-Modified HBV Core Protein Suppressed the Growth of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a deadly human malignant tumor that is among the most common cancers in the world, especially in Asia. Hepatitis B virus (HBV) infection has been well established as a high risk factor for hepatic malignance. Studies have shown that Pokemon is a master oncogene for HCC growth, suggesting it as an ideal therapeutic target. However, efficient delivery system is still lacking for Pokemon targeting treatment. In this study, we used core proteins of HBV, which is modified with RGD peptides, to construct a biomimetic vector for the delivery of Pokemon siRNAs (namely, RGD-HBc-Pokemon siRNA). Quantitative PCR and Western blot assays revealed that RGD-HBc-Pokemon siRNA possessed the highest efficiency of Pokemon suppression in HCC cells. In vitro experiments further indicated that RGD-HBc-Pokemon-siRNA exerted a higher tumor suppressor activity on HCC cell lines, evidenced by reduced proliferation and attenuated invasiveness, than Pokemon-siRNA or RGD-HBc alone. Finally, animal studies demonstrated that RGD-HBc-Pokemon siRNA suppressed the growth of HCC xenografts in mice by a greater extent than Pokemon-siRNA or RGD-HBc alone. Based on the above results, Pokemon siRNA delivery mediated by RGD-modified HBV core protein was shown to be an effective strategy of HCC gene therapy.