Boosting cisplatin chemotherapy by nanomotor-enhanced tumor penetration and DNA adducts formation.

Despite many nano-based strategies devoted to delivering cisplatin for tumor therapy, its clinical benefits are compromised by poor tissue penetration and limited DNA adducts formation of the drug. Herein, a cisplatin loading nanomotor based janus structured Ag-polymer is developed for cisplatin delivery of deeper tissue and increased DNA adducts formation. The nanomotor displayed a self-propelled tumor penetration fueled by hydrogen peroxide (H2O2) in tumor tissues, which is catalytically decomposed into a large amount of oxygen bubbles by Ag nanoparticles (NPs). Notably, cisplatin could elevate the intracellular H2O2 level through cascade reactions, further promote the degradation of Ag NPs accompanied with the Ag+ release, which could downregulate intracellular Cl- through the formation of AgCl precipitate, thereby enhancing cisplatin dechlorination and Pt-DNA formation. Moreover, polymer can also inhibit the activity of ALKBH2 (a Fe2+-dependent DNA repair enzyme) by chelating intracellular Fe2+ to increase the proportion of irreparable Pt-DNA cross-links. It is found that deep tissue penetration, as well as the increased formation and maintenance of Pt-DNA adducts induced by the nanomotor afford 80% of tumor growth inhibition with negligible toxicity. This work provides an important perspective of resolving chemotherapeutic barriers for boosting cisplatin therapy.

Effects of long noncoding RNA H19 on cementoblast differentiation, mineralisation, and proliferation.

OBJECTIVE: Cementum which is a layer of thin and bone-like mineralised tissue covering tooth root surface is deposited and mineralised by cementoblasts. Recent studies suggested long noncoding RNA H19 (H19) promotes osteoblast differentiation and matrix mineralisation, however, the effect of H19 on cementoblasts remains unknown. This study aimed to clarify the regulatory effects of H19 on cementoblast differentiation, mineralisation, and proliferation. MATERIAL AND METHODS: An immortalised murine cementoblast cell line OCCM-30 was used in this study. H19 expression was examined by real-time quantitative polymerase chain reaction (RT-qPCR) during OCCM-30 cell differentiation. OCCM-30 cells were transfected with lentivirus or siRNA to up-regulate or down-regulate H19, then the levels of runt-related transcription factor 2 (Runx2), osterix (Sp7), alkaline phosphatase (Alpl), bone sialoprotein (Ibsp), osteocalcin (Bglap) were tested by RT-qPCR or western blot. Alizarin red staining, ALP activity assay and MTS assay were performed to determine the mineralisation and proliferation ability of OCCM-30 cells. RESULTS: H19 was dramatically increased during OCCM-30 cell differentiation. Overexpression of H19 increased the levels of Runx2, Sp7, Alpl, Ibsp, and Bglap and enhanced ALP activity and the formation of mineral nodules. While down-regulation of H19 suppressed the above cementoblast differentiation genes and inhibited ALP activity and mineral nodule formation. However, the proliferation of OCCM-30 cells was not affected. CONCLUSIONS: H19 promotes the differentiation and mineralisation of cementoblasts without affecting cell proliferation.

Chemical oxygen demand removal efficiency and limited factors study of aminosilicone polymers in a water emulsion by iron-carbon micro-electrolysis.

Micro-electrolysis was applied in the present study to investigate the effect of pH, iron-carbon mass ratio, contact time, and treatment batch on the removal efficiency of chemical oxygen demand (COD) within an aminosilicone emulsion. The results exhibited that the removal efficiency of COD decreased linearly with the batch increase, and this tendency was consistent under the various conditions. The adsorption of activated carbons contributes a large portion to the elimination of COD within the aminosilicone emulsion. The oxidation action of iron-carbon micro-electrolysis was proven and the aminosilicone emulsion's COD removal contribution was approximately 16%. Aminosilicone polymers were adsorbed on the surface of activated carbons and iron chips, which contributes to the decline of COD removal efficiency and limits the contribution of oxidation action.

Toxic effects on ciliates under nano-/micro-plastics coexist with silver nanoparticles.

Owing to the degradation of plastics, microplastics (MPs) and nanoplastics (NPs) have remained the focus of global attention. Silver nanoparticles (AgNPs) could adversely affect marine organisms due to their broad application. So far, the combined effects of MPs/NPs (strong adsorbents) with AgNPs on marine organisms are scant. Thus, four sizes polystyrene beads (80 nm, 220 nm, 1.07 µm, and 2.14 µm) combined with AgNPs (30 nm) were assessed using ciliated protozoa Uronema marinum. Results showed that MPs/NPs dramatically decrease the abundance, biovolume, and carbon biomass of U. marinum. And, exposure could cause changes of antioxidant enzyme activity and antioxidant content on U. marinum. The combined toxicity of MPs/NPs with AgNPs to ciliates showed an enhanced effect compared to exposure alone. Additionally, the negative effects under exposure of NPs plus AgNPs were more significant than those of MPs plus AgNPs. Transcriptome sequencing showed that co-exposure could affect the energy metabolism and lipid metabolism of ciliates, even cause DNA and protein damage. Our study provided a novel insight and first-hand basic data for the understanding of combined toxicity of MPs /NPs with AgNPs on the basic trophic level ciliated protozoa in marine ecosystems.

Physiological and transcriptomic responses of seawater halobios to micro/nano-scale polystyrene-cadmium exposure in a marine food web.

Micro/nano-plastics (MPs/NPs) represent an emerging contaminant, posing a significant threat to oceanic halobios. While the adverse effects of joint pollutants on marine organisms are well-documented, the potential biological impacts on the food chain transmission resulting from combinations of MPs/NPs and heavy metals (HMs) remain largely unexplored. This study exposed the microbial loop to combined contaminants (MPs/NPs + HMs) for 48h, bacteria and contaminants are washed away before feeding to the traditional food chain, employing microscopic observation, biochemical detection, and transcriptome analysis to elucidate the toxicological mechanisms of the top predator. The findings revealed that MPs/NPs combined with Cd2+ could traverse both the microbial loop and classical food chain. Acute exposure significantly affected the carbon biomass of the top predator Tigriopus japonicus (75.8% lower). Elevated antioxidant enzyme activity led to lipid peroxidation, manifesting in increased malondialdehyde levels. Transcriptome sequencing showed substantial differential gene expression levels in T. japonicus under various treatments. The upregulation of genes associated with apoptosis and inflammatory responses, highlighting the impact of co-exposure on oxidative damage and necroptosis within cells. Notably, NPs-Cd exhibited stronger toxicity than MPs-Cd. NPs-Cd led to a greater decrease in the biomass of top predators, accompanied by lower activities of GSH, SOD, CAT, and GSH-PX, resulting in increased production of lipid peroxidation product MDA and higher oxidative stress levels. This investigation provides novel insights into the potential threats of MPs/NPs combined with Cd2+ on the microbial loop across traditional food chain, contributing to a more comprehensive assessment of the ecological risks associated with micro/nano-plastics and heavy metals.

Novel intelligent packaging films based on starch/PVA with Cu-ICA nanocrystal as functional compatibilizer for monitoring food freshness.

Considering public health and environmental safety, the development of reliable and efficient monitoring methods is essential to ensure food quality and safety. Herein, a new Cu-based metal organic framework (Cu-ICA) nanocrystal with ammonia-sensitive performance was built up and then introduced as a functional compatibilizer of starch/polyvinyl alcohol (STA/PVA) blend to develop high-performance intelligent packaging films for food freshness monitoring. The introduction of Cu-ICA upgraded the compatibility, mechanical strength (42.9 MPa), UV-protection (with UV transmittance of only 2.8 %), and moisture/oxygen barrier performances of STA/PVA film. Furthermore, the developed STA/PVA/Cu-ICA films presented long-term colour stability, outstanding antibacterial efficacy (over 99.5 %) toward both Escherichia coli and Staphylococcus aureus bacteria, as well as remarkable ammonia-sensitive discoloration capability. The STA/PVA/Cu-ICA films possessed visually identifiable colour change during the monitoring of shrimp spoilage. These findings indicate that the developed STA/PVA/Cu-ICA film possesses tremendous potential as an intelligent active packaging material.

Transfer from ciliate to zebrafish: Unveiling mechanisms and combined effects of microplastics and heavy metals.

The impacts and toxicological mechanisms of microplastics (MPs) or heavy metals on aquatic ecosystems have been the subject of extensive research and initial understanding. However, the combined toxicity of co-pollutants on organisms and cumulative toxic effects along the food chain are still underexplored. In this study, the ciliate protozoan Paramecium caudatum and zebrafish Danio rerio were used to represent the microbial loop and the higher trophic level, respectively, to illustrate the progressive exposure of MPs and cadmium (Cd2+). The findings indicate that MPs (ca. 1 ×105 items/L) containing with Cd2+ (below 0.1 µg/L) could permeate the bodies of zebrafish through trophic levels after primary ingestion by ciliates. This could cause adverse effects on zebrafish, including alterations in bioindicators (total sugar, triglycerides, lactate, and glycogen) associated with metabolism, delayed hepatic development, disruption of intestinal microbiota, DNA damage, inflammatory responses, and abnormal cellular apoptosis. In addition, the potential risks associated with the transfer of composite pollutants through the microbial loop into traditional food chain were examined, offering novel insights on the evaluation of the ecological risks associated with MPs. As observed, understanding the bioaccumulation and toxic effects of combined pollutants in zebrafish holds crucial implications for food safety and human health.

Micro-/nano-plastics as vectors of heavy metals and stress response of ciliates using transcriptomic and metabolomic analyses.

The escalating presence of microplastics and heavy metals in marine environments significantly jeopardizes ecological stability and human health. Despite this, research on the combined effects of microplastics/nanoplastics (MPs/NPs) and heavy metals on marine organisms remains limited. This study evaluated the impact of two sizes of polystyrene beads (approximately 2 µm and 200 nm) combined with cadmium (Cd) on the ciliate species Euplotes vannus. Results demonstrated that co-exposure of MPs/NPs and Cd markedly elevated reactive oxygen species (ROS) levels in ciliates while impairing antioxidant enzyme activities, thus enhancing oxidative damage and significantly reducing carbon biomass in ciliates. Transcriptomic profiling indicated that co-exposure of MPs/NPs and Cd potentially caused severe DNA damage and protein oxidation, as evidenced by numerous differentially expressed genes (DEGs) associated with mismatch repair, DNA replication, and proteasome function. Integrated transcriptomic and metabolomic analysis revealed that DEGs and differentially accumulated metabolites (DAMs) were significantly enriched in the TCA cycle, glycolysis, tryptophan metabolism, and glutathione metabolism. This suggests that co-exposure of MPs/NPs and Cd may reduce ciliate abundance and carbon biomass by inhibiting energy metabolism and antioxidant pathways. Additionally, compared to MPs, the co-exposure of NPs and Cd exhibited more severe negative effects due to the larger specific surface area of NPs, which can carry more Cd. These findings provide novel insights into the toxic effects of MPs/NPs and heavy metals on protozoan ciliates, offering foundational data for assessing the ecological risks of heavy metals exacerbated by MPs/NPs.

Connective tissue inspired elastomer-based hydrogel for artificial skin via radiation-indued penetrating polymerization.

Robust hydrogels offer a candidate for artificial skin of bionic robots, yet few hydrogels have a comprehensive performance comparable to real human skin. Here, we present a general method to convert traditional elastomers into tough hydrogels via a unique radiation-induced penetrating polymerization method. The hydrogel is composed of the original hydrophobic crosslinking network from elastomers and grafted hydrophilic chains, which act as elastic collagen fibers and water-rich substances. Therefore, it successfully combines the advantages of both elastomers and hydrogels and provides similar Young's modulus and friction coefficients to human skin, as well as better compression and puncture load capacities than double network and polyampholyte hydrogels. Additionally, responsive abilities can be introduced during the preparation process, granting the hybrid hydrogels shape adaptability. With these unique properties, the hybrid hydrogel can be a candidate for artificial skin, fluid flow controller, wound dressing layer and many other bionic application scenarios.

Remodeling Tumor Immunogenicity with Dual-Activatable Binary CRISPR Nanomedicine for Cancer Immunotherapy.

The specific recognition of cancer cells by the body's immune system is an essential step in initiating antitumor immunity. However, the decreased expression of major histocompatibility complex class I (MHC-1) and overexpression of programmed death ligand 1 (PD-L1) causes insufficient tumor-associated antigens presentation and inactivation of T cells, which accounts for poor immunogenicity. To remodel tumor immunogenicity, herein, a dual-activatable binary CRISPR nanomedicine (DBCN) that can efficiently deliver a CRISPR system into tumor tissues and specifically control its activation is reported. This DBCN is made of a thioketal-cross-linked polyplex core and an acid-detachable polymer shell, which can maintain stability during blood circulation, while detaching a polymer shell to facilitate the cellular internalization of the CRISPR system after entering tumor tissues and ultimately activating gene editing under exogenous laser irradiation, thereby maximizing the therapeutic benefits and reducing potential safety concerns. With the collaborative application of multiple CRISPR systems, DBCN efficiently corrects both dysregulation of MHC-1 and PD-L1 expression in tumors, thus initiating robust T cell-dependent antitumor immune responses to inhibit malignant tumor growth, metastasis, and recurrence. Given the increasing abundance of CRISPR toolkits, this research provides an appealing therapeutic strategy and a universal delivery platform to develop more advanced CRISPR-based cancer treatments.

Dual Enzyme-Like Performances of PLGA Grafted Maghemite Nanocrystals and Their Synergistic Chemo/Chemodynamic Treatment for Human Lung Adenocarcinoma A549 Cells.

In recent years, the emergence of non-toxic but catalytically active inorganic nanoparticles has attracted great attention for cancer treatment, but the therapeutic effect has been affected by the limited reactive oxygen species in tumors. Therefore, the combination of chemotherapy and chemodynamic therapy is regarded as a promising therapeutic strategy. In this paper, we reported the preparation and bioactivity evaluation of poly(lactic acid-co-glycolic acid) (PLGA) grafted-γ-Fe2O3 nanoparticles with dual response of endogenous peroxidase and catalase like activities. Our hypothesis is that PLGAgrafted γ-Fe2O3 nanoparticles could be used as a drug delivery system for the anti-tumor drug doxorubicin to inhibit the growth of lung adenocarcinoma A549 cells; meanwhile, based on its mimic enzyme properties, this kind of nanoparticles could be combined with doxorubicin in the treatment of A549 cells. Our experimental results showed that the PLGAgrafted γ-Fe2O3 nanoparticles could simulate the activity of catalase and decompose hydrogen peroxide into H2O and oxygen in neutral tumor microenvironment, thus reducing the oxidative damage caused by hydrogenperoxide to lung adenocarcinoma A549 cells. In acidic microenvironment, PLGA grafted γ-Fe2O3 nanoparticles could simulate the activity of peroxidase and effectively catalyze the decomposition of hydrogen peroxide to generate highly toxic hydroxyl radicals, which could cause the death of A549 cells. Furthermore, the synergistic effect of peroxidase-like activity of PLGA-grafted γ-Fe2O3 nanoparticles and doxorubicin could accelerate the apoptosisand destruction of A549 cells, thus enhancing the antitumor effect of doxorubicin-loaded PLGA-grafted γ-Fe2O3 nanoparticles. Therefore, this study provides an effective nanoplatform based on dual inorganic biomimetic nanozymes for the treatment of lung cancer.

Structurally coloured contact lens sensor for point-of-care ophthalmic health monitoring.

Point-of-care (POC) diagnosis is of great significance in offering precise and personalized treatment for patients with eye diseases. Contact lenses, as a kind of popular wearable device on the eye, provide a suitable platform for the integration of biosensors for the POC diagnosis of eye diseases. However, existing contact lens sensors usually involve complex electronics and circuits, the manufacturing of which is complicated and signal readout requires additional instruments. To realize the instrument-free detection of pathologically relevant signals of eye diseases, we successfully established a structurally coloured contact lens sensor with a tunable colour in this investigation, which can directly report changes in moisture and pressure that are critical signs for xerophthalmia and glaucoma diagnosis, respectively, by altering colours. Importantly, this structurally coloured contact lens sensor is made solely from a biocompatible hydrogel, without the addition of any chemical pigments, therefore exhibiting superior biosafety and wearing comfort for wearable applications. With both excellent biocompatibility and sensing capabilities, this structurally coloured contact lens sensors thus holds great promise for instrument-free ophthalmic health monitoring, which will benefit a large proportion of the population that have a high risk of eye disease.

Manufacture and characteristics of HA-Electrodeposited polylactic acid/polyvinyl alcohol biodegradable braided scaffolds.

This study proposes the braided bone scaffolds. First, biologically degradable polylactic acid (PLA) filaments and polyvinyl alcohol (PVA) filaments are plied into composite yarns using a doubling and twisting machine. The composite yarns are tested to determine the optimal mechanical properties and a stabilized morphology. The PLA/PVA composite yarns are then braided into bone scaffolds, during which the optimal braiding process parameters and yarn ratio are determined. Based on the surface observation and tensile strength, a gear ratio of 45:45 provides the tubular braids with an optimal morphology and porosity that meet the biological requirements. When the PLA/PVA ratio is 3:1, the braids exhibit the maximum tensile properties and the most stable space structure. Furthermore, to make the braids a bioactive material with surface active sites, the braids are coated with hydroxyapatite (HA) by electrodeposition. The resulting HA-electrodeposited bone scaffolds are tested by in vitro biological experiments using a scanning electronic microscope (SEM), energy dispersive x-ray analysis(EDAX), X-ray Diffraction(XRD), and Fourier transform infrared spectroscopy(FT-IR), thereby examining their characteristics and microstructure. Results suggest that HA is electrodeposited over the bone scaffolds successfully. The immersion in simulated body fluid (SBF) is proven to contribute a good in vitro bioactivity to bone scaffolds. As a result, bone scaffolds are a good candidate for the application in the cancellous bone repairing field.

Enhanced Therapeutic Effect of RGD-Modified Polymeric Micelles Loaded With Low-Dose Methotrexate and Nimesulide on Rheumatoid Arthritis.

Angiogenesis plays an essential role in the progression of rheumatoid arthritis (RA). RGD peptide shows high affinity and selectivity for integrin αvß3, which is one of the most extensively examined target of angiogenesis. Nimesulide could improve the anti-rheumatic profile of methotrexate. But the clinical application was limited due to water-insolubility of both methotrexate and nimesulide and lacking targeting ability. Therefore, this study aimed to design a targeted drug delivery system of micelles mediated by RGD plus the passive targeting of micelles to solve the application problems of methotrexate and nimesulide (M/N), and thus enhance their combined therapeutic effect on RA. Methods: RGD was conjugated with NHS-PEG-PLA to form RGD-PEG-PLA for the preparation of RGD-modified drug-loaded micelles (R-M/N-PMs). The size and zeta potential of micelles were measured by dynamic light scattering. Morphology was detected by transmission electron microscopy. The inhibition effect of R-M/N-PMs on angiogenesis was assessed by the chick chorioallantoic membrane assay. The real-time fluorescence imaging analysis was conducted to examine the in vivo distribution of the fluorescence-labeled R-M/N-PMs. Rats arthritis model induced by Freund's adjuvant was used to evaluate the in vivo anti-inflammatory efficacy of R-M/N-PMs. Results: The in vitro study indicated successful development of R-M/N-PMs. R-M/N-PMs could markedly suppress the angiogenesis of chick embryos. The fluorescence-labeled R-M/N-PMs mainly accumulated in arthritic joints. RGD enhanced the targeting ability of micelles and thus promoted retention of micelles in arthritic joints. Moreover, R-M/N-PMs significantly alleviated the joint swelling while reducing bone erosion and serum levels of inflammatory cytokines. It helped to recover the bone microstructure of arthritic rats. Conclusion: Our results confirmed that the targeted delivery of the combination of a low dose of methotrexate and nimesulide mediated by RGD-modified polymeric micelles could enhance the therapeutic effect on rheumatoid arthritis. These findings provide a promising potential for the clinical therapy of rheumatoid arthritis.

Regulation Effects of Biomimetic Hybrid Scaffolds on Vascular Endothelium Remodeling.

The formation of complete and well-functioning endothelium is critical for the success of tissue-engineered vascular grafts yet remaining a fundamental challenge. Endothelium remodeling onto the lumen of tissue-engineered vascular grafts is affected by their topographical, mechanical, and biochemical characteristics. For meeting multiple requirements, composite strategies have recently emerged for fabricating hybrid scaffolds, where the integrated properties are tuned by varying their compositions. However, the underlying principle how the integrated properties of hybrid scaffolds regulate vascular endothelium remodeling remains unclear. To uncover the regulation effects of hybrid scaffolds on vascular endothelium remodeling, we prepared different biomimetic hybrid scaffolds using gelatin methacrylamide (GelMA) and poly-ε-caprolactone (PCL) and then investigated vascular endothelial cell responses on them. GelMA and PCL, respectively, conferred the resulting scaffolds with biomimetic bioactivity and mechanical properties, which were tuned by varying GelMA/PCL mass ratios (3:1, 1:1, or 1:3). On different GelMA/PCL hybrid scaffolds, distinct vascular endothelial cell responses were observed. Firm cell-scaffold/cell-cell interactions were rapidly established on the hybrid scaffolds with the highest mass ratio of bioactive GelMA. However, they were mechanically insufficient as vascular grafts. On the contrary, the scaffolds with the highest mass ratio of PCL showed significantly reinforced mechanical properties but poor biological performance. Between the two extremes, the scaffolds with the same GelMA/PCL mass ratio balanced the pros and cons of two materials. Therefore, they could meet the mechanical requirements of vascular grafts and support the early-stage vascular endothelial cell remodeling by appropriate biological signaling and mechanotransduction. This investigation experimentally proves that scaffold bioactivity is the dominant factor affecting vascular endothelial cell adhesion and remodeling, whereas mechanical properties are crucial factors for the integrity of endothelium. This work offers a universal design strategy for desirable vascular grafts for improved endothelium remodeling.

Dentofacial traits in association with lower incisor alveolar cancellous bone thickness: A multiple regression analysis.

OBJECTIVE: To identify dentofacial anatomic traits associated with lower incisor cancellous bone thickness (LICBT) and then to assess their separate contributions and their combined contributions to the variation in LICBT. MATERIALS AND METHODS: A consecutive sample of cone beam computed tomography (CBCT) data taken in a university hospital within the same setting was retrospectively reviewed. Within the sample, CBCT data of 252 eligible subjects were reconstructed and measured for LICBT, facial traits, and mandibular symphyseal traits. A backward multiple linear regression was employed to explore the association between LICBT and seven representative dentofacial traits. RESULTS: Four dentofacial traits (vertical facial pattern, transverse jaw relationship, lower incisor cervical diameter, and mandibular symphyseal width) were identified as significantly associated with LICBT. The combination of these four factors could predict 64.3% of variations in LICBT (adjusted R2 = 0.643). Further comparison of LICBT among different transverse jaw relationships suggested that the LICBT of the normal (5.94 ± 1.58 mm) group and the inferior convergent group (5.38 ± 1.32 mm) were significantly larger than that of the crossbite group (4.34 ± 1.27 mm) and the superior convergent group (4.53 ± 1.67 mm). CONCLUSIONS: The bony support of lower incisors is significantly associated with several dentofacial traits. Reduced lower incisor bony support was statistically associated with increased vertical facial pattern, transverse jaw discrepancy, thinner mandibular symphyseal width, and smaller lower incisor cervical diameter.

Regulatory effects of bone morphogenetic protein-4 on tumour necrosis factor-α-suppressed Runx2 and osteoprotegerin expression in cementoblasts.

OBJECTIVES: Root resorption is a common phenomenon presented in periodontitis and orthodontic treatment, both of which are accompanied by an elevated TNF-α expression level in the periodontal tissues. Previously, we proved that TNF-α showed an inhibitory effect on cementoblast differentiation, mineralization and proliferation. However, the effect of TNF-α on Runx2 and osteoprotegerin (OPG) expression remains undetermined. This study aimed to identify the influence of TNF-α on Runx2 and OPG expression in cementoblasts and to test whether BMP-2,-4,-6,-7 would affect TNF-α-regulated Runx2 and OPG. MATERIALS AND METHODS: An immortalized murine cementoblast cell line OCCM-30 was used in this study. The expression of Runx2 and OPG were examined by qRT-PCR after stimulating cells with TNF-α. The role of signalling pathways, including MAPK, PI3K-Akt and NF-κB, were studied with the use of specific inhibitors. Cells were treated with TNF-α in combination with BMP-2,-4,-6 or -7, then the expression of Runx2 and OPG, the activity of MAPK and NF-κB pathways, and the proliferation ability were evaluated by qRT-PCR, Western blot and MTS assay respectively. RESULTS: TNF-α inhibited Runx2 and OPG mRNAs in OCCM-30 cells, and the inhibitory effects were further aggravated by blocking p38 MAPK or NF-κB pathway. TNF-α-inhibited Runx2 and OPG were up-regulated by BMP-4. The p38 MAPK and Erk1/2 pathways were further activated by the combined treatment of BMP-4 and TNF-α compared with TNF-α alone. Finally, the TNF-α-suppressed proliferation was not obviously affected by BMP-2,-4,-6 or -7. CONCLUSIONS: TNF-α inhibited Runx2 and OPG in cementoblasts, and the p38 MAPK and NF-κB pathways acted in a negative-feedback way to attenuate the inhibitory effects. TNF-α-inhibited Runx2 and OPG could be effectively up-regulated by BMP-4; however, further investigations are needed to fully elaborate the underlying mechanisms.

Optimized formulation of multivesicular liposomes loaded with oleanolic acid enhanced anticancer effect in vitro.

Invasion and metastasis are the main causes leading to the death of patients with hepatocellular carcinoma (HCC). Multivesicular liposomes loaded with oleanolic acid (OA-MVLs) have been well demonstrated to suppress survival, growth and angiogenesis of HCC cells. Emerging evidence demonstrates that OA was able to suppress the invasion of HCC cells by down-regulating myocyte enhancer factor-2. We hypothesized that the optimized OA-MVLs could inhibit the migration and invasion of HCC cells. In this study, we utilized central composite design and response surface methodology to assess the influence of some parameters on particle size and encapsulation efficiency and obtain the optimized formulation of OA-MVLs. Subsequently, the human HCC cell lines SMMC-7721 and HepG2 were treated with different doses of OA-MVLs and OA, respectively. Cellular survival, adhesion, migration and invasion in vitro were evaluated. We found that the optimized OA-MVLs significantly decreased the ability of HCC cells to adhere, migrate and invade in vitro. Furthermore, OA-MVLs significantly inhibited the survival of HCC cells at 160 µmol/L but showed no obvious inhibition effect on the cell vitality of normal liver cells. Our findings indicate that OA-MVLs did inhibit the cell survival, adhesion, invasion and metastasis of HCC cells in vitro. Although the involved mechanisms are still unclear, our findings can contribute to a better development of a preventive and therapeutic strategy for human HCC.

GX1-mediated anionic liposomes carrying adenoviral vectors for enhanced inhibition of gastric cancer vascular endothelial cells.

Gastric cancer is a highly lethal malignancy and its 5-year survival rate remains depressed in spite of multiple treatment options. Targeting drug delivery to tumor vasculature may be a promising strategy for gastric cancer therapy, for it can block the nutrition source of tumor and inhibit the metastasis and invasion in a certain extent. In present study, we have prepared the drug-targeting delivery system of peptide GX1-mediated anionic liposomes carrying adenoviral vectors (GX1-Ad5-AL), in which the tumor suppressor gene of PTEN was integrated into DNA of Ad5 and the GX1 peptide could play targeting role to vascular of gastric cancer. The inhibition ability of GX1-Ad5-AL to human gastric cancer cell lines (SGC-7901) and human umbilical vein endothelial cells (HUVEC) was evaluated by MTT assay. Further, the cell migration assay was carried out in transwell inserts and the cells uptaking of GX1-Ad5-AL was detected by confocal laser scanning microscopy. The experimental results indicated that the average cell proliferation inhibition rates resulted from the drug delivery system of GX1-Ad5-AL in SGC-7901 and HUVEC were 68.36% and 64.13%, respectively which were higher than that resulted from GX1 or Ad5-AL. Meanwhile, results of cell migration experiment demonstrated that GX1-Ad5-AL could significantly suppress the migration of gastric cancer cell of SGC-7901. Moreover, both the imaging from confocal laser scanning microscopy and the quantitative analysis of fluorescence intensity showed that, GX1-Ad5-AL was more easily uptaken by SGC-7901 cells, as compared to Ad5-AL. Therefore, the formulation of GX1-Ad5-AL was effective for enhancing the inhibition effect and suppressing the migration of gastric cancer vascular endothelial cells.

Preparation and multiple antitumor properties of AuNRs/spinach extract/PEGDA composite hydrogel.

In this study, a novel composite hydrogel that contains spinach extract (SE), gold nanorods (AuNRs), and poly(ethylene glycol) double acrylates (PEGDA) is prepared through a one-step in situ photopolymerization under noninvasive 660 nm laser irradiation for localized antitumor activity. SE plays a role as a photoinitiator for initiating the formation of the PEGDA hydrogel and as an excellent photosensitizer for generating cytotoxic singlet oxygen ((1)O2) with oxygen to kill tumor cells. AuNRs can be used as a photoabsorbing agent to generate heat from optical energy. Moreover, the introduction of AuNRs is conducive to the formation of the hydrogel and accelerates the rate of (1)O2 generation. The composite hydrogel shell, which has good biocompatibility on tumor cells, can prevent the photosensitizer from migrating to normal tissue and maintains a high concentration on lesions, thereby enhancing the curative effect. The combination of NIR light-triggered mild photothermal heating of AuNRs, the photodynamic treatment using SE, and localized gelation by photopolymerization exhibits a synergistic effect for the destruction of cancer cells.