Underlying anti-cancer mechanisms of histone deacetylase (HDAC) inhibitors in tamoxifen-resistant breast cancer cells.

Objectives: Breast cancer is an important women's malignancy with high cancer-related deaths worldwide. Drug resistance lowers the treatment efficacy in this malignancy. This study aimed to explore the underlying mechanisms of histone deacetylase (HDAC) inhibitor trichostatin A (TSA) to overcome resistance to tamoxifen in breast cancer cells. Materials and Methods: Tamoxifen-resistance in MCF-7 breast cancer cells was simulated. MTT assay was used to detect the cytotoxic effects of HDAC inhibitor and PI3K inhibitor on the cancer cells. Trans-well assay was applied to evaluate the invasion and migration of the treated cancer cells. Flow cytometer assay was also applied to evaluate cell cycle phases in the treated cancer cells. Finally, expression of vascular endothelial growth factor (VEGF), E-cadherin, Vimentin, phosphorylated phosphatidylinositol kinase (p-PI3k), phosphorylated protein kinase B (p-AKT), and phosphorylated mammalian target protein of rapamycin (p-mTOR) was evaluated by western blotting. Results: The obtained results indicated that HDAC inhibitor treatments significantly decreased viability, migration, and invasion in the cancer cells. Furthermore, the frequency of the treated cancer cells significantly increased in the S phase as well as significantly decreasing in the G2/M phase of the cell cycle. Moreover, HDAC inhibitor modified levels of VEGF, E-cadherin, Vimentin, p-PI3k, p-AKT, and p-mTOR proteins. However, HDAC inhibitor combined with PI3K inhibitor exerts more profound effects on the cancer cells as compared to HDAC inhibitor monotherapy. Conclusion: HDAC inhibitors inhibited the survival of breast cancer drug-resistant cells, invasion, migration, and angiogenesis by inhibiting the PI3k/Akt/mTOR signaling pathway.

Identification and validation of circulating biomarkers for detection of liver cancer with antibody array.

The aim of this study was to find new protein biomarkers that could be used to detect hepatocellular carcinoma (HCC) in the serum. We identified 11 proteins in the tissue that could be used to classify samples from HCC and control subjects. The 11 identified tissue biomarkers were combined with 10 commonly used serum HCC biomarkers for further verification in a large number of serum samples from HCC patients and healthy controls. 17 of the 21 prospective serum biomarkers were determined to be differentially expressed through collinearity and significance analysis. Through the method of supervised learning, a random forest model was constructed to reduce the dimensionality of the number of differentially expressed proteins, and finally, 4 differentially expressed proteins were identified: AFP, GDF15, CEACAM-1, and MMP-9, and suggested to have potential application in clinical diagnosis of HCC.

Comprehensive analysis of competitive endogenous RNAs networks reveals potential prognostic biomarkers associated with epithelial ovarian cancer.

Ovarian cancer (OC) is a major health threat to females, as it has high morbidity and mortality. Evidence has increasingly demonstrated that long non-coding RNAs (lncRNAs) regulate OC progression and they may have value as early diagnostic biomarkers, prognostic biomarkers and/or therapeutic targets. In the present study, the regulatory mechanisms and prognosis associated with cancer-specific lncRNAs and their related competing endogenous (ce)RNA network in OC were investigated. The differential expression profiles and prognostic significance of lncRNAs and mRNAs were systematically explored based on data from 359 OC cases from The Cancer Genome Atlas and 180 healthy individuals from the Genotype-Tissue Expression database. Functional enrichment analyses, RNA-RNA interactome prediction, ceRNA network analysis, correlation analysis and survival analysis were utilized to identify hub lncRNAs and biomarkers associated with OC diagnosis or prognosis. A total of 1,049 differentially expressed lncRNAs and 6,516 differentially expressed mRNAs between OC and healthy tissues were detected. An lncRNA-micro (mi)RNA-mRNA regulatory network in OC was further established, containing 91 lncRNAs, 23 miRNAs and 179 mRNAs. After survival analysis based on the expression of the RNAs in the ceRNA network, 8 lncRNAs, 4 miRNAs and 11 mRNAs that were significantly associated with OC patient survival (P<0.05) were obtained. Using least absolute shrinkage and selection operator-penalized Cox regression, an eight-lncRNA risk score model was generated, which was able to readily discriminate between OC and healthy individuals and predict the survival of patients with OC. In addition, the differential expression of several key lncRNAs and mRNAs was verified by reverse transcription-quantitative PCR and western blot analysis. The current study presents a novel lncRNA-miRNA-mRNA network, which provides insight into the potential pathogenesis of OC and allows the identification of prognostic biomarkers and treatment strategies for OC.

Atractylenolide III alleviates sepsis-mediated lung injury via inhibition of FoxO1 and VNN1 protein.

PURPOSE: To evaluate the influence of atractylenolide (Atr) III on sepsis-induced lung damage. METHODS: We constructed a mouse sepsis model through cecal ligation and puncture. These mice were allocated to the normal, sepsis, sepsis + Atr III-L (2 mg/kg), as well as Atr III-H (8 mg/kg) group. Lung injury and pulmonary fibrosis were accessed via hematoxylin-eosin (HE) and Masson's staining. We used terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and flow cytometry for detecting sepsis-induced lung cell apoptosis. The contents of the inflammatory cytokines in lung tissue were measured via enzyme-linked immunosorbent assay (ELISA). RESULTS: Atr III-H did not only reduce sepsis-induced lung injury and apoptosis level, but also curbed the secretion of inflammatory factors. Atr III-H substantially ameliorated lung function and raised Bcl-2 expression. Atr III-H eased the pulmonary fibrosis damage and Bax, caspase-3, Vanin-1 (VNN1), as well as Forkhead Box Protein O1 (FoxO1) expression. CONCLUSIONS: Atr III alleviates sepsis-mediated lung injury via inhibition of FoxO1 and VNN1 protein.

Efficacy and safety of anlotinib in patients with advanced malignancy: a single-center, single-arm, phase 2 trial.

BACKGROUND: For advanced tumors that lack specific oncogenic alteration and are resistant to chemotherapy, anti-angiogenesis therapy or immunotherapy or a combination of the two are the most important treatments. Anlotinib is a newly developed oral small molecule receptor tyrosine kinases inhibitor with the potency of inhibiting tumor angiogenesis. This was an open-label, single-arm, phase 2 study to validate the efficacy and safety of anlotinib in patients with various cancer types. METHODS: Patients with advanced malignancy who have failed previous therapies or lack effective treatment choices received daily oral administration of 12 mg anlotinib on days 1-14 every 3 weeks until disease progression, intolerable toxicity or physician decision. The primary endpoint was objective response rate (ORR). RESULTS: A total of 93 eligible patients with 26 different cancer types were enrolled. The overall ORR was 21.5%. The median PFS was 5.7 months and median OS was 12.0 months. The most common treatment-related AE of all grades and of grade 3 was both hypertriglyceridemia at an incidence of 40.9% and 5.4%, respectively. CONCLUSIONS: Anlotinib exhibits objective efficacy and safety in advanced malignancy and might be a possible treatment option for many types of cancer patients who have failed prior treatment and with no optimal therapy regimen.

Enhanced Protein Profiling Arrays for High-Throughput Quantitative Measurement of Cytokine Expression.

The antibody array has become a powerful technology in recent years and is widely used to detect the expression levels of various proteins such as cytokines, growth factors, chemokines, and angiogenic factors, some of which are involved in cancer progression. In this chapter, we describe a protein array technology called enhanced protein profiling array, which can simultaneously and quantitatively measure the expression levels of a few proteins in hundreds or thousands of samples, and an example of its use is presented.

Atractylenolide III alleviates sepsis-mediated lung injury via inhibition of FoxO1 and VNN1 protein

ABSTRACT Purpose: To evaluate the influence of atractylenolide (Atr) III on sepsis-induced lung damage. Methods: We constructed a mouse sepsis model through cecal ligation and puncture. These mice were allocated to the normal, sepsis, sepsis + Atr III-L (2 mg/kg), as well as Atr III-H (8 mg/kg) group. Lung injury and pulmonary fibrosis were accessed via hematoxylin-eosin (HE) and Masson's staining. We used terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and flow cytometry for detecting sepsis-induced lung cell apoptosis. The contents of the inflammatory cytokines in lung tissue were measured via enzyme-linked immunosorbent assay (ELISA). Results: Atr III-H did not only reduce sepsis-induced lung injury and apoptosis level, but also curbed the secretion of inflammatory factors. Atr III-H substantially ameliorated lung function and raised Bcl-2 expression. Atr III-H eased the pulmonary fibrosis damage and Bax, caspase-3, Vanin-1 (VNN1), as well as Forkhead Box Protein O1 (FoxO1) expression. Conclusions: Atr III alleviates sepsis-mediated lung injury via inhibition of FoxO1 and VNN1 protein.

Towards a better understanding of the aggregation mechanisms of iron (hydr)oxide nanoparticles interacting with extracellular polymeric substances: Role of pH and electrolyte solution.

Extracellular polymeric substances (EPS) are ubiquitous in the soil and water environment and interact strongly with mineral surfaces. However, these interactions and their impacts on the behavior and fate of minerals remain poorly understood. Here, for a better understanding of the colloidal stability of minerals in the environment, we investigated the aggregation of goethite (α-FeOOH) nanoparticles (NPs) in the presence of EPS from Bacillus subtilis under different environmental conditions (pH, ionic strength and ionic valence). Results showed that the aggregation processes of goethite NPs are determined by the solution chemistry, and the colloidal stability of goethite NPs is strongly influenced by the addition of EPS. In the absence of ionic strength, the addition of EPS promotes the aggregation of goethite NPs only when the pH (pH = 6) is less than the point of zero charge for the goethite nanoparticles (pHpzc ≈ 8). In the presence of ionic strength, the aggregation rate of goethite NPs increases with increasing concentration of NaCl, NaNO3 and Na2SO4 solutions, and after the addition of EPS solution, the critical coagulation concentrations (CCC) of goethite NPs are increased from 43.0, 56.7 and 0.39 mM to 168.0, 304.9 and 126.2 mM in the three electrolyte solutions, indicating that the addition of EPS inhibits the aggregation of goethite NPs. While in Na3PO4 solution, when the concentration of Na3PO4 solution ranged from 0 to 1 mM, the aggregation rate of goethite NPs increases first, followed by a decrease, and with the concentration of Na3PO4 solution exceeding 1 mM, the aggregation rate of goethite NPs increases again, due to the charge screening by sodium counter ions. This study provides a fundamental understanding of the behavior of goethite NPs in natural soil and water environments.

Indoleamine 2, 3-dioxygenase and B7-H1 expressions as prognostic and follow-up markers in human pancreatic carcinoma.

This study was to test hypotheses that indoleamine 2, 3-dioxygenase and B7-H1 expressions can be used as prognostic markers in human pancreatic carcinoma (PC). Ninety-five patients were recruited who had undergone radical surgical resection for PC. IDO and B7-H1 expressions in PC tissue specimens were evaluated by immunohistochemistry (IHC) techniques. The clinical and pathological features of these specimens were analyzed. IDO positive, B7-H1 positive, and combined IDO/B7-H1 positive tumors exhibited significant correlations with lymphocytic infiltration, perineural invasion, TNM status, and pathologic grade (p < .05), which tended to show strong correlations with malignant progression of PC. Also, IDO correlated with diabetes mellitus (DM) and HAD scale and B7-H1 correlated with smoke (p < .05). In addition, the correlation analysis indicated that IDO had a positive correlation with B7-H1 (p < .05). Moreover, the results showed that a combination of IDO and B7-H1 expressions could serve as independent prognostic marker after adjusting by Cox proportional hazards regression models (p < .05). IDO and B7-H1 expressions were observed in patient with PC tissues and are important markers for PC malignant progression. A combination of IDO and B7-H1 expression can be served as an independent prognostic marker for PC.

Effects of humic acid on the interactions between zinc oxide nanoparticles and bacterial biofilms.

The effects of humic acid (HA) on interactions between ZnO nanoparticles (ZnO NPs) and Pseudomonas putida KT2440 biofilms at different maturity stages were investigated. Three stages of biofilm development were identified according to bacterial adenosine triphosphate (ATP) activity associated with biofilm development process. In the initial biofilm stage 1, the ATP content of bacteria was reduced by more than 90% when biofilms were exposed to ZnO NPs. However, in the mature biofilm stages 2 and 3, the ATP content was only slightly decreased. Biofilms at stage 3 exhibited less susceptibility to ZnO NPs than biofilms at stage 2. These results suggest that more mature biofilms have a significantly higher tolerance to ZnO NPs compared to young biofilms. In addition, biofilms with intact extracellular polymeric substances (EPS) showed higher tolerance to ZnO NPs than those without EPS, indicating that EPS play a key role in alleviating the toxic effects of ZnO NPs. In both pure ZnO NPs and ZnO-HA mixtures, dissolved Zn2+ originating from the NPs significantly contributed to the overall toxicity. The presence of HA dramatically decreased the toxicity of ZnO NPs due to the binding of Zn2+ on HA. The combined results from this work suggest that the biofilm maturity stages and environmental constituents (such as humic acid) are important factors to consider when evaluating potential risks of NPs to ecological systems.

Bacillus subtilis biofilm development in the presence of soil clay minerals and iron oxides.

Clay minerals and metal oxides, as important parts of the soil matrix, play crucial roles in the development of microbial communities. However, the mechanism underlying such a process, particularly on the formation of soil biofilm, remains poorly understood. Here, we investigated the effects of montmorillonite, kaolinite, and goethite on the biofilm formation of the representative soil bacteria Bacillus subtilis. The bacterial biofilm formation in goethite was found to be impaired in the initial 24 h but burst at 48 h in the liquid-air interface. Confocal laser scanning microscopy showed that the biofilm biomass in goethite was 3-16 times that of the control, montmorillonite, and kaolinite at 48 h. Live/Dead staining showed that cells had the highest death rate of 60% after 4 h of contact with goethite, followed by kaolinite and montmorillonite. Atomic force microscopy showed that the interaction between goethite and bacteria may injure bacterial cells by puncturing cell wall, leading to the swarming of bacteria toward the liquid-air interface. Additionally, the expressions of abrB and sinR, key players in regulating the biofilm formation, were upregulated at 24 h and downregulated at 48 h in goethite, indicating the initial adaptation of the cells to minerals. A model was proposed to describe the effects of goethite on the biofilm formation. Our findings may facilitate a better understanding of the roles of soil clays in biofilm development and the manipulation of bacterial compositions through controlling the biofilm in soils.

The impact of advanced proteomics in the search for markers and therapeutic targets of bladder cancer.

Bladder cancer is the most common cancer of the urinary tract and can be avoided through proper surveillance and monitoring. Several genetic factors are known to contribute to the progression of bladder cancer, many of which produce molecules that serve as cancer biomarkers. Blood, urine, and tissue are commonly analyzed for the presence of biomarkers, which can be derived from either the nucleus or the mitochondria. Recent advances in proteomics have facilitated the high-throughput profiling of data generated from bladder cancer-related proteins or peptides in parallel with high sensitivity and specificity, providing a wealth of information for biomarker discovery and validation. However, the transmission of screening results from one laboratory to another remains the main disadvantage of these methods, a fact that emphasizes the need for consistent and standardized procedures as suggested by the Human Proteome Organization. This review summarizes the latest discoveries and progress of biomarker identification for the early diagnosis, projected prognosis, and therapeutic response of bladder cancer, informs the readers of the current status of proteomic-based biomarker findings, and suggests avenues for future work.

Alleviating Surface Degradation of Nickel-Rich Layered Oxide Cathode Material by Encapsulating with Nanoscale Li-Ions/Electrons Superionic Conductors Hybrid Membrane for Advanced Li-Ion Batteries.

Nickel-rich layered oxide cathode materials for advanced lithium-ion batteries have received much attention recently because of their high specific capacities and significant reduction of cost. However, these cathodes are facing a fundamental challenge of loss in performance as a result of surface lithium residue, side reactions with the electrolyte and structure rearrangement upon long-term cycling. Herein, by capturing the lithium residue on the surface of LiNi0.8Co0.1Mn0.1O2 (NCM) cathode material as Li source, we propose a hybrid coating strategy incorporating lithium ions conductor LixAlO2 with superconductor LixTi2O4 to overcome those obstinate issues. By taking full advantage of this unique hybrid nanomembrane coating architecture, both the lithium ion diffusion ability and electronic conductivity of LiNi0.8Co0.1Mn0.1O2 cathode material are improved, resulting in remarkably enhanced electrochemical performances during high voltage operation, including good cycle performance, high reversible capacity, and excellent rate capability. A high initial discharge capacity of 227 mAh g-1 at 4.4 V cutoff voltage with Coulombic efficiency of 87.3%, and reversible capacity of 200 mAh g-1 with 98% capacity retention after 100 cycles at a current density of 0.5 C can be attained. The improved electrochemical performance can be attributed to the synergetic contribution from the removal of lithium residues and the unique hybrid nanomembrane coating architecture. Most importantly, this surface modification technique could save some cost, simplify the technical procedure, and show great potential to optimize battery performance, apply in a large scale and extend to all nickel-rich cathode material.

Hyaluronic Acid Stabilized Iodine-Containing Nanoparticles with Au Nanoshell Coating for X-ray CT Imaging and Photothermal Therapy of Tumors.

In recent years, considerable efforts have been made for the development of multifunctional nanoparticles with diagnosis and therapy functions. To achieve enhanced CT imaging and photothermal therapy on the tumor, we employed iodinated nanoparticles as template to construct Au nanoshell structure and demonstrated a facile but effective approach to synthesize biocompatible and well-dispersed multifunctional nanoparticles by coating iodinated nanoparticles with Au nanoshell and subsequent surface modification by hyaluronic acid. The resultant poly(2-methacryl(3-amide-2,4,6-triiodobenzoic acid))/polyethylenimine/Au nanoshell/hyaluronic acid (PMATIB/PEI/Au nanoshell/HA) nanoparticles had relatively high X-ray attenuation coefficient and photothermal efficiency. After intravenous injection into MCF-7 tumor-bearing mice, PMATIB/PEI/Au nanoshell/HA nanoparticles were efficiently accumulated in the tumor, remarkably enhanced the tumor CT imaging, and selectively ablated the tumor through the thermal treatment of lesions under the NIR irradiation. Thus, PMATIB/PEI/Au nanoshell/HA nanoparticles displayed a great potential for CT diagnosis and CT-guided, focused photothermal tumor therapy.

Nanoemulsion for solubilization, stabilization, and in vitro release of pterostilbene for oral delivery.

Pterostilbene, being extracted from many plants, has significant biological activities in preventing cancer, diabetes, and cardiovascular diseases so as to have great potential applications in pharmaceutical fields. But the poor solubility and stability of pterostilbene strictly restrained its applications. As a good protection and oral delivery system, an optimal nanoemulsion for pterostilbene was developed by using low-energy emulsification method. Systematic pseudo-ternary phase diagrams have been studied in optimization of nanoemulsion formulations. The prepared pterostilbene nanoemulsion was characterized by transmission electron microscope, Fourier transform Raman spectrum, and laser droplet size analyzer. Nanoemulsion droplets are circular with smooth margin, and the mean size is 55.8 ± 10.5 nm. The results illustrated that the nanoemulsion as oral delivery system dramatically improved the stability and solubility of pterostilbene, and in vitro release of pterostilbene was significantly improved (96.5% in pH 3.6 buffer; 13.2% in pH 7.4 buffer) in comparison to the pterostilbene suspension (lower than 21.4% in pH 3.6 buffer; 2.6% in pH 7.4 buffer).