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Optical sources emitting in the ultraviolet (UV) to near-infrared wavelength range are an enabling tools for a wide variety of applications. To achieve broadband coherent generation within visible and UV spectrum, one fundamental obstacle is the strong material dispersion which limits efficient frequency conversion. Previous works have addressed this challenge by either using high input energies or delicate resonant structures. In this work, a simple device system is proposed to tackle the problem. Single crystalline aluminum nitride material with a threading dislocation density less than 109 cm–2 was used to provide broadband transparency, and a high order waveguide mode (transverse electric, TE10) was used to create anomalous dispersion near 800 nm, in which soliton fission processes are supported. As a result, supercontinuum generation from 490 nm to over 1100 nm with a second harmonic generated band covering from 407 to 425 nm is achieved with the total on-chip pulse energy of 0.6 nJ.

Aim Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, and its progression is implicated in the dysregulation of circular ribonucleic acids (RNAs). This study aimed to investigate the role of circular RNA nei-like DNA glycosylase 3 (circNEIL3) in HCC. Methods Real-time quantitative PCR was used for expression analysis of circNEIL3, microRNA-3150b-3p (miR-3150b-3p) and laminin subunit gamma 1 (LAMC1) message RNA. MTT assay, colony formation assay, wound healing assay, transwell assay, and flow cytometry assay were performed for functional analyses on cell proliferation, migration, invasion, apoptosis, and cycle. The expression of marker proteins and LAMC1 protein was quantified by western blot. The interaction between miR-3150b-3p and circNEIL3 or LAMC1 was confirmed by dual-luciferase reporter assay or RNA immunoprecipitation assay. An animal study was performed to confirm the role of circNEIL3 in vivo. Results CircNEIL3 was upregulated in tumor tissues and HCC cell lines. CircNEIL3 knockdown significantly suppressed HCC cell proliferation, migration and invasion and induced cell apoptosis and cell cycle arrest. MiR-3150b-3p was a target of circNEIL3, and its inhibition largely reversed the functional effects of circNEIL3 knockdown on cell behaviors. Moreover, LAMC1 served as a target of miR-3150b-3p, and its expression was elevated in HCC tissues and cells. LAMC1 overexpression recovered HCC cell proliferation, migration and invasion that were blocked by miR-3150b-3p restoration. Additionally, circNEIL3 knockdown inhibited tumor growth in mice. Conclusion CircNEIL3 dysregulation was responsible for the partial development of HCC by regulating the miR-3150b-3p/LAMC1 regulatory network.

Recent studies have shown that microRNAs and long noncoding RNAs (lncRNAs) regulate the expression of drug metabolizing enzymes (DMEs) in human hepatic cells and that a set of DMEs, including UDP glucuronosyltransferase (UGT) 2B15, is down-regulated dramatically in liver cells by toxic acetaminophen (APAP) concentrations. In this study we analyzed mRNA, microRNA, and lncRNA expression profiles in APAP-treated HepaRG cells to explore noncoding RNA-dependent regulation of DME expression. The expression of UGT2B15 and lncRNA LINC00574 was decreased in APAP-treated HepaRG cells. UGT2B15 levels were diminished by LINC00574 suppression using antisense oligonucleotides or small interfering RNA. Furthermore, we found that hsa-miR-129-5p suppressed LINC00574 and decreased UGT2B15 expression via LINC00574 in HepaRG cells. In conclusion, our results indicate that LINC00574 acts as an important regulator of UGT2B15 expression in human hepatic cells, providing experimental evidence and new clues to understand the role of cross-talk between noncoding RNAs. SIGNIFICANCE STATEMENT: We showed a molecular network that displays the cross-talk and consequences among mRNA, micro RNA, long noncoding RNA, and proteins in acetaminophen (APAP)-treated HepaRG cells. APAP treatment increased the level of hsa-miR-129-5p and decreased that of LINC00574, ultimately decreasing the production of UDP glucuronosyltransferase (UGT) 2B15. The proposed regulatory network suppresses UGT2B15 expression through interaction of hsa-miR-129-5p and LINC00574, which may be achieved potentially by recruiting RNA binding proteins.

Environments with high reactive oxygen species (ROS) levels, which are common in patients with diseases such as diabetes, periodontitis, and osteoporosis, impair the osseointegration of implants. To address this issue, by using a one-pot dopamine-assisted co-deposition method, we constructed a three-dimensional coating of hydroxyapatite-functionalised nanoparticles of polydopamine (HA/nPDAs) on implant surfaces, where polydopamine is designed to protect cells via scavenging excessive ROS and HA facilitates osteogenesis. First, nanoparticles of polydopamine (nPDAs) were prepared by self-polymerization and assembly of dopamine under alkaline conditions, and HA/nPDAs were obtained by incubating nPDAs in simulated body fluid (SBF) due to metal chelation and ionic interactions triggered by the catechol moieties of PDA. Thereafter, HA/nPDAs with thickness of ~4 μm were constructed on titanium surfaces by immersing titanium discs in a weak alkaline solution of HA/nPDAs and dopamine through interface interactions driven by catechol chemistry. The properties of coatings (e.g., thickness, composition, hydrophilia and morphology) can be controlled by preparation conditions such as mineralization time and reactant concentration. The coatings display efficient ROS-scavenging ability, promote cell proliferation, and upregulate the activity of alkaline phosphatase and the expression of osteogenesis-related genes in environments with high or normal ROS levels, demonstrating the great promise of such coatings for osseointegration promotion, especially in the state of high ROS in diseases. This study provides a facile, efficient, mild, and universal strategy in engineering functional surfaces on any substrates for diversified applications by simple variation of co-deposited components, through taking advantages of versatile catechol chemistry and nanoparticles with stereo structure and great specific surface area.

Hepatic metabolism catalyzed by the cytochrome P450 (CYP) superfamily affects liver toxicity associated with exposures to natural compounds and xenobiotic agents. Previously we generated a battery of HepG2-derived stable cell lines that individually express 14 CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7). In this study, we comprehensively characterized each cell line for its CYP expression and enzyme activity. Specifically, we measured the mRNA expression, protein expression, and metabolite formation. Using CYP3A4, 2D6, and 2C9-overexpressing cells as representatives, we examined the stability of these cells in long-term cultures for up to 10 passages. The results showed that CYPs can be stably overexpressed for up to 10 cell culture passages without losing their activities. The robustness of responses to stimuli among the cells at different passages was also investigated in CYP3A4-overexpressing cells and the response to amiodarone and dronedarone showed no difference between the cells at the passage 2 and 10. Moreover, the mRNA expression level of most CYPs was higher in CYP-overexpressing HepG2 cells than that in HepaRG cells and primary human hepatocytes. This study confirmed the stability of CYP-overexpressing HepG2 cell lines and provided useful information for a broader use of these cells in pharmacologic and toxicologic research.

Perhexiline is an anti-anginal drug developed in the late 1960s. Despite its therapeutic success, it caused severe hepatoxicity in selective patients, which resulted in its withdrawal from the market. In the current study we explored the molecular mechanisms underlying the cytotoxicity of perhexiline. In primary human hepatocytes, HepaRG cells, and HepG2 cells, perhexiline induced cell death in a concentration- and time-dependent manner. Perhexiline treatment also caused a significant increase in caspase 3/7 activity at 2 h and 4 h. Pretreatment with specific caspase inhibitors suggested that both intrinsic and extrinsic apoptotic pathways contributed to perhexiline-induced cytotoxicity, which was confirmed by increased expression of TNF-α, cleavage of caspase 3 and 9 upon perhexiline treatment. Moreover, perhexiline caused mitochondrial dysfunction, demonstrated by the classic glucose-galactose assay at 4 h and 24 h. Results from JC-1 staining suggested perhexiline caused loss of mitochondrial potential. Blocking mitochondrial permeability transition pore using inhibitor bongkrekic acid attenuated the cytotoxicity of perhexiline. Western blotting analysis also showed decreased expression level of pro-survival proteins Bcl-2 and Mcl-1, and increased expression of pro-apoptotic protein Bad. Direct measurement of the activity of individual components of the mitochondrial respiratory complex demonstrated that perhexiline strongly inhibited Complex IV and Complex V and moderately inhibited Complex II and Complex II + III. Overall, our data demonstrated that both mitochondrial dysfunction and apoptosis underlies perhexiline-induced hepatotoxicity.

Sertraline, an antidepressant, is commonly used to manage mental health symptoms related to depression, anxiety disorders, and obsessive-compulsive disorder. The use of sertraline has been associated with rare but severe hepatotoxicity. Previous research demonstrated that mitochondrial dysfunction, apoptosis, and endoplasmic reticulum stress were involved in sertraline-associated cytotoxicity. In this study, we reported that after a 24-h treatment in HepG2 cells, sertraline caused cytotoxicity, suppressed topoisomerase I and IIα, and damaged DNA in a concentration-dependent manner. We also investigated the role of cytochrome P450 (CYP)-mediated metabolism in sertraline-induced toxicity using our previously established HepG2 cell lines individually expressing 14 CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7). We demonstrated that CYP2D6, 2C19, 2B6, and 2C9 metabolize sertraline, and sertraline-induced cytotoxicity was significantly decreased in the cells expressing these CYPs. Western blot analysis demonstrated that the induction of ɣH2A.X (a hallmark of DNA damage) and topoisomerase inhibition were partially reversed in CYP2D6-, 2C19-, 2B6-, and 2C9-overexpressing HepG2 cells. These data indicate that DNA damage and topoisomerase inhibition are involved in sertraline-induced cytotoxicity and that CYPs-mediated metabolism plays a role in decreasing the toxicity of sertraline.

We propose a method to prepare few-layer black phosphorus by oxygen plasma etching, followed by boron nitride encapsulation and thermal annealing. This method produces few-layer black phosphorus with strongly enhanced photoluminescence and greatly improved stability.

microRNAs (miRNAs) modulate the expression of enzymes responsible for activation or detoxification of xenobiotics and toxicants. miRNAs are dysregulated in response to environmental exposure and have been implicated in toxicological events. Many in vivo and in vitro experimental approaches have been employed to delineate the mechanisms by which miRNAs regulate target genes; however, all these methods provide only indirect evidence for the interaction between miRNAs and their counterpart mRNA molecules. In this chapter, we describe a novel approach—a fluorescent-based RNA electrophoretic mobility shift assay (FREMSA) that is a sensitive and time-saving method, with a high specificity, to visualize the interactions among miRNAs, mRNAs, and proteins, as direct evidence of mRNA/miRNA complex formation.

Calcium silicate particles containing mesoporous SiO2 (CaSiO3@SiO2) on the surface were grafted onto polypropylene nonwoven. The PP nonwoven grafted CaSiO3 containing mesoporous SiO2 (PP-g-CaSiO3@SiO2) was characterized by TEM and TG. The adsorption behaviors of bisphenol A (BPA) on PP-g-CaSiO3@SiO2 were investigated. The results indicated that the large surface area and the Si–OH groups of the material improved the adsorption capacities and affinity for BPA. The adsorption rate was fast, and the adsorption capacity was high, even with the background organic compound alginate sodium. The adsorption mechanism of BPA by PP-g-CaSiO3@SiO2 was investigated. Isothermal titration calorimetry (ITC) was used to illustrate the driving force for the adsorption of BPA. PP-g-CaSiO3@SiO2 was prepared simply without using any organic solvent and could be recycled and reused.

Androgen receptor splice variants (AR-V) are implicated in resistance of prostate cancer to androgen-directed therapies. When expressed alone in cells, some AR-Vs (e.g., AR-V7) localize primarily to the nucleus, whereas others (e.g., AR-V1, AR-V4, and AR-V6) localize mainly to the cytoplasm. Significantly, the latter are often coexpressed with the nucleus-predominant AR-Vs and the full-length AR (AR-FL). An important question to be addressed is whether the cytoplasmic-localized AR-Vs play a role in castration-resistant prostate cancer (CRPC) through interaction with the nucleus-predominant AR-Vs and AR-FL. Here, it is demonstrated that AR-V1, -V4, and -V6 can dimerize with both AR-V7 and AR-FL. Consequently, AR-V7 and androgen-bound AR-FL induced nuclear localization of AR-V1, -V4, and -V6, and these variants, in turn, mitigated the ability of the antiandrogen enzalutamide to inhibit androgen-induced AR-FL nuclear localization. Interestingly, the impact of nuclear localization of AR-V4 and -V6 on AR transactivation differs from that of AR-V1. Nuclear localization leads to an increased ability of AR-V4 and -V6 to transactivate both canonical AR targets and AR-V–specific targets and to confer castration-resistant cell growth. However, although AR-V1, which lacks inherent transcriptional activity, appears to activate AR-FL in an androgen-independent manner, it significantly antagonizes AR-V7 transactivation. Together, these data demonstrate that the complex interactions among different AR-Vs and AR-FL play a significant role in castration-resistant disease. Implications: This study suggests important consequences for clinical castration resistance due to simultaneous expression of AR-FL and AR-Vs in patient tumors and suggests that dissecting these interactions should help develop effective strategies to disrupt AR-V signaling. Mol Cancer Res; 15(1); 59–68. ©2016 AACR.

Noncoding RNAs, such as long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), regulate gene expression in many physiological and pathological processes, including drug metabolism. Drug metabolizing enzymes (DMEs) are critical components in drug-induced liver toxicity. In this study, we used human hepatic HepaRG cells treated with 5 or 10 mM acetaminophen (APAP) as a model system and identified LINC00844 as a toxicity-responsive lncRNA. We analyzed the expression profiles of LINC00844 in different human tissues. In addition, we examined the correlations between the levels of LINC00844 and those of key DMEs and nuclear receptors (NRs) for APAP metabolism in humans. Our results showed that lncRNA LINC00844 is enriched in the liver and its expression correlates positively with mRNA levels of CYP3A4, CYP2E1, SULT2A1, pregnane X receptor (PXR), and hepatocyte nuclear factor (HNF) 4α. We demonstrated that LINC00844 regulates the expression of these five genes in HepaRG cells using gain- and loss-of-function assays. Further, we discovered that LINC00844 is localized predominantly in the cytoplasm and acts as an hsa-miR-486-5p sponge, via direct binding, to protect SULT2A1 from miRNA-mediated gene silencing. Our data also demonstrated a functional interaction between LINC00844 and hsa-miR-486-5p in regulating DME and NR expression in HepaRG cells and primary human hepatocytes. We depicted a LINC00844-mediated regulatory network that involves miRNA and NRs and influences DME expression in response to APAP toxicity.

Drug metabolizing enzymes mediate biotransformation of drugs and play an essential role in drug efficacy and toxicity. Human sulfotransferases are a superfamily of Phase II detoxification enzymes that metabolize a wide spectrum of endogenous compounds and xenobiotics. SULT2A1 is one of the most abundant hepatic sulfotransferases and it catalyzes the sulfate conjugation of many endogenous substrates, such as bile acids and steroids. In the current study, we utilized a systematic approach by combining a series of computational analyses and in vitro methods to identify miRNAs that repress SULT2A1 expression post-transcriptionally. Our in silico analyses predicted miRNA response elements for hsa-miR-495-3p and hsa-miR-486-5p within the 3'-UTR of SULT2A1 mRNA and the levels of these miRNAs were inversely correlated with that of SULT2A1 mRNA in human liver. Using fluorescence-based RNA electrophoretic mobility shift assays, we found that hsa-miR-495-3p and hsa-miR-486-5p interacted directly with the SULT2A1 3'-UTR. The activity of a luciferase reporter gene construct containing sequences from the SULT2A1 3-UTR was suppressed by hsa-miR-486-5p and hsa-miR-495-3p. Furthermore, gain- and loss-of-function assays demonstrated that hsa-miR-486-5p and hsa-miR-495-3p negatively modulate basal and rifampicin-induced expression of SULT2A1 in HepG2 cells by decreasing mRNA stability.

The purpose of this research is to synthesize mesoporous calcium silicate grafted non-woven polypropylene (PP-g-CaSiO3@SiO2) and to evaluate its adsorption performance for dibutyl phthalate (DBP). The results indicated that the adsorption capacity of PP-g-CaSiO3@SiO2 was superior to non-woven polypropylene fabric (PP) and CaSiO3 grafted PP non-woven (PP-g-CaSiO3). The adsorption mechanism of DBP by PP-g-CaSiO3@SiO2 at different pH values was investigated. When the initial concentration of DBP was 130 mg/L (pH = 3.0, 298 K) the adsorption capacity of DBP by PP-g-CaSiO3@SiO2 reached 54.8 mg/g, and the adsorption equilibrium time was two hours. The large surface area and Si OH groups on PP-g-CaSiO3@SiO2 could improve the adsorption capacity and affinity for DBP. Isothermal titration calorimetry (ITC) was used to illustrate the driving force for the adsorption of DBP to CaSiO3@SiO2. The binding constant K, binding enthalpy (ΔH) and binding entropy (ΔS) between DBP and CaSiO3@SiO2 were obtained to be 3.54 × 103 L/mol, −66.2 kJ/mol and 0.154 kJ/(K*mol), respectively. The Gibbs’ energy change during the binding process was −20.24 kJ/mol, indicating that the adsorption process was thermodynamically favorable. Freundlich model was more suitable to describe the adsorption of DBP onto PP-g-CaSiO3@SiO2. Lower temperature and lower pH can promote the adsorption of DBP. PP-g-CaSiO3@SiO2 can be recycled for reuse. It is promising to be used as a good adsorption material to remove DBP or other contaminants from aqueous solutions.

Purpose: Most prostate cancer mortality can be attributed to metastatic castration resistant prostate cancer, an advanced stage that remains incurable despite recent advances. The AR (androgen receptor) signaling axis remains active in castration resistant prostate cancer. Recent studies suggest that expression of the AR-V (AR splice variant) AR-V7 may underlie resistance to abiraterone and enzalutamide. However, controversy exists over the optimal assay. Our objective was to develop a fast and sensitive assay for AR-Vs in patients.Materials and Methods: Two approaches were assessed in this study. The first approach was based on depletion of leukocytes and the second one used RNA purified directly from whole blood preserved in PAXgene® tubes. Transcript expression was analyzed by quantitative reverse transcription-polymerase chain reaction.Results: Through a side-by-side comparison we found that the whole blood approach was suitable to detect AR-Vs. The specificity of the assay was corroborated in a cance...

The androgen receptor (AR) is a ligand-activated nuclear receptor that plays a critical role in normal prostate physiology, as well as in the development and progression of prostate cancer. In addition to the classical paradigm in which AR exerts its biological effects in the nucleus by orchestrating the expression of the androgen-regulated transcriptome, there is considerable evidence supporting a rapid, nongenomic activity mediated by membrane-associated AR. Although the genomic action of AR has been studied in depth, the molecular events governing AR transport to the plasma membrane and the downstream AR signaling cascades remain poorly understood. In this study, we report that AR membrane transport is microtubule-dependent. Disruption of the function of kinesin 5B (KIF5B), but not of kinesin C3 (KIFC3), interfered with AR membrane association and signaling. Co-immunoprecipitation and pulldown assays revealed that AR physically interacts with KIF5B and that androgen enhances this interaction. Furthermore, we show that heat shock protein 27 (HSP27) is activated by membrane-associated AR and that HSP27 plays an important role in mediating AR-mediated membrane-to-nuclear signal transduction. Together, these results indicate that AR membrane translocation is mediated by the microtubule cytoskeleton and the motor protein KIF5B. By activating HSP27, membrane-associated AR potentiates the transcriptional activity of nuclear AR. We conclude that disruption of AR membrane translocation may represent a potential strategy for targeting AR signaling therapeutically in prostate cancer.

We review the recent progress in studying and utilizing 2D monolayer transition metal dichalcogenides as gain materials to be integrated with various micro and nano-cavities for the realization of low energy lasers including room-temperature operation.

A series of iron-vanadium mixed oxide catalysts prepared by the coprecipitation method were used for the selective catalytic reduction NO with NH3. The activity evaluation results exhibited that the activity of Fe2O3 was enhanced by addition of a little V, and the Fe–V–Ox catalyst also showed high resistant to the SO2 and H2O poisoning in the tested condition. The XRD, NH3-TPD, H2-TPR and in situ DRIFTS characterization results displayed that the lower grain size of Fe2O3, the reinforced acidity and high redox ability should be the critical factors for the Fe–V–Ox catalyst to achieve the high NH3-SCR performance.

The feasibility of an all-semiconductor plasmonic structure is studied using highly doped InAs for Mid infrared (MIR) wavelength range. We proposed an all-semiconductor active plasmonic system on-a-chip with integrated plasmonic source, waveguide, and detector.