Towards Efficient and Stable Donor-Acceptor Luminescent Radicals.

In contrast to closed-shell luminescent molecules, the electronic ground state and lowest excited state in organic luminescent radicals are both spin doublet, which results in spin-allowed radiative transitions. Most reported luminescent radicals with high photoluminescent quantum efficiency (PLQE) have a donor-acceptor (D-A•) chemical structure where an electron-donating group is covalently attached to an electron-withdrawing radical core (A•). Understanding the main factors that define the efficiency and stability of D-A• type luminescent radicals remains challenging. Here, we designed and synthesized a series of tri(2,4,6-trichlorophenyl)methyl (TTM) radical derivatives with donor substituents varying by their extent of conjugation and their number of imine-type nitrogen atoms. The experimental results suggest that the luminescence efficiency and stability of the radicals are proportional to the degree of conjugation but inversely proportional to the number of imine nitrogen atoms in the substituents. These experimental trends are very well reproduced by density functional theory calculations. The theoretical results indicate that both the luminescence efficiency and radical stability are related to the energy difference between the charge transfer (CT) and local-excitation (LE) states, which decreases as either the number of imine nitrogen atoms in the substituent increases or its conjugation length decreases.

Probiotic Limosilactobacillus fermentum GR-3 ameliorates human hyperuricemia via degrading and promoting excretion of uric acid.

Probiotics have demonstrated the potential to ameliorate hyperuricemia in animals, but their effectiveness and mechanism of action in humans has been understudied. A randomized, double-blinded, controlled research was conducted with 120 volunteers, who consume either a probiotic yogurt containing a UA-degrading strain Limosilactobacillus fermentum GR-3 or a conventional yogurt for 2 months, to investigate probiotic yogurt helped decrease uric acid levels in the at-risk human population. Serum UA levels showed that the probiotic yogurt caused a significant decrease than the consumption of conventional yogurt (26.2% ± 2.3% vs. 8.6% ± 1.1%), and contributed to the UA excretion in the feces and urine (7.4% ± 2.1% and 13.8% ± 3.4%, respectively, 1.9% ± 1.1% and 5.1% ± 2.2%, respectively). Metabolomics and microbial community analysis showed a positive correlation with enhanced anti-inflammation of the host. Our findings suggest an effective and economical therapeutic adjuvant in treating hyperuricemia.

Ultrafast Sulfur Mustard Simulant Gas Fluorescent Chemosensors Based on Triazole AIEE Material with High Selectivity and Sensitivity at Room Temperature.

Herein, a novel blue aggregation-induced enhanced emission (AIEE) material 4-N-(naphthalen-l-yl)-3,5-bis(4-N-phenyl-1-naphthylamine)phenyl-4H-1,2,4-triazole (NDTAZ) is developed and used as a fluorescent chemosensor for sulfur mustard (SM) simulant 2-chloroethyl ethyl sulfide (2-CEES) vapor. The NDTAZ chemosensor is designed by introducing an electron-donating N-phenyl-1-naphthylamine group at 3 and 5 position of 4H-1,2,4-triazole (TAZ) to enhance the nucleophilicity of the TAZ group, and a naphthalene ring is connected to 4 position of the TAZ group to construct an AIEE molecule. The NDTAZ films show extraordinary stability and then are further used as reliable and portable fluorescent chemosensors. Upon exposure to 2-CEES vapor, the NDTAZ chemosensor exhibits an instantaneous fluorescence response (not more than 1 s). What should be noted is that this fluorescent chemosensor realizes the visualized detection of fluorescent color change from blue to green at "room temperature", which is rarely reported. The limit of detection is estimated to be 0.55 ppm, which is below the AEGL-1 (0.6 ppm for 1 min) safety ceiling level to SM exposure. Moreover, the NDTAZ chemosensor shows high selectivity toward 2-CEES vapor over closely related substances, including alkylating agents, aryl halide compounds, sulphur-containing compounds, and nerve agent mimics. More impressively, the NDTAZ chemosensor demonstrates good recyclability by water treatment. Also, the sensing mechanism is adequately proved by using multiple experimental methods and theoretical calculation. In addition, the NDTAZ-based facile filter paper-constructed test strips are fabricated for real-time and on-spot detection of leaked 2-CEES gas specifically. Therefore, this fluorescent chemosensor with excellent sensing performance greatly advances the practical detection of SM species at room temperature.

Chemical signature and fractionation of trace elements in fine particles from anthropogenic and natural sources.

The health effects of trace metal elements in atmospheric fine particulate matter (PM2.5) are widely recognized, however, the emission factor profiles and chemical fractionation of metal elements in different sources were poorly understand. In this study, sixteen metal elements, including Cd, Pb, V, Zn, Ba, Sb, As, Fe, Sr, Cr, Rb, Co, Mn, Cu, Ni and Sn from biomass burning, bituminite and anthracite combustion, as well as dust, were quantified. The results show different emission sources were associated with distinct emission profiles, holding important implications for source apportionment of ambient particulate metals. Specifically, Fe was the dominant metal species (28-1922 mg/kg) for all samples, and was followed by different metals for different samples. For dust, Mn (39.9 mg/kgdust) had the second-highest emission factor, while for biomass burning, it was Cr and Ba (7.5 and 7.4 mg/kgbiomass, respectively). For bituminous coal combustion, the emission factor of Zn and Ba was 6.2 and 6.0 mg/kgbituminous, respectively, while for anthracite combustion the corresponding emission factor was 5.6 and 4.3 mg/kganthracite, respectively. Moreover, chemical fractionation (i.e., the exchangeable, reducible fraction, oxidizable, and residual fraction) and the bioavailability index (BI) values of the metal elements from different sources were further investigated to reveal the link between different emission sources and the potential health risk. The findings from this study hold important implications for source apportionment and source-specific particulate metal-associated health effects.

Concentration, optical characteristics, and emission factors of brown carbon emitted by on-road vehicles.

Atmospheric brown carbon (BrC) is a light-absorbing component that affects radiative forcing; however, this effect requires further clarification, particularly with respect to BrC emission sources, chromophores, and optical properties. In the present study, the concentrations, optical properties, and emission factors of organic carbon (OC), water-soluble OC (WSOC), and humic-like substances (HULIS) in fine particulate matter (PM2.5) emitted from vehicles in three road tunnels (the Wucun, Xianyue, and Wenxing tunnels in Xiamen, China) were investigated. The mass concentrations and light absorption of OC, WSOC, and HULIS were higher at the exits of each tunnel than at entrances, demonstrating that vehicle emissions were a BrC source. At each tunnel's exit, the average light absorption contributed by HULIS-BrC to water-soluble BrC (WS-BrC) and total BrC at 365 nm was higher than the corresponding carbon mass concentration contributed by HULIS (HULIS-C) to WSOC and OC, indicating that the chromophores of HULIS emitted from vehicles had a disproportionately high effect on the light absorption characteristics of BrC. The emission factors (EFs) of HULIS-C and WSOC mass concentrations were highest at the Xianyue tunnel; however, the EFs of HULIS-BrC and WS-BrC light absorption were highest at the Wenxing tunnel, indicating that the chromophore composition of BrC was different among the tunnels and that the mass concentration EFs did not correspond directly to the light absorption EFs.

Concentrations, optical properties and sources of humic-like substances (HULIS) in fine particulate matter in Xi'an, Northwest China.

Humic-like substances (HULIS) are ubiquitous in the atmospheric environment, which affects both human health and climate. We present here the mass concentration and optical characteristics of HULIS isolated from aerosol samples collected in Xi'an, China. Both mass concentration and absorption coefficient (Abs365) of HULIS show clear seasonal differences, with the highest average in winter (3.91 µgC m-3 and 4.78 M m-1, respectively) and the lowest in summer (0.65 µgC m-3 and 0.55 M m-1, respectively). The sources of HULIS_C and light absorption of HULIS were analyzed by positive matrix factorization (PMF) and four major sources were resolved, including secondary formation, biomass burning, coal burning, and vehicle emission. Our results show that secondary formation (i.e., gas-to-particle conversion from e.g., photochemical oxidation) was the major contributor to both HULIS_C (50%) and light absorption (55%) of HULIS in summer, biomass burning and coal burning were major sources of HULIS_C (~70%) and light absorption (~80%) of HULIS in winter. It is worth noting that biomass burning and coal burning had higher contribution to HULIS light absorption (47% in spring, 37% in summer, 73% in fall, and 77% in winter) than their corresponding contribution to HULIS_C concentration (41% in spring, 37% in summer, 54% in fall, and 69% in winter). However, vehicle emission had lower contribution to HULIS light absorption (26% in spring, 8% in summer, 18% in fall, and 11% in winter) than to HULIS_C concentration (24% in spring, 13% in summer, 28% in fall, and 18% in winter). These results suggest that HULIS from biomass burning and coal burning have higher light absorption ability than from vehicle emission.

Rapid Screening and Identification of Antitumor Ingredients from the Mangrove Endophytic Fungus Using an Enzyme-Immobilized Magnetic Nanoparticulate System.

As a consequence of recent progression in biomedicine and nanotechnology, nanoparticle-based systems have evolved as a new method with extensive applications in responsive therapy, multimodal imaging, drug delivery and natural product separation. Meanwhile, the magnetic nanoparticulate system has aroused great interest for separation and purification because of its excellent magnetic properties. Phospholipase A2 (PLA2) is a highly expressed regulator to promote the growth of various cancers and is an ideal target to treat cancers. In this study, a novel strategy based on ligand-receptor interactions to discover novel PLA2 inhibitors was established, in which PLA2-functionalized Fe3O4@PLGA-PEG-NH2 magnetic nanoparticles were used as a supporting material combined with high-performance liquid chromatography-mass spectrometry, aiming to accelerate the discovery of novel PLA2 inhibitors from natural sources such as mangrove endophytic fungi. Under the optimized ligand fishing conditions, six target compounds were ultimately fished and identified to be cyclic peptides (1-3) and sterols (4-6), which compounds 1, 2 and 4-6 have well-documented cytotoxicities. Compound 3 exerted better inhibitory effect on A549 cells by experiment. In conclusion, PLA2-functionalized Fe3O4@PLGA-PEG-NH2 magnetic nanoparticles-based ligand fishing provided a feasible, selective and effective platform for the efficient screening and identification of antitumor components from natural products.

Ultrafast-response, highly-sensitive and recyclable colorimetric/fluorometric dual-channel chemical warfare agent probes.

In this paper, two donor (D)-acceptor (A) type of small organic fluorescent molecules (T1 and T2) based on terpyridine group are synthesized, characterized and used as colorimetric/fluorometric dual-channel probes towards diethylchlorophosphate (DCP, the mimic of chemical warfare agent sarin) not only in solution but also in gas phase featuring instantaneous responses, excellent recyclability, high selectivity and sensitivity. Interestingly though the discriminated units of both chemosensors are terpyridine, their fluorescent responded signals are different, which is due to the different electron-donating substituents of T1 and T2 caused the different responded mechanism to DCP. And the possible sensing mechanism was proved by using nuclear magnetic resonance (1H NMR, 31P NMR) spectra and natural transition orbitals calculations. Furthermore, facile testing filter paper-constructed strips with the visualization of colorimetric/fluorometric dual-channel responses based on T1 and T2 have been fabricated for real-time, on-site high selective and sensitive, recyclable monitor of DCP vapor.

Smad7 down-regulation via ubiquitin degradation mediated by Smurf2 in fibroblasts of hypertrophic scars in burned patients.

TGF-ß1 (transforming growth factor ß1) was considered to play a critical role in the forming of hypertrophic scars. Smad, as a kind of signal downstream mediators, can modulate the functions of TGF-ß1. Smad7 can regulate TGF-ß1/Smad pathway and present negative feedbacks, which prevents fibrosis mediated by TGF-ß1. Nonetheless, the mechanisms related to Smad7 activity in regulating hypertrophic scarring are hardly known. The studies have shown that Smad7 decrease induced by the increase of Smurf2 (Smad ubiquitination regulatory factor 2, an E3 ubiquitin ligase of Smad7) ubiquitination degradation plays a part in fibrosis. We thus made a hypothesis that Smad7 could not inhibit TGF-ß1 because Smurf2 ubiquitin degradation was increased in hypertrophic scar fibroblasts. In our research, it was discovered that there was an increase in Smad7 mRNA levels but no increase in Smad7 protein levels in the fibroblasts of hypertrophic scars after TGF-ß1 treatment. The ubiquitination activity and degradation of Smad7 protein were increased in the fibroblasts of hypertrophic scars compared with the fibroblasts of normal skin. Enhanced degradation of Smad7 protein in the fibroblasts of hypertrophic scars was prevented by proteasome inhibitors MG132 / MG115. Furthermore, it was found that TGF-ß1 stimulation increased Smad7 protein expression after silencing Smurf2 gene in hypertrophic scar fibroblasts, and enhanced Smad7 degradation was prevented in hypertrophic scar fibroblasts after Smurf2 was silenced. It was implied that ubiquitin degradation mediated by Smurf2 might contribute to decreased Smad7 protein levels following TGF-ß1 stimulation in the fibroblasts of hypertrophic scars.

Teratogenic Toxicity Evaluation of Bladder Cancer-Specific Oncolytic Adenovirus on Mice.

BACKGROUND: In our previous studies, we had demonstrated the efficiency and specificity of constructed bladder tissue-specific adenovirus Ad-PSCAE-UPII-E1A-AR (APU-EIA-AR) on bladder cancer. The virus biodistribution and body toxicity in nude mice have also been investigated. However, the safety of the bladder cancer-specific oncolytic adenovirus on fetal mice and F1 mice should be under intense investigation. OBJECTIVE: In order to evaluate the teratogenic toxicity of bladder cancer-specific oncolytic adenovirus APU-EIA-AR on mice, in this study, we investigated the fetal mice weight, fetal body length and tail length, fetal skeleton development, as well as the F1 mice weight, growth curve, and major organ pathology. These teratogenic toxicity data of bladder tissue-specific adenovirus Ad-PSCAE- UPII-E1A-AR (AD) would provide safe information prior to embarking on clinical trials. METHODS: On the sixth day of being fertilized, the pregnant mice began to be intramuscularly administrated with AD (1×107VP, 1×108VP, 1×109VP) every other day for ten days. The pregnant mice were then divided into two groups. One group was euthanized on the seventeenth day; the fetal mice were taken out, and the bone structure of the infants was observed. The other group was observed until natural childbirth. The Filial Generation (F1) is fed for 30 days; the variations in the growth progress and development were assessed. The mice were then euthanized; The tissues from major organs were harvested and observed under the microscope. RESULTS: In the process of teratogenic toxicity test, the Placenta weight, fetal mice weight, body length, and a tail length of mice fetal in adenovirus treated group did not reveal any alteration. Meanwhile, comparing with the PBS group, there is no obvious change in the skeleton of fetal mice treated with adenovirus. During the development process of F1 mice treated with adenovirus, the changes in mice weight show statistical significance. However, in the progress of the growth curve, this difference is not very obvious. Furthermore, the pathological section showed no obvious alteration in major organs. CONCLUSION: Our study demonstrated that bladder cancer-specific adenovirus Ad-PSCAE-UPII- E1A-AR appears safe in pregnant mice without any discernable effects on fetal mice and F1 development. Hence, it is relatively safe for tumor gene therapy.

Water-Insoluble Organics Dominate Brown Carbon in Wintertime Urban Aerosol of China: Chemical Characteristics and Optical Properties.

The chromophores responsible for light absorption in atmospheric brown carbon (BrC) are not well characterized, which hinders our understanding of BrC chemistry, the links with optical properties, and accurate model representations of BrC to global climate and atmospheric oxidative capacity. In this study, the light absorption properties and chromophore composition of three BrC fractions of different polarities were characterized for urban aerosol collected in Xi'an and Beijing in winter 2013-2014. These three BrC fractions show large differences in light absorption and chromophore composition, but the chromophores responsible for light absorption are similar in Xi'an and Beijing. Water-insoluble BrC (WI-BrC) fraction dominates the total BrC absorption at 365 nm in both Xi'an (51 ± 5%) and Beijing (62 ± 13%), followed by a humic-like fraction (HULIS-BrC) and high-polarity water-soluble BrC. The major chromophores identified in HULIS-BrC are nitrophenols and carbonyl oxygenated polycyclic aromatic hydrocarbons (OPAHs) with 2-3 aromatic rings (in total 18 species), accounting for 10% and 14% of the light absorption of HULIS-BrC at 365 nm in Xi'an and Beijing, respectively. In comparison, the major chromophores identified in WI-BrC are PAHs and OPAHs with 4-6 aromatic rings (in total 16 species), contributing 6% and 8% of the light absorption of WI-BrC at 365 nm in Xi'an and Beijing, respectively.

Fibrochondrogenic differentiation potential of tendon-derived stem/progenitor cells from human patellar tendon.

BACKGROUND: Bone-tendon junction (BTJ) is a unique structure connecting tendon and bone through a fibrocartilage zone. Owing to its unique structure, the regeneration of BTJ remains a challenge. Here, we study the fibrochondrogenic differentiation of human tendon-derived stem/progenitor cells (TSPCs) both in vitro and in vivo. METHODS: TSPCs were isolated from human patellar tendon tissues and investigated for their multidifferentiation potential. TSPCs were cultured in chondrogenic medium with transforming growth factor beta 3 (TGF-ß3) and BMP-2 in vitro â€‹and examined for the expression of fibrochondrogenic marker genes by quantitative real-time reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and immunofluorescence. TSPCs pretreated were also seeded in collage II sponge and then transplanted in immunocompromised nude mice to examine if the fibrochondrogenic characteristics were conserved in vivo. RESULTS: We found that TSPCs were differentiated towards fibrochondrogenic lineage, accompanied by the expression of collagen I, collagen II, SRY-box transcription factor 9 (Sox 9), and tenascin C. Furthermore, after TSPCs were seeded in collagen II sponge and transplanted in immunocompromised nude mice, they expressed fibrochondrogenic genes, including proteoglycan, collagen I, and collagen II. CONCLUSION: Taken together, this study showed that TSPCs are capable of differentiating towards fibrocartilage-like cells, and the fibrochondrogenic characteristics were conserved even in vivo, and thus might have the potential application for fibrocartilage regeneration in BTJ repair. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: TSPCs are able to differentiate into fibrocartilage-like cells and thus might well be one potential cell source for fibrocartilage regeneration in a damaged BTJ repair.

Conservation implications of population genetic structure in a threatened orchid Cypripedium tibeticum.

Cypripedium tibeticum is a threatened orchid which efficient conservation requires knowledge of its extent and structure of genetic variation. Using two chloroplast DNA fragments (rps16 and trnL-F), we analyzed 157 individuals from 9 populations representing the species range in China. Seven haplotypes were identified. C. tibeticum had high total genetic diversity (H T = 0.80) with major contribution to this diversity made by among-population component (G ST  = 0.64, Φ ST  = 0.86). However, despite high population differentiation there was no clear phylogeographic structure. The populations CY and DC made the greatest contribution to the total gene diversity as well as allelic richness. The possible mechanisms and implications of these findings for conservation of the species are discussed.

Improved dialysis removal of protein-bound uremic toxins by salvianolic acids.

BACKGROUND: Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are two key protein-bound uremic toxins that accumulate in patients with end-stage renal disease. IS and pCS cannot be efficiently removed by conventional hemodialysis because they are highly bound to proteins. One promising means to optimize the removal of protein-bound uremic toxins involves using binding competitors to liberate uremic toxins from protein-binding partners. PURPOSE: In this study, we try to identify potential binding competitors that can enhance the dialysis removal of IS and pCS in natural compounds of phytomedicine. METHODS: We employed microdialysis to evaluate whether Danhong injection (DHI) and its salvianolic acids can increase the free fractions of IS and pCS and thus improve their dialysis efficiency in vitro. Furthermore, we confirmed the positive effects of DHI and salvianolic acids in vivo on chronic kidney disease model rats in which IS and pCS had heavily accumulated. RESULTS: DHI significantly increased the dialysis efficiency of IS and pCS by 99.13% and 142.00% in vitro (10-fold dilution), respectively, and by 135.61% and 272.13% in vivo (4.16 ml/kg). Salvianolic acids including lithospermic acid (LA), salvianolic acid A (SaA), tanshinol (DSS), caffeic acid (CA), salvianolic acid B (SaB), protocatechuic aldehyde (PA) and rosmarinic acid (RA) significantly enhanced the dialysis removal of IS and pCS in a concentration-dependent manner. LA, the best competitor of the tested salvianolic acids, increased dialysis efficiency levels of IS and pCS by 197.23% and 198.31% in vitro (400 µM), respectively, and by 119.55% and 127.56% in vivo (24.69 mg/kg). CONCLUSION: The removal of protein-bound uremic toxins IS and pCS using DHI or salvianolic acids as protein-bound competitors is superior to previously reported strategies and drugs and may contribute to clinical hemodialysis therapeutic practice.

Icariin suppresses cell cycle transition and cell migration in ovarian cancer cells.

Ovarian cancer is the third most common type of gynecological tumor, in addition to being the most lethal. Cytoreductive surgery with chemotherapy is the standard treatment for ovarian cancer. It is necessary to identify novel chemotherapeutic methods, since current chemotherapy treatments are rarely effective for patients with advanced­stage or recurrent ovarian cancer and may cause acute systemic toxicity. Icariin (ICA) is a prenylated flavonol glycoside derived from Herba Epimedii, a medicinal plant with a variety of pharmacological activities, including anticancer, antidiabetic and anti­obesity effects. By analyzing cell viability, cell cycle and cell migration, the present study demonstrated that ICA inhibited the cell viability of the ovarian cancer cell line, SKOV3, and blocked cell cycle transition. ICA inhibited the expression of fuse binding protein 1 (FBP1), a critical regulator of proliferation and tumorigenesis through binding to the c­Myc promoter, as well as ß­catenin, a key regulator in ovarian cancer initiation, metastasis, chemoresistance and recurrence. Furthermore, it was indicated that ICA inhibited the migration of SKOV3 cells. In accordance with our previous findings on high FBP1 expression in ovarian cancer, FBP1 was a potential target of ICA in ovarian cancer cells. Based on these results, the present study demonstrated that ICA may be a potential therapeutic agent for ovarian cancer treatment.

FBP1 promotes ovarian cancer development through the acceleration of cell cycle transition and metastasis.

Epithelial ovarian cancer (EOC) is the fifth most common malignancy in women, with a 5-year mortality of >70% in North America. As the symptoms are often not observed until the cancer has spread extensively, few women are diagnosed at an early stage of disease. Large-scale gene expression analyses have identified molecular subtypes within high-grade ovarian cancer with variable survival rates and drug resistance. The understanding of gene expression, the mechanisms underlying cancer processes and drug resistances have facilitated the development of targeted therapies. The far-upstream element (Fuse)-binding protein 1 (FBP1) is overexpressed in a number of malignancies such as hepatocellular carcinoma, and has been identified as an oncoprotein. In our early studies, FBP1 was demonstrated to physically interact with p53 and suppresses p53 transcription activity. In the present study, FBP1 expression increased as ovarian cancer developed. Among ovarian normal, adenoma and carcinoma tissues, the highest FBP1 expression was identified in carcinoma tissues. Furthermore FBP1 did not influence the apoptosis of ovarian carcinoma cells, yet enhanced cell cycle transition and metastasis. Therefore, it was hypothesized that FBP1 promotes ovarian cancer development through the acceleration of cell cycle transition and metastasis, and FBP1 is a novel potential biological marker for epithelial ovarian cancer diagnosis.

Understanding the translocation mechanism of PLGA nanoparticles across round window membrane into the inner ear: a guideline for inner ear drug delivery based on nanomedicine.

BACKGROUND: The round window membrane (RWM) functions as the primary biological barrier for therapeutic agents in the inner ear via local application. Previous studies on inner ear nano-drug delivery systems mostly focused on their pharmacokinetics and distribution in the inner ear, but seldom on the interaction with the RWM. Clarifying the transport mechanism of nanoparticulate carriers across RWM will shed more light on the optimum design of nano-drug delivery systems intended for meeting demands for their clinical application. METHODS: The poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) encapsulating coumarin-6 were prepared by emulsifying solvent evaporation method. We utilized confocal laser scanning microscope (CLSM) in combination with transmission electron microscope to investigate the transport pathway of PLGA NPs in the RWM. Simultaneously, the concentration and time dependence of NPs across the RWM were also determined. The endocytic mechanism of NPs through this membrane interface was classically analyzed by means of various endocytic inhibitors. The intracellular location of NPs into lysosomes was evaluated using CLSM scanning microscope colocalization analysis. The Golgi-related inhibitors were employed to probe into the function of Golgi and endoplasmic reticulum (ER) in the discharge of NPs out of cells. RESULTS: PLGA NPs were herein transported through the RWM of a sandwich-like structure into the perilymph via the transcellular pathway. NPs were internalized predominantly via macropinocytosis and caveolin-mediated endocytic pathways. After being internalized, the endocytosed cargos were entrapped within the lysosomal compartments and/or the endoplasmic reticulum/Golgi apparatus which mediated the exocytotic release of NPs. CONCLUSION: For the first time, we showed the translocation itinerary of NPs in RWM, providing a guideline for the rational fabrication of inner ear nanoparticulate carriers with better therapeutic effects.

Knockdown of FUSE binding protein 1 enhances the sensitivity of epithelial ovarian cancer cells to carboplatin.

Epithelial ovarian cancer (EOC) affects almost 25,000 women annually and is the fifth most common malignancy in women in North America. A combination of surgery and cytotoxic chemotherapy may produce a favorable clinical response. The platinum-paclitaxel combination regimen is the chemotherapy gold-standard for advanced ovarian cancer, and carboplatin is one of the agents in this combination therapy. However, the majority of patients eventually experience a relapse due to the development of platinum resistance. FUSE binding protein 1 (FBP1) has been identified as an anti-apoptotic and pro-proliferative oncoprotein that is overexpressed in hepatocellular carcinoma. Its high expression is also associated with carboplatin resistance. In the present study, it was identified that the expression of FBP1 was significantly higher in EOC tissues than in normal epithelial ovarian or in epithelial ovarian adenoma tissue. FBP1 expression was significantly correlated with the grade of epithelial ovarian cancer. Carboplatin inhibited the expression of FBP1 in epithelial ovarian cancer cells and the knockdown of FBP1 enhanced the inhibition of cell viability and migration by carboplatin. In addition to FBP1, carboplatin also inhibited the expression of ß-catenin and matrix metalloproteinase (MMP)-9. Furthermore, the expression of ß-catenin and MMP-9 were lower in FBP1 knockdown cells compared with control EOC cells. FBP1 may thus serve a role in the regulation of the expression of ß-catenin and MMP-9; the inhibition of ß-catenin and MMP-9 by carboplatin may be mediated through the inhibition of FBP1. The inhibition of FBP1 expression by carboplatin may be a mechanism in the treatment of EOC by carboplatin.

Targeting strategies of adenovirus­mediated gene therapy and virotherapy for prostate cancer (Review).

Prostate cancer (PCa) poses a high risk to older men and it is the second most common type of male malignant tumor in western developed countries. Additionally, there is a lack of effective therapies for PCa at advanced stages. Novel treatment strategies such as adenovirus­mediated gene therapy and virotherapy involve the expression of a specific therapeutic gene to induce death in cancer cells, however, wild­type adenoviruses are also able to infect normal human cells, which leads to undesirable toxicity. Various PCa­targeting strategies in adenovirus­mediated therapy have been developed to improve tumor­targeting effects and human safety. The present review summarizes the relevant knowledge regarding available adenoviruses and PCa­targeting strategies. In addition, future directions in this area are also discussed. In conclusion, although they remain in the early stages of basic research, adenovirus­mediated gene therapy and virotherapy are expected to become important therapies for tumors in the future due to their potential targeting strategies.

A novel bladder cancer - specific oncolytic adenovirus by CD46 and its effect combined with cisplatin against cancer cells of CAR negative expression.

BACKGROUND: Conditionally replicative oncolytic adenoviruses (CRAds) display significant anti-tumor effects. However, the traditional adenovirus of serotype 5 (Ad5) entering cancer cells via coxsackie virus and adenovirus receptor (CAR) can't be utilized for bladder cancer with low expression of CAR, which limits the application of Ad5. METHODS: We utilized Ad5/F11p containing the chimeric fiber gene encoding the Ad5 fiber tail domain and Ad11p fiber shaft and knob domains to construct bladder cancer-specific chimeric type viruses Ad5/F11p-PSCAE-UPII-E1A, which can infect bladder cancer cells mediated by CD46 molecule. We carried out series of experiments in vitro to research anti-tumor effect of Ad5/F11p-PSCAE-UPII-E1A and the interaction in combination with cisplatin. RESULTS: The results demonstrated Ad5/F11p-PSCAE-UPII-E1A could infect bladder cancer cells (T24, EJ and 5637) in a CAR-independent way, and exert anti-tumor effect by blocking the cancer cells in G1 phase and inducing apoptosis. Ad5/F11p-PSCAE-UPII-E1A plus cisplatin enhanced the anti-proliferative effect and increased the number of apoptotic cells compared with viruses or cisplatin alone. Ad5/F11p-PSCAE-UPII-E1A plus cisplatin could upregulate the proteins expression of p53, Bax, and cleaved caspase-3, and downregulated Bcl-2 protein expression in T24, EJ and 5637 cells. CONCLUSION: We constructed a bladder cancer-specific oncolytic adenovirus and provided new combination treatment strategies for bladder cancer.