Presence of carbazole and polyhalogenated carbazoles in human urine.

Exposure to carbazole (CZ) and polyhalogenated carbazoles (PHCZs) may pose a threat to human health, owing to their potential dioxin-like toxicity. Until now, the presence of these chemicals in the human urine from the general population is still unclear. Human urine samples (n = 210) were taken from the general population in Quzhou, China in this study, and were analyzed for CZ and 14 PHCZs. CZ and nine PHCZs were detected in collected human urine. CZ (detection frequency 100 %), 3-chlorocarbazole (3-CCZ; 88 %), 3,6-dichlorocarbzole (36-CCZ; 84 %), and 3-bromocarbazole (3-BCZ; 80 %) were more frequently detected. Among detected PHCZs, 3-CCZ (mean 0.49 ng/mL, < LOD-4.3 ng/mL) had comparatively higher urinary levels, followed by 3-BCZ (0.30 ng/L, < LOD-1.9 ng/mL) and 36-CCZ (0.20 ng/L, < LOD-1.4 ng/mL). Urinary concentrations of CZ in male participants (1.3 ± 0.26 ng/mL) were significantly (p < 0.05) higher than that in female participants (0.92 ± 0.24 ng/mL). No obvious trend in urinary concentrations with the age of participants was found for CZ and detected PHCZs. The mean daily excretion was found highest for CZ (31 ng/kg bw/day), followed by 3-CCZ (19 ng/kg bw/day) and 3-BCZ (8.5 ng/kg bw/day). This study provides the first data, to our knowledge, on the presence and levels of CZ and PHCZs in human urine, which is necessary for conducting the human exposure risk assessment.

Signal mining study of severe cutaneous adverse events of valaciclovir or acyclovir based on the FAERS database.

OBJECTIVE: This study aimed to explore a comprehensive empirical investigation and assess SCARs related to valaciclovir or acyclovir based on FAERS database from FDA, thus providing a theoretical foundation for the rational application of drugs in clinic. METHODS: SCARs reports relevant to valaciclovir or acyclovir were searched in FAERS database from the 2004 Q1 to 2023 Q2. These data were further mined by a proportional analysis and Bayesian approach to detect signals of SCARs caused by two drugs. Meanwhile, the clinical characteristics, onset time, correlation, and stratification analysis of the two drugs in SCARs were analyzed. RESULTS: Both drugs exhibited positive signals for drug reaction with DRESS, AGEP, TEN, SJS-TEN overlap and SJS. The median onset time of SCARs caused by valaciclovir or acyclovir was 30 days vs 10 day for DRESS, 11 days vs 9 days for AGEP, 17 days vs 12 days (TEN) and 12 days vs 8 days (SJS). Excluding the effect of combinational drugs, there was an association between the two antiviral drugs and SCARs. CONCLUSION: By analyzing the FAERS database, the risk trends of SCARs caused by valaciclovir or acyclovir have been identified, providing valuable insights to recognize various types of SCARs in clinics.

Efficacy and safety of Danlou tablets in traditional Chinese medicine for coronary heart disease: a systematic review and meta-analysis.

Background: Danlou tablets exert auxiliary advantages in treating coronary heart disease (CHD), but a summary of evidence-based proof is lacking. This study aims to systematically evaluate Danlou tablets in treating CHD from two aspects, including efficacy and safety. Methods: By a thorough retrieval of the four English databases, namely, PubMed, The Cochrane Library, Embase, and Web of Science, and the four Chinese databases, namely, CNKI, Wanfang, VIP database, and China Biomedical Literature Service System, we found all randomized controlled trials (RCTs) related to Danlou tablets in treating CHD. The retrieval time was from the construction of the database to April 2022. We engaged two researchers to screen the studies, extract the required data, and assess the risk of bias. We then used RevMan5.3 and STATA.14 software to conduct a meta-analysis. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to evaluate the quality of outcome indicators. Results: Seventeen RCTs involving 1,588 patients were included. The meta-analysis results are displayed as follows: clinical treatment effect [risk ratio (RR) = 1.22, 95% confidence interval (CI): 1.16, 1.28, P < 0.00001], angina pectoris duration [MD = -0.2.15, 95% CI: -2.91, -1.04, P < 0.00001], angina pectoris frequency [standard mean difference (SMD) = -2.48, 95% CI: -3.42, -1.54, P < 0.00001], angina pectoris degree [SMD = -0.96, 95% CI: -1.39, -0.53, P < 0.0001], TC [MD = -0.71, 95% CI: -0.92, -0.51, P < 0.00001], TG [MD = -0.38, 95% CI: -0.53, -0.22, P < 0.00001], low-density lipoprotein cholesterol [MD = -0.64, 95% CI: -0.76, -0.51, P < 0.00001], high-density lipoprotein cholesterol [MD = 0.16, 95% CI: 0.11, 0.21, P < 0.00001], and adverse events [RR = 0.46, 95% CI: 0.24, 0.88, P = 0.02]. Conclusion: The current evidence suggests that the combination of Danlou tablets and Western medicine can enhance the efficacy of CHD and does not increase adverse events. However, because of the limited number and quality of the included studies, the results of our study should be treated with caution. Further large-scale RCTs are necessary to verify the benefits of this approach.

Ultra-small micelles together with UTMD enhanced the therapeutic effect of docetaxel on Glioblastoma.

Owing to the difficult-to-penetrate blood-brain barrier (BBB), glioblastoma (GBM) doesn't respond well to the current chemical therapeutics. In this study, ultra-small micelles (NMs) self-assembled by RRR-a-tocopheryl succinate-grafted-ε-polylysine conjugate (VES-g-ε-PLL) as the delivery vehicle of chemical therapeutics in conjunction with ultrasound-targeted microbubble destruction (UTMD) to surmount BBB and treat GBM. Docetaxel (DTX) as a hydrophobic model drug was incorporated into NMs. DTX-loaded micelles (DTX-NMs) with 3.08% of drug loading exhibited a hydrodynamic diameter (33.2 nm) and positive Zeta potential (16.9 mV), having a remarkable tumor-permeating capacity. Furthermore, DTX-NMs presented good stability in physiologic condition. The sustained- release profile of DTX-NMs was also displayed by dynamic dialysis. Treatment of DTX-NMs together with UTMD led to more pronounced apoptosis of C6 tumor cells than DTX-NMs alone. Moreover, compared with the DTX solution or DTX-NMs alone, the combination of DTX-NMs with UTMD had a stronger inhibitory effect on tumor growth for GBM-bearing rats. The median survival period of GBM-bearing rats was extended to 75 days in the DTX-NMs+UTMD group from under 25 days in the control group. The invasive growth of glioblastoma was largely inhibited by the combination of DTX-NMs with UTMD, which was demonstrated by staining of Ki67, caspase-3, and CD31, together with TUNEL assay. In conclusion, the combination of ultra-small micelles (NMs) with UTMD may be a promising strategy to overcome the limitations of the first-line chemotherapeutics against GBM.

LncRNA expression analysis by comparative transcriptomics among closely related poplars and their regulatory roles in response to salt stress.

Long noncoding ribonucleic acids (lncRNAs) play crucial roles in regulating key biological processes; however, our knowledge of lncRNAs' roles in plant adaptive evolution is still limited. Here, we determined the divergence of conserved lncRNAs in closely related poplar species that were either tolerant or sensitive to salt stress by comparative transcriptome analysis. Among the 34,363 identified lncRNAs, ~3% were shared among poplar species with conserved sequences but diversified in their function, copy number, originating genomic region and expression patterns. Further cluster analysis revealed that the conserved lncRNAs showed more similar expression patterns within salt-tolerant poplars (Populus euphratica and P. pruinosa) than between salt-tolerant and salt-sensitive poplars. Among these lncRNAs, the antisense lncRNA lncERF024 was induced by salt and the differentiated expression between salt-sensitive and salt-tolerant poplars. The overexpression of lncERF024 in P. alba var. pyramidalis enhanced poplar tolerance to salt stress. Furthermore, RNA pull-down and RNA-seq analysis showed that numerous candidate genes or proteins associated with stress response and photosynthesis might be involved in salt resistance in PeulncERF024-OE poplars. Altogether, our study provided a novel insight into how the diversification of lncRNA expression contributes to plant adaptation traits and showed that lncERF024 may be involved in the regulation of both gene expression and protein function conferring salt tolerance in Populus.

Associations between urinary parabens and lung cancer.

Parabens are a family of endocrine-disrupting chemicals. Environmental estrogens may play a vital role in the development of lung cancer. To date, the association between parabens and lung cancer is unknown. Based on the 189 cases and 198 controls recruited between 2018 and 2021 in Quzhou, China, we measured 5 urinary parabens concentrations and examined the association between urinary concentrations of parabens and lung cancer risk. Cases showed significantly higher median concentrations of methyl-paraben (MeP) (2.1 versus 1.8 ng/mL), ethyl-paraben (0.98 versus 0.66 ng/mL), propyl-paraben (PrP) (2.2 versus 1.4 ng/mL), and butyl-paraben (0.33 versus 0.16 ng/mL) than controls. The detection rates of benzyl-paraben were only 8 and 6% in the control and case groups, respectively. Therefore, the compound was not considered in the further analysis. The significant correlation between urinary concentrations of PrP and the risk of lung cancer (odds ratio (OR)adjusted = 2.22, 95% confidence interval (CI): 1.76, 2.75; Ptrend < 0.001) was identified in the adjusted model. In the stratification analysis, we found that urinary concentrations of MeP were significantly associated with lung cancer risk (OR = 1.16, 95% CI: 1.01, 1.27 for the highest quartile group). Besides, comparing the second, third, and fourth quartile groups with the lowest group of PrP, we also observed urinary PrP concentrations associated with lung cancer risk, with the adjusted OR of 1.52 (95% CI: 1.29, 1.65, Ptrend = 0.007), 1.39 (95% CI: 1.15, 1.60, Ptrend = 0.010), and 1.85 (95% CI: 1.53, 2.30, Ptrend = 0.001), respectively. MeP and PrP exposure, reflected in urinary concentrations of parabens, may be positively associated with the risk of lung cancer in adults.

A pan-cancer analysis of FAT atypical cadherin 4 (FAT4) in human tumors.

Objective: We performed a pan-cancer analysis to explore the potential mechanisms of FAT4 in 33 different tumors. Methods: In this study, we selected 33 types of cancers based on the datasets of TCGA (the cancer genome atlas). We analyzed the expression of FAT4 in tumor and normal tissues. Meanwhile, we analyzed the expression levels of FAT4 in tissues from tumors of different stages. Kaplan-Meier survival analysis, Tumor Mutational Burden (TMB), Microsatellite Instability (MSI), immune infiltration analysis, Gene set enrichment analysis (GSEA), and FAT4-related gene enrichment analysis were performed. Results: FAT4 expression in most tumor tissues was lower than in corresponding control tissues. FAT4 expression was different in different stages of bladder cancer (BLCA), kidney clear cell carcinoma (KIRC), and breast cancer (BRCA). In addition, the expression level of FAT4 in different types of tumors has an important impact on the prognosis of patients. FAT4 might influence the efficacy of immunotherapy via tumor burden and microsatellite instability. We observed a statistically positive correlation between cancer-associated fibroblasts and FAT4 expression in most tumors. GSEA of BLCA indicated that low FAT4 expression groups were mainly enriched in calcium signaling pathway and chemokine signaling pathway. GSEA analysis of KIRC suggested low FAT4 expression groups were mainly involved in olfactory transduction and oxidative phosphorylation. Kyoto Encyclopedia of Genes and Genomes (KEGG) indicated that the role of FAT4 in the pathogenesis of cancer may be related to human papillomavirus infection, Hippo signaling pathway, PI3K-Akt signaling pathway, etc. Gene Ontology (GO) enrichment analysis further showed that most of these genes were related to the pathways or cell biology, such as peptidyl-tyrosine phosphorylation, cell junction assembly, protein tyrosine kinase activity, etc. Conclusion: Our study summarized and analyzed the antitumor effect of FAT4 in different tumors comprehensively, which aided in understanding the role of FAT4 in tumorigenesis from the perspective of clinical tumor samples. Pan-cancer analysis showed that FAT4 to be novel biomarkers for various cancers prognosis.

A recognition strategy combining effective boron affinity technology and surface imprinting to prepare highly selective and easily recyclable polymer membrane for separation of drug molecule.

Cellulose acetate membrane (CAM) has become one of the most widely used membrane materials by virtue of stability and hydrophilicity. In this work, to achieve the aim of selective recognition and separation of drug molecule shikimic acid (SA), an effective recognition tactics was proposed by combining boron affinity technology with surface imprinting strategy based on cellulose acetate membrane with low price and biocompatibility. The supporting CAM material was prepared through the phase inversion technique by continuous adjustment of different factors including solvent type and kinds of pore-forming agents, and the optimal CAM with multistage structure and highly porosity was applied for the imprinting of SA. Then the imprinted polymer membrane (MIPs-CAM) was developed via boron affinity surface imprinting polymerization. Various methods (FT-IR, UV-vis, SEM, XPS, AFM and TGA) were used to characterize the structure, morphology, elemental composition, surface roughness and thermal property of the obtained membrane. The as-prepared MIPs-CAM showed homogeneous and abundant imprinted layer, good thermal stability. The batch adsorption results showed that the MIPs-CAM had fast adsorption kinetics, specific recognition ability, and the adsorption capacity could obtain 63.598 mg g-1, which was two times higher than that of non-imprinted membrane (NIPs-CAM). The adsorption isotherms conformed to the Langmuir isotherm and the adsorption processes were spontaneous and endothermic. Additionally, the adsorption capacity of MIPs-CAM still reached 85% of the initial result after five cycles. The experimental results revealed that the molecularly imprinted membrane possessed the advantages of high selectivity and easy recovery compared with the traditional molecular imprinted polymers for SA separation. These results indicate that boron affinity MIPs-CAM with high performance will provide a promising platform for the separation and purification of other cis-diol drug molecules from environmental resources.

Efficacy and safety of Kanglaite injection combined with chemotherapy for colorectal cancer: A protocol for systematic review and meta-analysis.

BACKGROUND: The incidence and mortality of colorectal cancer are high. Chemotherapy is currently the commonly used therapeutic scheme, but there are drug resistance and toxic and side effects. Kanglaite (KLT) injection is a broad-spectrum anticancer drug extracted from Semen Coicis (Yi Yi Ren), which has been widely used in the treatment of colorectal cancer. Clinical practice shows that KLT injection combined with chemotherapy has certain therapeutic advantages, but there is a lacking of evidence of evidence-based medicine. The purpose of this study is to systematically investigate the efficacy and safety of KLT injection combined with chemotherapy in the treatment of colorectal cancer. METHODS: Randomized controlled trials of KLT injection combined with chemotherapy in the treatment of colorectal cancer were retrieved from English databases (PubMed, Embase, Web of Science, the Cochrane Library) and Chinese databases (China National Knowledge Infrastructure, Wanfang, Chongqing VIP Chinese Science and Technology Periodical Database, Chinese Biological and Medical database), as well as searching Baidu academic and Google academic manually, and the retrieval time was from their establishment to August 2020. Two researchers independently conducted data extraction and literature quality evaluation on the quality of the included literatures, and meta-analysis was conducted on the included literatures using RevMan 5.3 (developed by the UK's International Cochrane Collaboration). RESULTS: This study assessed the efficacy and safety of KLT injection combined with chemotherapy in the treatment of colorectal cancer by effective rate, Karnofsky Performance Status, Carcinoemybryonic Angtigen remission rate, pain remission rate, and incidence of adverse reactions etc. CONCLUSIONS:: This study will provide reliable evidence-based evidence for the clinical application of KLT injection combined with chemotherapy in the treatment of colorectal cancer. ETHICS AND DISSEMINATION: The private information from individuals will not be published. This systematic review also will not involve endangering participant rights. Ethical approval is not required. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/EKVAF.

Covalent laccase immobilization on the surface of poly(vinylidene fluoride) polymer membrane for enhanced biocatalytic removal of dyes pollutants from aqueous environment.

Biocatalytic removal with laccase immobilized on diverse membranes offers an attractive option to search alternative to traditional wastewater treatment processes for the removal of high toxic azo dye. In this work, the modified poly(vinylidene fluoride) membrane (PVDF) with chemical stability and high mechanical strength was developed for laccase immobilization via covalent bonding. The key design for the synthesis of biocatalytic membrane is the construction of hybrid bio-inorganic structure on the surface of polydopamine (PDA)-coated PVDF (PDA@PVDF). In this respect, the PDA layer was used as a secondary platform for the grafting of 3-triethoxysilylpropylamine (APTES) modified Fe2O3@SiO2 cubes (FS@cubes) via a solvothermal process, resulting in the formation of FS@cubes-PDA@PVDF membrane. Subsequently, laccase was immobilized on the surface of FS@ cubes-PDA@PVDF via gluteraldehyde (GA) crosslinking (Lac-FS@ cubes-PDA@PVDF). The removal efficiency of congo red by Lac-FS@cubes-PDA @PVDF reached 97.1 % under optimal reaction conditions (pH 7.0 and temperature 35 ℃), which was more efficient than free laccase. Moreover, the as-prepared Lac-FS@cubes-PDA@PVDF not only exhibited an excellent stability after low temperature storage, but also showed an outstanding reusability. Therefore, we believe that this work opens up a potential strategy for removal of other water pollutants, and provide a simple and convenient way for large-scale applications of enzyme-catalysis.

Highly dispersive NiCo2S4 nanoparticles anchored on nitrogen-doped carbon nanofibers for efficient hydrogen evolution reaction.

To solve the energy crisis problem, many efforts have been devoted to develop clean and sustainable alternatives to fossil fuels. Among varieties of pathways to obtain clean energy, electrochemical water splitting is a promising approach. Herein, we had successfully synthesized the NiCo2S4@porous nitrogen-doped carbon nanofibers (NiCo2S4@NCNF) nanocomposite via three successive steps consisted of in-situ oxidative polymerization, calcination, and solvothermal sulfuration reaction processes. The effect of controlled molar ratios to electrocatalytic performance was studied in detail. The optimized NiCo2S4@NCNF nanocomposite exhibits superior electrocatalytic activity for hydrogen evolution reaction with a small overpotential of 117 mV to drive a current density of 10 mA cm-2. More importantly, it exhibits similar electrocatalytic activity to the initial state even after successive cyclic voltammetry scan for 3000 cycles, indicating its excellent long-term stability. The superior electrochemical performance is attributed to the developed three-dimensional (3D) network nanostructure derived from bacterial cellulose nanofibers, the highly conductive porous nitrogen-doped carbon nanofibers, and the synergistic effect between metal Ni and Co of NiCo2S4. This study permits a new pathway to design efficient electrocatalysts based on eco-friendly materials for the production of clean hydrogen energy.

Rho-Associated Protein Kinase (ROCK) Promotes Proliferation and Migration of PC-3 and DU145 Prostate Cancer Cells by Targeting LIM Kinase 1 (LIMK1) and Matrix Metalloproteinase-2 (MMP-2).

BACKGROUND In the pathogenesis and progression of prostate cancer, cell proliferation and cell migration results in tumor invasion and metastasis that is associated with patient morbidity and mortality. Rho-associated protein kinase (ROCK) has previously been shown to be upregulated in prostate cancer, but its biological role remains poorly understood. This study aimed to investigate the role of ROCK in the proliferation and migration of PC-3 and DU145 prostate cancer cells and to identify the possible targets involved by knockdown of ROCK1 and ROCK2 RNA expression. MATERIAL AND METHODS An RNA interference (RNAi) assay was performed to silence the expression of ROCK1 and ROCK2 in the PC-3 and DU145 human prostate cancer cell lines. Cells were also treated with a specific ROCK inhibitor, Y27632. A cell counting kit-8 (CCK-8) assay was used to determine the proliferation rate of prostate cancer cells, and cell migration and invasion assays were performed. Western blot and polymerase chain reaction were used to measure protein and RNA expression levels. RESULTS In PC-3 and DU145 prostate cancer cells, knockdown of ROCK1 and ROCK2 reduced cell migration and invasion. ROCK1 and ROCK2 regulated cell proliferation in PC-3 and DU145 prostate cancer cells. Protein levels of phosphorylated LIM kinase 1 (p-LIMK1) and matrix metalloproteinase-2 (MMP-2) were reduced in ROCK1 and ROCK2 siRNA transfected cells. CONCLUSIONS In PC-3 and DU145 human prostate cancer cells, ROCK promoted cell proliferation and migration by targeting LIMK1 and MMP-2.

Skin-penetrating polymeric nanoparticles incorporated in silk fibroin hydrogel for topical delivery of curcumin to improve its therapeutic effect on psoriasis mouse model.

A poor percutaneous penetration capability for most topical anti-inflammatory drugs is one of the main causes compromising their therapeutic effects on psoriatic skin. Even though curcumin has shown a remarkable efficacy in the treatment of psoriasis, its effective penetration through the stratum corneum is still a major challenge during transdermal delivery. The aim of our study was to design skin-permeating nanoparticles (NPs) to facilitate delivery of curcumin to the deeper layers of the skin. A novel amphiphilic polymer, RRR-α-tocopheryl succinate-grafted-ε-polylysine conjugate (VES-g-ε-PLL) was synthesized and self-assembled into polymeric nanoparticles. The nanoparticles of VES-g-ε-PLL exhibiting an ultra-small hydrodynamic diameter (24.4nm) and a positive Zeta potential (19.6mV) provided a strong skin-penetrating ability in vivo. Moreover, curcumin could effectively be encapsulated in the polymeric nanoparticles with a drug loading capacity of 3.49% and an encapsulating efficiency of 78.45%. In order to prolong the retention time of the ultra-small curcumin-loaded nanoparticles (CUR-NPs) in the skin, silk fibroin was used as a hydrogel-based matrix to further facilitate topical delivery of the model drug. In vitro studies showed that CUR-NPs incorporated in silk fibroin hydrogel (CUR-NPs-gel) exhibited a slower release profile of curcumin than the plain CUR-gel, without compromising the skin penetration ability of CUR-NPs. In vivo studies on miquimod-induced psoriatic mice showed that CUR-NPs-gel exhibited a higher therapeutic effect than CUR-NPs as the former demonstrated a more powerful skin-permeating capability and a more effective anti-keratinization process. CUR-NPs-gel was therefore able to inhibit the expression of inflammatory cytokines (TNF-α, NF-κB and IL-6) to a greater extent. In conclusion, the permeable nanoparticle-gel system may be a potential carrier for the topical delivery of lipophilic anti-psoriatic drugs.

Proanthocyanidin prevents lipopolysaccharide-induced depressive-like behavior in mice via neuroinflammatory pathway.

Recent studies have demonstrated neuroinflammation and increased cytokine levels are associated with depression. Aware of the efficacy the potential anti-inflammatory and antioxidative activity of proanthocyanidin, the present study was designed to investigate the effects of proanthocyanidin on lipopolysaccharide (LPS)-induced depressive-like behavior in mice. In depressive behavior tests, the immobility time of forced swimming test (FST) and tail suspension test (TST) was increased when mice were administrated a single dose of LPS (0.83mg/kg, i.p.), whereas these alterations were reversed by proanthocyanidin treatment (80mg/kg, p.o.). In anxiety behavior tests, all the anxiety-related parameters, such as number of buried marble, time spent in the open arm and close arm did not show statistical differences between LPS and control groups. However, anxiolytic effects were observed in marble-burying test and elevated plus maze test in single proanthocyanidin treatment and proanthocyanidin treatment together with LPS group. Further assays indicated that LPS-induced overexpression of pro-inflammatory cytokines in the hippocampus, prefrontal cortex (PFC) and amygdala were reversed by proanthocyanidin treatment. Furthermore, proanthocyanidin inhibited the LPS-induced iNOS and COX-2 overexpression, via the modulation of NF-κB in the hippocampus, PFC and amygdala. Taken together, proanthocyanidin may be an effective therapeutic agent for LPS-induced depressive-like behaviors via its potent anti-inflammatory property.

Superparamagnetic iron oxide nanoparticles conjugated with folic acid for dual target-specific drug delivery and MRI in cancer theranostics.

Monodispersed SPIONs (superparamagnetic iron oxide nanoparticles) co-coated with PEG and PEI polymers were prepared by an improved polyol method. To accomplish cancer-specific targeting properties, FA (folic acid) was then modified on the SPIONs via EDC/NHS method (FA-SPIONs). Doxorubicin (DOX) as an example anticancer drug was loaded within FA-SPIONs (DOX@FA-SPIONs), the DOX release rate of DOX@FA-SPIONs was much high in low pH PBS. The SPIONs, FA-SPIONs and DOX@FA-SPIONs with mean hydrodynamic diameters of 23, 40 and 67nm, respectively, performed excellent colloidal stability in PBS. Confocal laser scanning microscope (CLSM) study implicates that the DOX@FA-SPIONs target MCF-7 cells efficiently through the FA receptor-mediated endocytosis. DOX@FA-SPIONs were tested in nude mice with xenograft MCF-7 breast tumor though tail intravenous injection and were found inhibiting tumor growth more efficiently. The application of a magnetic field (MF) greatly improved the growth inhibiting efficiencies of DOX@FA-SPIONs on MCF-7 cells in vitro and on xenograft MCF-7 breast tumor of nude mice in vivo. The aggregation of SPIONs in tumor was monitored by magnetic resonance imaging (MRI) as the DOX@FA-SPIONs exhibited high r2 relaxivity (81.77mM-1S-1). Histology on liver, Lung, kidney and heart in mice showed no significant toxicity of DOX@FA-SPIONs on mice organs after 35-day treatment. The FA-SPIONs are a high efficient drug delivery nanoplatform for advanced cancer theranostics.

An injectable acellular matrix scaffold with absorbable permeable nanoparticles improves the therapeutic effects of docetaxel on glioblastoma.

Intratumoral drug delivery (IT) is an inherently appealing approach for concentrating toxic chemotherapies at the site of action. However, for most chemotherapies, poor tumor penetration and short retention at the administration site limit their anti-tumor effects. In this work, we describe permeable nanoparticles (NPs) prepared with a novel amphiphilic polymer, RRR-α-tocopheryl succinate-grafted-ε-polylysine conjugate (VES-g-ε-PLL). The nanoparticles (NPs) of VES-g-ε-PLL exhibited an ultra-small hydrodynamic diameter (20.8 nm) and positive zeta potential (20.6 mV), which facilitate strong glioma spheroid penetration ability in vitro. Additionally, the hydrophobic model drug docetaxel (DTX) could be effectively encapsulated in the nanoparticles with 3.99% drug loading and 73.37% encapsulation efficiency. To prolong the retention time of DTX-loaded nanoparticles (DTX-NPs) in the tumor, intact decellularized brain extracellular matrix (dBECM) derived from healthy rats was used as a drug depot to adsorb the ultra-small DTX-NPs. The intact DTX-NPs-adsorbing dBECM scaffold was further homogenized into an injectable DTX-NPs-dBECM suspension for intratumoral administration. The DTX-NPs-dBECM suspension exhibited slower DTX release than naked DTX-NPs without compromising the tumor penetration ability of DTX-NPs. An antitumor study showed that the DTX-NPs-dBECM suspension exhibited more powerful in vitro inhibition of tumor spheroid growth than free DTX solution or DTX-NPs. Due to strong tumor penetration ability and prolonged retention, DTX-NPs-dBECM led to complete suppression of glioma growth in vivo at 28 days after treatment. The therapeutic mechanism was due to enhanced proliferation inhibition and apoptosis of tumor cells and angiogenesis inhibition of glioma after treatment with DTX-NPs-dBECM. Finally, the safety of DTX-NPs-dBECM at the therapeutic dose was demonstrated via pathological HE assay from heart, liver, spleen, lung and kidney tissues. In conclusion, permeable nanoparticle-absorbing dBECM is a potential carrier for intratumoral delivery of common chemotherapeutics.

Glioma-targeted superparamagnetic iron oxide nanoparticles as drug-carrying vehicles for theranostic effects.

Multifunctional nanoparticles capable of the specific delivery of therapeutics to diseased cells and the real-time imaging of these sites have the potential to improve cancer treatment through personalized therapy. In this study, we have proposed a multifunctional nanoparticle that integrate magnetic targeting, drug-carrier functionality and real-time MRI imaging capabilities in one platform for the theranostic treatment of tumors. The multifunctional nanoparticle was designed with a superparamagnetic iron oxide core and a multifunctional shell composed of PEG/PEI/polysorbate 80 (Ps 80) and was used to encapsulate DOX. DOX-loaded multifunctional nanoparticles (DOX@Ps 80-SPIONs) with a Dh of 58.0 nm, a zeta potential of 28.0 mV, and a drug loading content of 29.3% presented superior superparamagnetic properties with a saturation magnetization (Ms) of 24.1 emu g(-1). The cellular uptake of DOX@Ps 80-SPIONs by C6 cells under a magnetic field was significantly enhanced over that of free DOX in solution, resulting in stronger in vitro cytotoxicity. The real-time therapeutic outcome of DOX@Ps 80-SPIONs was easily monitored by MRI. Furthermore, the negative contrast enhancement effect of the nanoparticles was confirmed in glioma-bearing rats. Prussian blue staining and ex vivo DOX fluorescence assays showed that the magnetic Ps 80-SPIONs and encapsulated DOX were delivered to gliomas by imposing external magnetic fields, indicating effective magnetic targeting. Due to magnetic targeting and Ps 80-mediated endocytosis, DOX@Ps 80-SPIONs in the presence of a magnetic field led to the complete suppression of glioma growth in vivo at 28 days after treatment. The therapeutic mechanism of DOX@Ps 80-SPIONs acted by inducing apoptosis through the caspase-3 pathway. Finally, DOX@Ps 80-SPIONs' safety at therapeutic dosage was verified using pathological HE assays of the heart, liver, spleen, lung and kidney. Multifunctional SPIONs could be used as potential carriers for the theranostic treatment of CNS diseases.

ELS1, a novel MATE transporter related to leaf senescence and iron homeostasis in Arabidopsis thaliana.

The multidrug and toxic compound extrusion (MATE) transporters mediate the coupled exchange of organic substrates and monovalent cations have been recently implicated in various plant biological activities. In this work, we isolated a dominant mutant from an Arabidopsis activation-tagging mutant pool. This mutant exhibits pleiotropic phenotype including early flowering, dwarf and bushy architecture, minified lateral organs and early leaf senescence, and is therefore designated early leaf senescence 1-Dominaint (els1-D). Genotyping assays showed that els1-D is a gain-of-function mutant of a novel MATE transporter gene, ELS1, which encodes a close homolog of the previously reported ADP1, BCD1 and DTX50. Further investigations revealed that the overexpression of ELS1 reduces iron content in els1-D, and the accelerated senescence of the detached els1-D leaves can be recovered by exogenous iron supply. In addition, we also found that ELS1 is an iron responsive gene. Based on these findings, we proposed that ELS1 is related to leaf senescence and iron homeostasis in Arabidopsis.

Using Gelatin Nanoparticle Mediated Intranasal Delivery of Neuropeptide Substance P to Enhance Neuro-Recovery in Hemiparkinsonian Rats.

PURPOSE: Intranasal administration of phospholipid-based gelatin nanoparticles (GNP) was prepared to investigate the neuro-recovery effects of neuropeptide Substance P (SP) on hemiparkinsonian rats. METHODS: The SP-loaded gelatin nanoparticles (SP-GNP) were prepared by a water-in-water emulsion method and possessed high stability, encapsulating efficiency and loading capacity. PC-12 cells were used to examine the growth enhancement of SP-GNP in vitro by MTT assays and flow cytometry (FCM). The therapeutic effects of SP-GNP on 6-hydroxydopamine (6-OHDA) induced hemiparkinsonian rats were assessed by quantifying rotational behavior and the levels of tyrosine hydroxylase (TH), phosphorylated c-Jun protein (p-c-Jun) and Caspase-3 (Cas-3) expressed in substantia nigra (SN) region of hemiparkinsonian rats. RESULTS: PC-12 cells under SP-GNP treatment showed better cell viability and lower degree of apoptosis than those under SP solution treatment. Hemiparkinsonian rats under intranasal SP-GNP administration demonstrated better behavioral improvement, higher level of TH in SN along with much lower extent of p-c-Jun and Cas-3 than those under intranasal SP solution administration and intravenous SP-GNP administration. CONCLUSIONS: With the advantages of GNP and nose-to-brain pathway, SP can be effectively delivered into the damaged SN region and exhibit its neuro-recovery function through the inhibition on JNK pathway and dopaminergic neuron apoptosis.

High RhoA expression at the tumor front in clinically localized prostate cancer and association with poor tumor differentiation.

Ras homolog gene family, member A (RhoA) has been reported as essential to the invasion process and aggressiveness of numerous cancers. However, there are only sparse data on the expression and activity of RhoA in clinically localised prostate cancer. In numerous cancers, tumour cells at the invasive front demonstrate more aggressive behaviour in comparison with the cells in the central regions. In the present study, the expression and activity of RhoA was evaluated in 34 paraffin-embedded and 20 frozen prostate tissue specimens obtained from 45 patients treated with radical prostatectomy for clinically localised cancer. The expression patterns of RhoA were assessed by immunohistochemical staining and western blotting. Additional comparisons were performed between the tumour centre, tumour front and distant peritumoural tissue. RhoA activity was assessed by G-LISA. Associations between RhoA expression and the clinical features and outcome of the patients were also analysed. The present study found an increasing gradient of expression from the centre to the periphery of index tumour foci. RhoA expression was significantly increased at the tumour front compared to the tumour centre, which was determined using immunohistochemistry (P=0.001). Increased RhoA expression was associated with poor tumour differentiation in the tumour front (P=0.044) and tumour centre (P=0.039). Subsequent to a median follow-up period of 52 months, the rate of prostate-specific antigen (PSA) relapse was increased in patients with higher RhoA expression at the tumour front when compared with patients with lower RhoA expression (62.5 vs. 35.0%), although the difference was not significant (P=0.09). There was no association between RhoA expression and the PSA level or pathological stage in the present study. In conclusion, RhoA expression was increased at the tumour front and was associated with poor tumour differentiation in the tumour front and tumour centre, indicating the potential role of RhoA in prostate cancer. RhoA expression may also act as a prognostic factor in prostate cancer. The present data provide a foundation for novel therapeutic approaches by targeting RhoA in prostate cancer.