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Aster tataricus, a traditional Chinese herb, has been used to treat cough and asthma for many years. Its raw and processed products have different pharmacological effects in clinical applications. To explore the chemical profile differences of components in A. tataricus processed with different methods, metabolomics methods based on ultra-high-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry and gas chromatography-mass spectrometry were developed. Chemometrics strategy was applied to filter and screen the candidate compounds. The accuracy of differential markers was validated by back propagation neural network. The established methods showed that raw A. tataricus, honey-processed A. tataricus, vinegar-processed A. tataricus, and steamed A. tataricus were clearly divided into four groups, suggesting that the components were closely related to the processing methods. A total of 64 nonvolatile and 43 volatile compounds were identified in A. tataricus, and 22 nonvolatile and 12 volatile differential constituents were selected to distinguish the raw and processed A. tataricus. This study demonstrated that the metabolomics methods coupled with chemometrics were a comprehensive strategy to analyze the chemical profile differences and provided a reliable reference for quality evaluation of A. tataricus.

Although organic nanomaterials and inorganic nanoparticles possess inherent flexibility, facilitating functional modification, increased intracellular uptake and controllable drug release, their underlying cytotoxicity and lack of specificity still cause safety concerns. Owing to their merits, which include natural biocompatibility, structural stability, unsurpassed programmability, ease of internalization and editable functionality, tetrahedral DNA nanostructures show promising potential as an alternative vehicle for drug delivery and biomedical treatment. Here, we describe the design, fabrication, purification, characterization and potential biomedical applications of a self-assembling tetrahedral DNA nanostructure (TDN)-based multifunctional delivery system. First, relying on Watson-Crick base pairing, four single DNA strands form a simple and typical pyramid structure via one hybridization step. Then, the protocol details four different modification approaches, including replacing a short sequence of a single DNA strand by an antisense peptide nucleic acid, appending an aptamer to the vertex, direct incubation with small-molecular-weight drugs such as paclitaxel and wogonin and coating with protective agents such as cationic polymers. These modified TDN-based complexes promote the intracellular uptake and biostability of the delivered molecules, and show promise in the fields of targeted therapy, antibacterial and anticancer treatment and tissue regeneration. The entire duration of assembly and characterization depends on the cargo type and modification method, which takes from 2 h to 3 d.

Recent studies have revealed that tissue macrophages are derived from yolk sac precursors or fetal liver monocytes, in addition to bone marrow monocytes. The relative contribution of these cells to the tissue macrophage pool is not fully understood, but embryo-derived cells are supposed to be more important because of their capacity to self-renew. Here, we show the presence of adult bone marrow-derived macrophages that retain self-renewing capacity. The self-renewing macrophages were readily obtained by long-term culture of mouse bone marrow cells with macrophage colony-stimulating factor (M-CSF), a key cytokine for macrophage development. They were non-tumorigenic and proliferated in the presence of M-CSF in unlimited numbers. Despite several differences from non-proliferating macrophages, they retained many features of cells of the monocytic lineage, including the differentiation into dendritic cells or osteoclasts. Among the transcription factors involved in the self-renewal of embryonic stem cells, Krüppel-like factor 2 (KLF2) was strongly upregulated upon M-CSF stimulation in the self-renewing macrophages, which was accompanied by the downregulation of MafB, a transcription factor that suppresses KLF2 expression. Indeed, knockdown of KLF2 led to cell cycle arrest and diminished cell proliferation in the self-renewing macrophages. Our new cell model would be useful to unravel differences in phenotype, function, and molecular mechanism of proliferation among self-renewing macrophages with different origins.

ATP6L, the C subunit of the V‐ATPase V0 domain, is involved in regulating the acidic tumor micro‐environment and may promote tumor progression. However, the expression and functional role of ATP6L in tumors have not yet been well explored. In this study, we found that ATP6L protein overexpression was related to colorectal cancer histological differentiation (P, ATP6L is markedly overexpressed in the poorly differentiated colorectal cancer tissues evidently located in the invasive front and metastatic foci. More importantly, in vitro and in vivo data demonstrated that ATP6L can induce the EMT program in CRC cells. Ectopic ATP6L expression can promote microvessel density in animal xenograft tissue.

DNA, a genetic material, has been employed in different scientific directions for various biological applications as driven by DNA nanotechnology in the past decades, including tissue regeneration, disease prevention, inflammation inhibition, bioimaging, biosensing, diagnosis, antitumor drug delivery, and therapeutics. With the rapid progress in DNA nanotechnology, multitudinous DNA nanomaterials have been designed with different shape and size based on the classic Watson-Crick base-pairing for molecular self-assembly. Some DNA materials could functionally change cell biological behaviors, such as cell migration, cell proliferation, cell differentiation, autophagy, and anti-inflammatory effects. Some single-stranded DNAs (ssDNAs) or RNAs with secondary structures via self-pairing, named aptamer, possess the ability of targeting, which are selected by systematic evolution of ligands by exponential enrichment (SELEX) and applied for tumor targeted diagnosis and treatment. Some DNA nanomaterials with three-dimensional (3D) nanostructures and stable structures are investigated as drug carrier systems to delivery multiple antitumor medicine or gene therapeutic agents. While the functional DNA nanostructures have promoted the development of the DNA nanotechnology with innovative designs and preparation strategies, and also proved with great potential in the biological and medical use, there is still a long way to go for the eventual application of DNA materials in real life. Here in this review, we conducted a comprehensive survey of the structural development history of various DNA nanomaterials, introduced the principles of different DNA nanomaterials, summarized their biological applications in different fields, and discussed the current challenges and further directions that could help to achieve their applications in the future., This work was supported in part by National Key R&D Program of China (Grant Nos. 2019YFA0110600) and National Natural Science Foundation of China (Grant Nos. 81970916 and 81671031).

In this study, a sensitive and reliable HPLC-MS/MS method was established to quantify tamarixetin in rat plasma. This method was then applied to research on the pharmacokinetic and bioavailability of tamarixetin after intravenous and oral administrationin vivo. The study was performed on CORTECS C18column (4.6 mm × 150 mm, 2.7 μm) using mobile phase composed of methanol-water-formic acid (85 : 15 : 0.1, v/v) at a flow rate of 0.3 mL/min by a tandem mass system with an electrospray ionization (ESI) source in the negative multiple-reaction monitoring (MRM) mode. The calibration curves showed good linearity in the range of 5–4000 ng/mL. The intra- and interday precision of tamarixetin was less than 8.7% and 4.8%, respectively, and accuracy was within ±9.5%. Extraction recovery (91.4–100.0%) and matrix effect (99.4–107.4%) met the guidelines published by regulatory authorities. The oral bioavailability of tamarixetin was 20.3 ± 12.4%.

A high-throughput HPLC-MS/MS method was developed and validated for the determination of four antihypertensive drugs including metoprolol tartrate, hydrochlorothiazide, nifedipine, and valsartan in rat plasma. The Sprague-Dawley rats were randomly divided into three groups: A Group: gastric-administration of metoprolol tartrate, hydrochlorothiazide, nifedipine, or valsartan; B Group: a single intravenous injection of SXT, then dosing as the A group; C Group: daily injection of SXT through the tail vein for 8 consecutive days and dosing as the A group on the eighth day. For metoprolol tartrate and valsartan, blood samples were collected before administration and at time points 0.03, 0.08, 0.17, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 h from the fossa orbitalis vein. For hydrochlorothiazide and nifedipine, the time points were 0, 0.08, 0.17, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, and 24 h. The plasma samples containing different individual antihypertensive drug were mixed and prepared by protein precipitation with methanol. The chromatographic separation was performed on an Agilent Eclipse Plus C18 column (2.1 mm×100 mm, 3.5 μm) using gradient elution with mobile phase consisting of acetonitrile and water (containing 0.1% formic acid). The flow rate was 0.3 mL/min. The detection was accomplished on a tandem mass spectrometer with an electrospray ionization (ESI) source by multiple reaction monitoring (MRM) in both positive and negative modes. The method was successfully applied to a pharmacokinetic interaction study of Shuxuetong injection on the antihypertensive drugs. The results suggested that SXT could increase the total amount of metoprolol tartrate and nifedipine in plasma and showed little influence on the pharmacokinetic behaviors of hydrochlorothiazide and valsartan.

DNA nanorobots have emerged as new tools for nanomedicine with the potential to ameliorate the delivery and anticancer efficacy of various drugs. DNA nanostructures have been considered one of the most promising nanocarriers. In the present study, we report a DNA framework-based intelligent DNA nanorobot for selective lysosomal degradation of tumor-specific proteins on cancer cells. We site-specifically anchored an anti-HER2 aptamer (HApt) on a tetrahedral framework nucleic acid (tFNA). This DNA nanorobot (HApt-tFNA) could target HER2-positive breast cancer cells and specifically induce the lysosomal degradation of the membrane protein HER2. An injection of the DNA nanorobot into a mouse model revealed that the presence of tFNA enhanced the stability and prolonged the blood circulation time of HApt, and HApt-tFNA could therefore drive HER2 into lysosomal degradation with a higher efficiency. The formation of the HER2-HApt-tFNA complexes resulted in the HER2-mediated endocytosis and digestion in lysosomes, which effectively reduced the amount of HER2 on the cell surfaces. An increased HER2 digestion through HApt-tFNA further induced cell apoptosis and arrested cell growth. Hence, this novel DNA nanorobot sheds new light on targeted protein degradation for precision breast cancer therapy.

Recently, a DNA tetrahedron has been reported to be a novel nanomedicine and promising drug vector because of its compactness, biocompatibility, biosafety, and editability. Here, we modified the DNA tetrahedron with a DNA aptamer (AS1411) as a DNA-based delivery system, which could bind to nucleolin for its cancer cell selectivity. Nucleolin is a specific biomarker protein overexpressed on membranes of malignant cancer cells and its deregulation is implicated in cell proliferation. The antimetabolite drug 5-fluorouracil (5-FU) is an extensively used anticancer agent; however, its major limitation is the lack of target specificity. Cyanine 5 (Cy5), a fluorescent probe, can be used to label DNA tetrahedron and enhance photostability with minimal effects on its basic functions. In this study, we additionally attached 5-FU to the DNA-based delivery system as a new tumor-targeting nanomedicine (AS1411-T-5-FU) to enhance the therapeutic efficacy and targeting of breast cancer. We examined the difference of the cellular uptake of AS1411-T-5-FU between breast cancer cells and normal breast cells and concluded that AS1411-T-5-FU had a better targeting ability to kill breast cancer cells than 5-FU. We further evaluated the expressions of cell apoptosis-related proteins and genes, which are associated with the mitochondrial apoptotic pathway. Ultimately, our results suggest the potential of DNA tetrahedron in cancer therapies, and we develop a novel approach to endow 5-FU with targeting property.

The purpose of this study was to show a systematic strategy for assessing the pharmacokinetics of indocyanine green (ICG)-loaded nanoparticles in the tumor tissue based on a dynamic diffuse fluorescence tomography (DFT) system. Twelve-seven-week-old male Balb/c nude mice bearing HepG2/ADR hepatocellular carcinoma were randomly divided into four groups (n = 3 per group). Four hundred microliters of three types of ICG-loaded nanoparticles (content of ICG: 50 μg/ml) and free ICG (50 μg/ml) was intravenously injected into the mice in each group, respectively. Afterwards, the real-time tomographic images on the spatial level were acquired at 2–11 min, 30 min, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h post-injection, and pharmacokinetic rates were derived for semi-quantitative assessment of the pharmacokinetics of nanoparticles at the tumor site using our proposed pharmacokinetic analysis method. The results obtained from our proposed dynamic DFT experiment demonstrated the distribution of different ICG formulations on the spatial level and enabled the semi-quantitative analysis of the pharmacokinetics of nanoparticles in the tumor tissue. The obtained pharmacokinetic rates effectively reflected the metabolic processes of nanoparticles in the tumor tissue, which proves to be beneficial for the development of tumor diagnosis and therapy.

DNAzymes are synthetic oligonucleotides that are capable of cleavaging target mRNA to exert gene-silencing activity and are considered as promising therapeutic agents. Dz13 is a DNAzyme that cleaves the mRNA of c-Jun and suppresses the growth of squamous cell carcinomas. However, DNAzymes exhibit low cellular uptake efficacy and require a suitable drug delivery system. In this study, we directly added the Dz13 sequence to the 5'-end of single-stranded DNA to form modified tetrahedral DNA nanostructures (TDN-Dz13). The TDNs were used to deliver the single-stranded DNAzyme Dz13 into cells. Dz13 delivered by the TDNs showed high cellular uptake efficiency and still maintained intracellular gene-silencing activity to cleave the target c-Jun mRNA, which reduced cell proliferation. This study may help find a convenient approach for the delivery of DNAzymes to regulate target genes.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the world. Inhibitor of differentiation 1 (Id1) is overexpressed in NSCLC and involved in promoting its progression and metastasis. Identifying natural compounds targeting Id1 may have utility in NSCLC treatment. Here, we sought to determine whether the anti-tumor activities of Scutellaria flavonoids (SFs) were related to Id1. We reported that three SFs (baicalin, baicalein and wogonin) exhibited strong antitumor activity in NSCLC cells in vitro and in vivo. Id1 played a pivotal role on blockage of migration and invasion by SFs. Abrogation of invasion and migration mediated by baicalin, baicalein and wogonin were totally abolished by ectopic overexpression of Id1. Mechanistically, baicalin, baicalein and wogonin activated Rap1-GTP binding and dephosphorylated Akt and Src by suppressing a7nAChR, consequently triggering inhibition of Id1. Then attenuation of its downstream mediators, VEGF-A, N-cadherin, vimentin, combined with augment of E-cadherin led to the blockage of proliferation, EMT and angiogenesis of NSCLC. Overall, our data shed light on heretofore-undescribed role of SFs as modulators of Id1, which may be a useful strategy in the treatment of NSCLC.

A sensitive ultra-high performance liquid chromatography-tandem mass spectrometry method was developed and validated to clarify pharmacokinetic properties of 15 compounds (quercetin, isorhamnetin, chlorogenic acid, isoquercitrin, caffeic acid, scopoletin, 7-hydroxycoumarin, shionone, ferulic acid, kaempferol-7-O-β-D-glucopyranoside, methyl caffeate, luteolin, kaempferol, epifriedelinol, and protocatechuic acid) in raw and honey-processed Aster tataricus. Separation was carried out on an ACQUITY UPLC®BEH C18 column (2.1 × 100 mm, 1.7 μm) using a gradient elution with mobile phase constituting 0.1% formic acid-water and 0.05% formic acid-methanol. Quantitative analysis was performed using multiple reaction monitoring detection in both positive and negative ionization modes. Calibration curves showed good linearity (r2 > 0.991) over the corresponding concentration range. The intra-day and inter-day precisions were within 10.1%, and accuracy ranged from -11.4% to 12.4%. The extraction recoveries and matrix effects were 78.1%-100.0% and 81.1%-113.7%, respectively. The analytes were stable under four storage conditions with relative standard deviations less than 12.6%. The validated method was successfully applied to compare the pharmacokinetic behaviors of raw and honey-processed Aster tataricus for the first time. The results indicated that the AUCs of shionone, ferulic acid, and protocatechuic acid in honey-processed Aster tataricus group were significantly lower than that of raw Aster tataricus group. This article is protected by copyright. All rights reserved.

Ethnopharmacological relevance Realgar has been used in traditional remedies for a long history in China and India. It is clinically used to treat diverse cancers, especially acute promyelocytic leukemia (APL), chronic myelogenous leukemia (CML) in China. However, paradoxic roles of realgar to increase or decrease immunity are reported. It is urgent to address this question, due to immune depression can be strongly benefit to cancer development, but detrimental to patients. Aim of the study This present work is to explore whether realgar promote or suppress immune responses, and shed light on its mode of action. Our results should provide cues for rational strategy to explore realgar for clinical use. Material and methods Infection model in vivo was established by using Enterococcus faecalis to attack Caenorhabditis elegans, then realgar was used to treat the infected worms to investigate its effects on infectivity and the underlying mechanism. Killing analysis was carried out to test whether realgar can mitigate worm infection. Thermotolerance resistance analysis was used to evaluate if realgar functions hormetic effect. Quantification of live E. faecalis in nematode intestine was employed to ascertain if realgar alleviate the bacterial load in worm gut. Quantitative real-time PCR (qRT-PCR) was used to test the expression of antibacterial effectors. Western blot was used to test the effect of realgar on the expressions of p38 and phospho-p38 in worms infected by E. faecalis. Results Realgar alleviated the infected worms in strains of N2, glp-4, and daf-2, but failed in sek-1, glp-4; sek-1, and daf-2; daf-16 when p38 MAPK or daf-16 was blocked or inactivated. Western blot assay demonstrated that realgar increased the expression of phosph-p38. Thermotolerance assay showed that realgar played a hormetic role on nemtodes, triggered protective response and reduced bacterial load after realgar treatment for 120 h qRT-PCR demonstrated that realgar significantly increased antibacterial effectors, thus leading to pathogen elimination. Conclusion Realgar increased defenses against E. faecalis in C. elegans by inducing both immune responses and protective responses. It was regulated by p38 MAPK pathway and DAF-16.

Objectives To provide a new research direction for nerve regeneration and strategy for Alzheimer's disease treatment, tetrahedral DNA nanostructures (TDNs)—novel tetrahedral framework nucleic acid molecule nanoparticles (tFNA) that can inhibit the apoptosis of nerve cells are employed in the experiment. Materials and methods To verify the successful preparation of TDNs, the morphology of TDNs was observed by atomic force microscopy (AFM) and transmission electron microscopy (TEM). The expression of apoptosis‐related genes and proteins was investigated by confocal microscope, flow cytometry, PCR and Western blot to detect the impact of TDNs on the Alzheimer's model. And finally, Morris water maze experiment was used to test behavioural changes and Nissl stain was detected to observe the morphology and quantity of neurons in the hippocampus. Immunofluorescence stain was used to observe the Aβ stain, and TUNEL dyeing was utilized to observe neuronal apoptosis. Results In vitro and in vivo experiments confirm that TDNs, in a specific concentration range, have no toxic or side effects on nerve cells, can effectively inhibit apoptosis in an Alzheimer's disease cell model and effectively improve memory and learning ability in a rat model of Alzheimer's disease. Conclusions These findings suggest that TDNs may be a promising drug for the treatment of Alzheimer's disease.

Red ginseng is often combined with Aconiti Lateralis Radix Praeparata to reduce alkaloids-related toxicity of the latter. Such herb-pairing also results in better therapeutic effect in heart failure, as compared to the singular use of either herb. The purpose of this study was to investigate the effect of Aconiti Lateralis Radix Praeparata and its combination with red ginseng on the activities of CYP450 enzymes in rats. A sensitive and reliable HPLC-MS/MS method was established and validated for the simultaneous determination of eight probe drugs, phenacetin (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), dapsone (CYP3A4), 7-hydroxycoumarin (CYP2A6), bupropion (CYP2B6), and amodiaquine (CYP2C8), in rat plasma using diazepam as internal standard (IS). The chromatographic separation was performed on a Waters XBridge™ C18 column (2.1 mm × 100 mm, 3.5 μm) using a gradient elution with the mobile phase consisting of acetonitrile and water (containing 0.1% formic acid) at a flow rate of 0.3 mL/min. The method was successfully applied in evaluating the effect of Aconiti Lateralis Radix Praeparata and red ginseng on the activities of CYP450 enzymes. The pharmacokinetic results of the eight probe drugs suggested that Aconiti Lateralis Radix Praeparata may inhibit the activity of CYP2A6, CYP2C19, CYP2B6, CYP1A2, CYP3A4, and CYP2C9 enzymes in rats. Comparison between the two groups, Aconiti Lateralis Radix Praeparata combined with red ginseng and Aconiti Lateralis Radix Praeparata, indicated that red ginseng may inhibit the activity of CYP2D6 and CYP2B6 enzymes while inducing the activity of CYP1A2, CYP3A4, and CYP2C9 enzymes.

Asarum (Aristolochiaceae) is one of the common herbs used to relieve exterior syndromes. Some volatile components of Asarum which have toxic effect may cause adverse reactions such as headache, general tension, unconsciousness, and respiratory paralysis. Therefore, Asarum is normally processed to reduce such toxicity and adverse effects. The bioactive ingredients contained in different Asarum herbs vary significantly; this variation may be attributed to their differences in species, origins, or processing methods. In this study, 16 batches of Asarum herbs were collected, and their species were identified using DNA barcoding, which is a method for distinguishing plant species, coupled with microscopy. A gas chromatography-mass spectrometry (GC-MS) method for simultaneous determination of 10 compounds was established to evaluate the contents of raw and processed Asarum herbs. Multivariate analysis was then applied to compare different batches of herbs based on the GC-MS data. DNA barcoding identified the herbs as being derived from four sources, and herbs from different origins showed different microscopic features. The results demonstrated that most of the samples were clearly clustered into distinct groups that corresponded to species types. All raw and processed samples were classified by partial least squares discriminant analysis (PLS-DA) based on the 10 analyzed compounds. The findings suggested that safrole and methyleugenol with a variable importance in the project (VIP) > 1 are unique compounds that can be used to differentiate between Asarum species. Safrole, methyleugenol, and 2,6,6-trimethylcyclohepta-2,4-dien-1-one were identified as significant constituents, the presence of which can be used to differentiate between raw and processed Asarum samples. These results indicate that species and processing methods show important effects on the composition of Asarum herbs.

A rapid and reliable UPLC-MS/MS method was developed and validated for the simultaneous quantification of thirteen bioactive compounds (luteolin, cynaroside, luteolin 7-O-glucuronide, isochlorogenic acid C, chlorogenic acid, cryptochlorogenic acid, apigenin, apigenin 7-glucoside, acacetin, hyperoside, isoquercitrin, tilianin, and hesperidin) in rat plasma. The compounds were separated on an ACQUITY UPLC BEH C18 column (2.1×100 mm, 1.7 μm) with a gradient mobile phase system of acetonitrile and 0.1% (v/v) formic acid aqueous solution at a flow rate of 0.3 mL/min. All compounds were quantitated using Agilent Jet Stream electrospray ionization (AJS ESI) in a negative ion mode. The lower limit of quantification (LLOQ) for all compounds was below 5 ng/mL. The intra- and interday accuracy ranged from -13.0% to 14.0%, and precisions were less than 12.2%. The extraction recoveries of the compounds were in the range of 56.9% to 95.0%, and the matrix effect ranged between 71.6% and 109.3%. Stability studies proved that the thirteen compounds were stable under tested conditions, with a relative standard deviation (RSD) of less than 11.4%. This developed method was successfully applied to the pharmacokinetic study of the 13 bioactive compounds after oral administration of Flos Chrysanthemi extract in rat by UPLC-MS/MS. Pharmacokinetic parameters of 8 out of the 13 compounds investigated are presented in this paper.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) represent a large family of RNA-binding proteins. Heterogeneous nuclear ribonucleoprotein D-like (HNRPDL) is a member of this family. Though aberrant expression of HNRPDL has been reported in a few cancers, whether HNRPDL is deregulated in colon cancer patients and what role this protein plays in these cells are not known yet. In this study, we found that HNRPDL was significantly up-regulated in colon cancer specimens than control. We also demonstrated that HNRPDL silencing inhibited the growth of SW620 cells both in vitro and in vivo. Conversely, we constructed a retroviral vector to deliver HNRPDL into non-malignant NIH-3T3 cells and injected these cells into nude mice. HNRPDL-overexpressing NIH-3T3 cells generated tumors in nude mice but not the control cells. Mechanistically, HNRPDL promoted cell-cycle progression associated with enhanced expressions of cyclin D3 and Ki-67 but decreased expressions of p53 and p21. Taken together, our data demonstrate that HNRPDL is aberrantly expressed in colon cancer cells, which promotes the growth of these cells by activating cell-cycle progression.

Osteoclast differentiation is a dynamic differentiation process, which is accompanied by dramatic changes in metabolic status as well as in gene expression. Recent findings have revealed an essential connection between metabolic reprogramming and dynamic gene expression changes during osteoclast differentiation. However, the upstream regulatory mechanisms that drive these metabolic changes in osteoclastogenesis remain to be elucidated. Here, we demonstrate that induced deletion of a tumor suppressor gene, Folliculin (Flcn), in mouse osteoclast precursors causes severe osteoporosis in 3 weeks through excess osteoclastogenesis. Flcn-deficient osteoclast precursors reveal cell autonomous accelerated osteoclastogenesis with increased sensitivity to receptor activator of NF-κB ligand (RANKL). We demonstrate that Flcn regulates oxidative phosphorylation and purine metabolism through suppression of nuclear localization of the transcription factor Tfe3, thereby inhibiting expression of its target gene Pgc1. Metabolome studies revealed that Flcn-deficient osteoclast precursors exhibit significant augmentation of oxidative phosphorylation and nucleotide production, resulting in an enhanced purinergic signaling loop that is composed of controlled ATP release and autocrine/paracrine purinergic receptor stimulation. Inhibition of this purinergic signaling loop efficiently blocks accelerated osteoclastogenesis in Flcn-deficient osteoclast precursors. Here, we demonstrate an essential and novel role of the Flcn-Tfe3-Pgc1 axis in osteoclastogenesis through the metabolic reprogramming of oxidative phosphorylation and purine metabolism. © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

Objective: The aim of this study is finding an optimal and convenient aging marker. Method: The information of participants’ occupation, family background, life style, physical condition, etc. was obtained by a self-administered questionnaire. Spot urine and saliva samples were collected during the early morning after fasting overnight. 8-hydroxydeoxygunaosine (8-OHdG), 8-iso-prostaglandin F2[Formula: see text] (8-isoPGF2[Formula: see text]), advanced oxidation protein products (AOPPs), malondialdehyde (MDA), and dehydroepian drosterone sulfate (DHEA-S) were measured by ELISA. Results: Around 112 non-smokers (males/females [Formula: see text] 61/51; mean age [Formula: see text] 44.9 years) were eligible and analyzed in this study. The mean urinary 8-OHdG level was [Formula: see text] (ng/mmol, creatinine) and mean 8-isoPGF2[Formula: see text] level was [Formula: see text] (pg/mmoL, creatinine). In saliva, the mean level of AOPPs, MDA, and DHEA-S was [Formula: see text] ([Formula: see text]mol/L), [Formula: see text] ([Formula: see text]mol/L) and [Formula: see text] (ng/mL), respectively. After analysis in multiple regression model, urinary 8-OHdG was influenced by age and tea consumption ([Formula: see text]); urinary 8-isoPGF2[Formula: see text] level was correlated with gender ([Formula: see text]); salivary DHEA-S was related to gender ([Formula: see text]) and marital status ([Formula: see text]); AOPPs and MDA in saliva presented no relationships with those factors. Conclusion: Among healthy non-smokers, urinary 8-OHdG is the best aging biomarker comparing to other markers.

Summary Pollen germination and pollen tube growth are important physiological processes of sexual reproduction of plants and also are involved in signal transduction. Our previous study reveals that ZmSTK1 and ZmSTK2 are two receptor‐like cytoplasmic kinases (RLCK) homologs in Zea mays as members of receptor‐like protein kinase (RLK) subfamily, sharing 86% identity at the amino acid level. Here, we report that ZmSTK1 and ZmSTK2, expressed at late stages of pollen development, regulate maize pollen development with additive effect. ZmSTK1 or ZmSTK2 mutation exhibited severe pollen transmission deficiency, which thus influenced pollen fertility. Moreover, the kinase domains of ZmSTKs were cross‐interacted with C‐terminus of enolases detected by co‐immunoprecipitation (Co‐IP) and yeast two‐hybrid system (Y2H), respectively. Further, the detective ZmSTK1 or ZmSTK2 was associated with decreased activity of enolases and also reduced downstream metabolite contents, which enolases are involved in glycolytic pathway, such as phosphoenolpyruvate (PEP), pyruvate, ADP/ATP, starch, glucose, sucrose and fructose. This study reveals that ZmSTK1 and ZmSTK2 regulate maize pollen development and indirectly participate in glycolytic pathway.

Stem cell-based therapy is considered a promising approach for the repair of nervous tissues. Neural stem cells (NSCs) cannot proliferate or differentiate efficiently; hence, different biomaterials have been explored to improve NSC proliferation and differentiation. However, these agents either had low bioavailability or poor biocompatibility. In this work, our group investigated the effects of tetrahedral DNA nanostructures (TDNs), a novel DNA biological material, on the self-renew and differentiation of neuroectodermal (NE-4C) stem cells. We observed that TDN treatment promoted self-renew of the stem cells via activating the Wnt/β -catenin pathway. In addition, our findings suggested that NE-4C stem cells' neuronal differentiation could be promoted effectively by TDNs via inhibiting the notch signaling pathway. In summary, this is the first report about the effects of TDNs on the proliferation and differentiation of NE-4C stem cells and the results demonstrate that TDNs have a great potential in nerve tissue regeneration.

Paclitaxel (PTX) is an effective drug against diseases such as lung cancer, ovarian cancer, and breast cancer. However, multidrug resistance limits the clinical applications of this drug. Tetrahedral DNA nanostructures (TDNs) offer great promise as a drug delivery candidate. In our study, we prepared TDNs that were subsequently loaded with PTX (PTX/TDNs). The cytotoxicity of PTX/TDNs and PTX alone on non-small cell lung cancer (NSCLC) cells (A549) and the PTX-resistant cell line (A549/T) was determined using a cell count kit-8 (CCK-8) assay. PTX/TDNs exerted strong lethality on both cell lines. Moreover, drug resistance was overcome. Furthermore, the mechanisms used by PTX/TDNs to overcome drug resistance were studied. The expression of mdr 1 gene and P-glycoprotein (P-gp) in A549/T was found to be downregulated, thus indicating that TDNs serve as a P-gp inhibitor. We also showed that PTX/TDNs killed cancer cells via apoptosis. Thus, PTX/TDNs have great potential for use as a nanodelivery system for the treatment of PTX-resistant NSCLC.

Bone tissue engineering emerges as an advantageous technique to achieve tissue regeneration. Its scaffolds must present excellent biomechanical properties, where bare polymers poorly perform. Development of new biomaterials with high osteogenic capacity is urgently pursued. In this study, an electrospun poly(3-hydroxybutyrate-co-4-hydroxybutyrate)/graphene oxide (P34HB/GO) nanofibrous scaffold is successfully fabricated and characterized. The effects of GO amount on scaffold morphology, biomechanical properties, and cellular behaviors are investigated. GO reduces the fiber diameter and enhances porosity, hydrophilicity, mechanical properties, cellular performance, and osteogenic differentiation of scaffolds. P34HB/GO triumphs over P34HB in in vivo bone regeneration in critical-sized calvarial defect of rats. We believe that this study is the first to evaluate the capability of in vivo bone repair of electrospun P34HB/GO scaffold. With facile fabrication process, favorable porous structures, enhanced biomechanical properties, and fast osteogenic capability, P34HB/GO scaffold holds practical potentials for bone tissue engineering application.

The aim of the present study was to investigate the synergistic antitumor effects of emodin and 3'‑azido‑3'‑deoxythymidine (AZT) on human chronic myeloid leukemia cells and to explore the possible underlying mechanisms. The K562 cells were treated with emodin and AZT, and the rates of cell inhibition and apoptosis were determined by MTT assay and flow cytometry, respectively. The mRNA expression of EGR1 was detected by reverse transcription‑polymerase chain reaction (RT‑PCR) analysis. The expression of EGR1 was silenced using siRNA, and then protein expression of β‑catenin was detected by western blotting. The results demonstrated that AZT enhanced the inhibitory effect of emodin in K562 cells. The IC50 of the emodin/AZT combination at 24, 48 or 72 h was 23.6/235.6, 10.2/101.6 or 5.9/58.5 µmol/l, respectively, which was significantly lower compared with the IC50 of emodin (all >32 µmol/l) or AZT (all >320 µmol/l) alone. There was a dose‑dependent response to the combined emodin and AZT treatment, and the calculation of the combination index yielded values

We investigated crude Aster tataricus, vinegar-processed Aster tataricus, honey-processed Aster tataricus, and steamed Aster tataricus as a case study and developed a comprehensive strategy integrating quantitative analysis and chemical pattern recognition methods for the evaluation and differentiation of Aster tataricus from different regions, as well as related processed products. In the study, 15 batches of raw Aster tataricus collected from seven provinces were analyzed. A sensitive and rapid ultra-high performance liquid chromatography with tandem mass spectrometry method for simultaneous determination of 15 compounds was established to evaluate the quality of raw and processed Aster tataricus. Furthermore, multivariate statistical techniques were applied to compare the differences among Aster tataricus samples. As a result, the herbs collected from seven provinces were divided into two categories, and chlorogenic acid was the most important component distinguishing between the regions. Moreover, all of the raw and processed samples were classified by partial least squares discriminant analysis based on the 15 analyzed compounds. Results showed that raw Aster tataricus, vinegar-processed Aster tataricus, honey-processed Aster tataricus, and steamed Aster tataricus were clustered in four different areas. Shionone, chlorogenic acid and kaempferol were the significant constituents differentiating the raw and differently processed Aster tataricus samples.

Objectives Pegaptanib might be a promising anti‐tumour drug targeting VEGF to inhibit tumour vascular endothelial cell proliferation. However, the poor biostability limited its application. In this study, we took tetrahedron DNA nanostructures (TDNs) as drug nanocarrier for pegaptanib to explore the potent anti‐angiogenesis and anti‐tumour activity of this drug delivery system. Materials and methods The successful synthesis of TDNs and pegaptanib‐TDNs was determined by 8% polyacrylamide gel electrophoresis (PAGE), capillary electrophoresis and dynamic light scattering (DLS). The cytotoxicity of pegaptanib alone and pegaptanib‐TDNs on HUVECs and Cal27 was evaluated by the cell count kit‐8 (CCK‐8) assay. The effect of pegaptanib and pegaptanib‐TDNs on proliferation, migration and tube formation of HUVECs induced by VEGF was examined by CCK‐8 assay, wound healing assay and tubule formation experiment. The cell binding capacity and serum stability were detected by flow cytometry and PAGE, respectively. Results Pegaptanib‐TDNs had stronger killing ability than pegaptanib alone, and the inhibiting effect was in a concentration‐dependent manner. What's more, pegaptanib‐loaded TDNs could effectively enhance the ability of pegaptanib to inhibit proliferation, migration and tube formation of HUVECs induced by VEGF. These might attribute to the stronger binding affinity to the cell membrane and greater serum stability of pegaptanib‐TDNs. Conclusions These results suggested that pegaptanib‐TDNs might be a novel strategy to improve anti‐angiogenesis and anti‐tumour ability of pegaptanib.

DNA nanotechnology is a new frontier in the field of tumor biotherapy. Simple DNA strands can be precisely constructed for integration into nanostructures of desired shapes and sizes, with excellent stability and biocompatibility. In this review, an account of the wide range of nanostructures composed of DNA sequences and related advances in oncotherapy using aptamers and chemical drugs is given. Functional ligands, including enzymes, antibodies, and agents, have been appended to DNA frameworks based on their external and internal modifiability. Hence, additional functionalities, such as immunogenicity and enzymatic activity, have been obtained, which extend their practical applications. Importantly, aptamers and drugs can be attached to or incorporated into the wireframes, bringing in highly selective targeting and killing abilities for the modified DNA nanostructures (DNs). In conclusion, distinct DNA sequences, various functional molecules, and different interactions and modifications lead to the diversity of DNs. Currently, one of the leading areas is their applications in tumor therapy. But beyond that, DNs should have much wider application prospects.

Non-small cell lung cancer (NSCLC) is one of the most lethal cancers worldwide. Inhibitor of differentiation 1 (Id1) is the member mostly linked to tumorigenesis in Id family and a potential molecular target in cancer therapy. In the current study, we established an orthotopic lung cancer model by injecting athymic nude mice with A549 cells and evaluated the antitumor effect of baicalein and expression of Id1-related proteins in vivo and in vitro. Micro-CT images showed that tumor volume in baicalein group was significantly reduced. Western blot analysis revealed that baicalein suppressed the expression of Id1 protein, epithelial-to-mesenchymal transition (EMT) related molecules (N-Cadherin, vimentin), and angiogenesis related protein (VEGF-A), accompanied by upregulation of epithelial markers (such as E-cadherin). In addition, phosphorylation of upstream molecular Src was significantly restrained after baicalein treatment. This study firstly demonstrates that baicalein inhibits tumor growth in orthotopic human NSCLC xenografts via targeting Src/Id1 pathway.

Due to the unique physiological and behavioral characteristics, children are easier to be exposed to environmental pollutants than general population. Children are more sensitive to chemical exposure as their organs are still developing and not yet mature. With the globalization of environmental pollution and the rapid economic growth, the exposure of low concentrations of heavy metals in children is increasingly a global health concern. In this chapter, we systematically review the exposure levels of heavy metals (such as lead, mercury, and cadmium, etc.) and their adverse effects on children’s nerve system, kidney, and bone development. As a result, clarifying the major health effects of heavy metals on children will be beneficial for controlling the body burden of heavy metals.

This study developed a method for simultaneous determination of 13 elements of Semen Cuscutae (quercitrin, quercetin, hyperoside, caffeic acid, chlorogenic acid, luteolin, apigenin, kaempferol, isoquercitrin, cryptochlorogenic acid, isorhamnetin-3-O-glucoside, astragalin, and rutin) in rat plasma using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) in the negative MRM mode. The analytes were analyzed with CORTECS®C18 column (4.6 × 150 mm, 2.7 μm) with mobile phases consisting of 0.1% formic acid in water (A) and acetonitrile (B). The intra- and interday precision of the target compounds were expressed as relative standard deviation (RSD) in the range of 0.5%–10.4%, and the accuracy of the target compounds was expressed as relative error (RE) not exceeding ±14.5% for all analytes. In the meantime, the extraction recovery of the target compounds in plasma samples ranged from 87.4% to 106.2% and matrix effect from 81.0% to 115.5%. The established method was successfully accomplished for the pharmacokinetic study of the analytes in rat plasma samples following oral administration of Semen Cuscutae extract, and the pharmacokinetic parameters of seven compounds were obtained.

Photosensitizers are crucial for photodynamic therapy. However, conventional photosensitizers have poor selectivity, and their targeted delivery by nanocarriers has become a major research focus. The aim of this study was to construct a targeted delivery system for new photosensitizers using aptamer-guided DNA tetrahedra. Mucin 1 protein is overexpressed in some cancer cells. The sequence of a Mucin 1 aptamer (MUC1) was linked to a DNA tetrahedron to form MUC1 aptamer-modified tetrahedral nanostructures (MUC1-TDNs) for the selective targeting of MUC1-positive tumor cells. The photosensitizer, TMPyP4, was loaded into MUC1-TDNs owing to the high affinity of TMPyP4 for DNA; consequently, a targeted photosensitizer delivery system (MUC1-TDNs-TMPyP4, MTT) was obtained. This system allowed for the selective delivery of TMPyP4 to MUC1-positive cancer cells. Moreover, MTT promoted the production of reactive oxygen species as well as cytotoxicity in MUC1-positive cells, while less killing effect were observed in MUC1-negative cells. We designed a MUC1-targeted delivery system of photosensitizers based on DNA tetrahedron, thus providing a new approach for the targeted release of photosensitizers.

Angiogenesis is a hallmark of cancer. However, most malignant solid tumors exhibit robust resistance to current anti-angiogenic therapies that primarily target VEGF pathways. As such, bevacizumab, a humanized anti-VEGF monoclonal antibody, fails to prolong the overall survival time in patients with newly diagnosed glioblastoma (GBM). Here, we show that endothelial mesenchymal transformation induces GBM resistance to anti-VEGF therapy by downregulating VEGFR-2 expression in tumor-associated endothelial cells (ECs). Analyzing human GBM tumor-derived ECs and mouse EC lineage-derived cells in a genetically engineered GBM model, we show that VEGFR-2 expression is markedly reduced in GBM-associated ECs. Transcriptome analysis by RNA-seq shows abrogated VEGFR2 expression in GBM ECs and reveals a robust genetic reprograming with increased mesenchymal gene expression in these ECs. Furthermore, we identify a PDGF/NF-κB/Snail axis that controls mesenchymal transformation and reduces VEGFR2 expression, which induces EC resistance to anti-VEGF treatment. Finally, dual inhibition of VEGFR and PDGFR eliminates tumor-associated ECs and improves animal survival in the genetic mouse GBM model. Notably, EC-specific knockout of PDGF receptor-β (PDGFR-β) sensitizes tumors to antibody-based VEGF-neutralizing treatment. Taken together, these findings reveal a previously unidentified mechanism for anti-angiogenic treatment resistance, namely, cell plasticity-driven endothelial unresponsiveness to anti-VEGF treatment, and suggest that vascular de-transformation may offer promising opportunities for anti-vascular therapy in GBM and possibly other malignant solid tumors.

With the incidence of different bone diseases increasing, effective therapies are needed that coordinate a combination of various technologies and biological materials. Bone tissue engineering has also been considered as a promising strategy to repair various bone defects. Therefore, different biological materials that can promote stem cell proliferation, migration, and osteoblastic differentiation to accelerate bone tissue regeneration and repair have also become the focus of research in multiple fields. Stem cell therapy, biomaterial scaffolds, and biological growth factors have shown potential for bone tissue engineering; however, off-target effects and cytotoxicity have limited their clinical use. The application of nucleic acids (deoxyribonucleic acid or ribonucleic acid) and nucleic acid analogs (peptide nucleic acids or locked nucleic acids), which are designed based on foreign genes or with special structures, can be taken up by target cells to exert different effects such as modulating protein expression, replacing a missing gene, or targeting specific gens or proteins. Due to some drawbacks, nucleic acids and nucleic acid analogs are combined with various delivery systems to exert enhanced effects, but current studies of these molecules have not yet satisfied clinical requirements. In-depth studies of nucleic acid or nucleic acid analog delivery systems have been performed, with a particular focus on bone tissue regeneration and repair. In this review, we mainly introduce delivery systems for nucleic acids and nucleic acid analogs and their applications in bone repair and regeneration. At the same time, the application of conventional scaffold materials for the delivery of nucleic acids and nucleic acid analogs is also discussed., Bone Regeneration: Nucleic acids and analogs in bone repair Used with an appropriate delivery system, nucleic acids and nucleic acid analogs have excellent potential for bone repair and regeneration. Owing to various challenges with bone tissue regeneration, current research is largely focused on gene therapy, which employs genes to treat or prevent disease, and such new materials as nucleic acids (DNA and RNA) and nucleic acid analogs (compounds structurally similar to naturally occurring nucleic acids). A team headed by Yunfeng Lin at Sichuan University, China conducted a review of delivery systems for nucleic acids and nucleic acid analogs and their application in bone repair and regeneration. The authors identified the use of biomaterial scaffolds (which mimic living tissue) as one of the most important research areas for gene therapy, and that strategy has proven effective with all types of bone regeneration and repair.

Angiogenesis is a hallmark of cancer. However, most malignant solid tumors exhibit robust resistance to current anti-angiogenic therapies that primarily target VEGF pathways. Here we report that endothelial-mesenchymal transformation induces glioblastoma (GBM) resistance to anti-angiogenic therapy by downregulating VEGFR-2 expression in tumor-associated endothelial cells (ECs). We show that VEGFR-2 expression is markedly reduced in human and mouse GBM ECs. Transcriptome analysis verifies reduced VEGFR-2 expression in ECs under GBM conditions and shows increased mesenchymal gene expression in these cells. Furthermore, we identify a PDGF/NF-κB/Snail axis that induces mesenchymal transformation and reduces VEGFR-2 expression in ECs. Finally, dual inhibition of VEGFR and PDGFR eliminates tumor-associated ECs and improves animal survival in GBM-bearing mice. Notably, EC-specific knockout of PDGFR-β sensitizes tumors to VEGF-neutralizing treatment. These findings reveal an endothelial plasticity-mediated mechanism that controls anti-angiogenic therapy resistance, and suggest that vascular de-transformation may offer promising opportunities for anti-vascular therapy in cancer., Resistance to anti-angiogenic therapies often occurs in patients. Here, the authors demonstrate the role of PDGF signaling in GBM resistance to anti-VEGF treatment via a mechanism that involves endothelial-mesenchymal transformation and transcriptional regulation of VEGFR-2.

One of the biggest obstacles for the use of antisense oligonucleotides as antibacterial therapeutics is their limited uptake by bacterial cells without a suitable carrier, especially in multi-drug-resistant bacteria with a drug efflux mechanism. Existing vectors, such as cell-penetrating peptides, are inefficient and nontargeting, and accordingly are not ideal carriers. A noncytotoxic tetrahedral DNA nanostructure (TDN) with a controllable conformation has been developed as a delivery vehicle for antisense oligonucleotides. In this study, antisense peptide nucleic acids (asPNAs) targeting a specific gene ( ftsZ) were efficiently transported into methicillin-resistant Staphylococcus aureus cells by TDNs, and the expression of ftsZ was successfully inhibited in an asPNA-concentration-dependent manner. The delivery system specifically targeted the intended gene. This novel delivery system provides a better platform for future applications of antisense antibacterial therapeutics and provides a basis for the development of a new type of antibacterial drug for multi-drug-resistant bacterial infections.

Objectives Aptamer sgc8c is a short DNA sequence that can target protein tyrosine kinase 7 (PTK7), which was overexpressed on many tumour cells. This study aimed to fabricate a novelty DNA nanostructure drug delivery system target on PTK7‐positive cells—CCRF‐CEM (human T‐cell ALL). Methods Aptamer‐modified tetrahedron DNA was synthesized through one‐step thermal annealing process. The sgc8c‐TDNs (s‐TDNs) loading DOX complexes were applied to investigate the effect to PTK7‐negative and ‐positive cells. Results When s‐TDN:DOX acted on PTK7‐positive and ‐negative cells respectively, the complexes exhibited specific toxic effect on PTK7‐positive cells but not on PTK7‐negative Ramos cells in vitro research. Conclusions In this work, we successfully constructed a PTK7‐targeting aptamer‐guided DNA tetrahedral nanostructure (s‐TDN) as a drug delivery system via a facile one‐pot synthesis method. The results showed that s‐TDN:DOX exhibited enhanced cytotoxicity against PTK7‐positive CCRF‐CEM cells, with a minor effect against PTK7‐negative Ramos cells. Hence, this functionalized TDNs drug delivery system displayed its potential application in targeting PTK7‐positive tumour T‐cell acute lymphoblastic leukaemia.

Real-time and continuous monitoring of drug release in vivo is an important task in pharmaceutical development. Here, we devoted to explore a real-time continuous study of the pharmacokinetics of free indocyanine green (ICG) and ICG loaded in the shell-sheddable nanoparticles in tumor based on a dynamic diffuse fluorescence tomography (DFT) system: A highly-sensitive dynamic DFT system of CT-scanning mode generates informative and instantaneous sampling datasets; An analysis procedure extracts the pharmacokinetic parameters from the reconstructed time curves of the mean ICG concentration in tumor, using the Gauss-Newton scheme based on two-compartment model. Compared with the pharmacokinetic parameters of free ICG in tumor, the ICG loaded in the shell-sheddable nanoparticles shows efficient accumulation in tumor. The results demonstrate our proposed dynamic-DFT can provide an integrated and continuous view of the drug delivery of the injected agents in different formulations, which is helpful for the development of diagnosis and therapy for tumors.

Objectives Human salivary adenoid cystic carcinoma (SACC) is one of the most common malignant tumours of the salivary gland and has strong migratory and invasive ability, which often lead to poor prognosis and lower survival rate. Tumour tissue tends to stiffen during solid tumour progression. This study aimed to investigate the influence of various substrate stiffness on the migration and invasion of SACC. Methods Salivary adenoid cystic carcinoma cell line ACC2 cells were cultured on polydimethylsiloxane substrates (PDMS) with varying stiffness for investigating the effects of substrate stiffness on the activities of MMPs and TIMPs. The underlying mechanism was also explored. Results When ACC2 cells were cultured on various stiffness of PDMS, the expressions of matrix metalloproteinases 2 (MMP2), MMP9, MMP14, RhoA, Rac1, Rho-associated protein kinase 1 (ROCK1) and ROCK2 were up-regulated with increasing substrate stiffness, whereas that of tissue inhibitor of matrix metalloproteinase 1 (TIMP1), TIMP2 and TIMP4 were down-regulated with increasing substrate stiffness. Conclusions Our results showed that substrate stiffness regulated the activities of MMPs and TIMPs and then modulate migratory and invasive ability of ACC2 cells via RhoA/ROCK pathway. This work indicate that matrix stiffness played an important role in progression of SACC, which not only can help understand the strong invasive ability of SACC, but also suggested that therapeutically targeting matrix stiffness may help reduce migration and invasion of SACC and improve effective therapies.

Cytotoxicity of β-Amyloid (Aβ) is a major contributor to the pathogenesis of Alzheimer's disease. Dexmedetomidine (Dex) has been revealed to have multiple neuroprotective actions as a clinical anesthetic agent. The aim of the present study was to investigate the protection of Dex against Aβ in neurons and astrocytes, and the possible protective mechanisms. Primary neurons and astrocytes were isolated respectively from the hippocampus and cerebral cortex of neonatal Sprague Dawley rats. The neurons and astrocytes were incubated with Aβ in the presence or absence of Dex, which was followed by evaluation of the cell viability and apoptosis. Reverse transcription‑quantitative polymerase chain reaction, western blotting and ELISA assays were performed to assess the levels of specific genes or proteins. The results revealed that Aβ decreased the viabilities of neurons and astrocytes in a dose‑dependent manner, and elevated the rate of apoptosis. However, Dex attenuated the detrimental effects of Aβ. Aβ caused deacetylation of histone H3 by promoting the accumulation of histone deacetylase (HDAC)‑2 and HDAC5 in the cell nucleus, resulting in the reduced production of brain‑derived neurotrophic factor (BDNF). However, Dex reversed the Aβ‑induced deacetylation of histone H3 and thus, increased BDNF production. Using a HDAC inhibitor or recombinant BDNF protein also protected the neurons and astrocytes against Aβ cytotoxicity. These results suggested that the protective effect of Dex against Aβ is particularly relevant to BDNF. Thus, the present study provides a foundation for the further study of Dex protection against Aβ in animal models and pre‑clinical researches.

A novel, efficient and reusable heterogeneous catalytic assembly of peroxophosphotungstate held in an ionic liquid brush was synthesized and an extraction and catalytic oxidative desulfurization (ECODS) procedure was developed for a model oil of benzothiophene (BT) and dibenzothiophene (DBT) using 30 wt% hydrogen peroxide as terminal oxidant and methanol as solvent under mild conditions. Several factors that affect sulfur removal were investigated in detail. The highest sulfur removal can reach 100% for BT in 7 h at 70 °C when the molar ratio of H2O2, S and catalyst is 10:1:0.025. The sulfur removal for DBT can also reach 100% in 4 h at 50 °C with the same molar ratio of H2O2, S and catalyst. The experimental results demonstrate that this ECODS process has no apparent scale-up effect. The catalyst can be easily recovered (via simple filtration) and recycled five times without a significant decrease in activity. Copyright © 2015 John Wiley & Sons, Ltd.

Dental pulp stem cells (DPSCs) derived from the human dental pulp tissue have multiple differentiation capabilities, such as osteo/odontogenic differentiation. Therefore, DPSCs are deemed as ideal stem cell sources for tissue regeneration. As new nanomaterials based on DNA, tetrahedral DNA nanostructures (TDNs) have tremendous potential for biomedical applications. Here, the authors aimed to explore the part played by TDNs in proliferation and osteo/odontogenic differentiation of DPSCs, and attempted to investigate if these cellular responses could be driven by activating the canonical Notch signaling pathway. Upon exposure to TDNs, proliferation and osteo/odontogenic differentiation of DPSCs were dramatically enhanced, accompanied by up regulation of Notch signaling. In general, our study suggested that TDNs can significantly promote proliferation and osteo/odontogenic differentiation of DPSCs, and this remarkable discovery can be applied in tissue engineering and regenerative medicine to develop a significant and novel method for bone and dental tissue regeneration.

This paper reports a systematic study of the Capillary number (Ca) effect on cell viability in Microfluidic Elasto-Filtration (MEF) devices for ex vivo circulating tumor cell (CTC) isolation. CTC viability decreases with increasing Ca because of the higher hydrodynamic shear stress. CTC viability also decreases with increasing cell diameter to filter-pore size ratio, d∗, due to the larger interaction forces between cells and filter pores. The cell viability dependence on Ca can be well fitted by two distinct functions for two ranges of d∗, larger and smaller than 2.5. Together with previously reported Ca effects on CTC capture efficiency and depletion of white blood cells, a complete design rule for MEF chips is proposed, yielding 92% CTC capture efficiency, 4-log WBC depletion, and 85% CTC viability at an optimized Ca∗.

Silver nanoparticles (AgNPs) are the most commonly used engineered nanomaterials in commercialized products because of their antimicrobial activity. Previously, we have shown that polyvinylpyrrolidone (PVP)-coated AgNPs have an anti-leukemia effect against human myeloid leukemia cells; however, whether AgNPs are able to trigger autophagy in normal hematopoietic cells and the role of autophagy in AgNP-induced cytotoxicity remain unclear. In the current study, we observed that AgNPs were taken up by murine pro-B cells (Ba/F3), and then promoted accumulation of autophagosomes, which resulted from the induction of autophagy rather than the blockade of autophagic flux. AgNPs induced cytotoxicity in a dose-dependent manner accompanied by apoptosis and DNA damage through the production of reactive oxygen species (ROS) and the release of silver ions. The ROS-mediated mTOR signaling pathway was responsible for the induction of autophagy. More importantly, the inhibition of autophagy with the addition of 3-methyladenine (3-MA) or silencing of Atg5 significantly attenuated the cytotoxicity of AgNPs in Ba/F3. These findings suggest that autophagy is involved in the cytotoxicity of PVP-coated AgNPs in normal hematopoietic cells, and the inhibition of autophagy is a novel and potent strategy to protect normal hematopoietic cells upon treatment with AgNPs.

Solid–liquid equilibrium in the ternary systems (Na2SO4 + NaH2PO4 + H2O) and (Na2SO4 + NaCl + H2O) at 313.15 K and atmospheric pressure was investigated by using isothermal solution saturation and moist residue method. The solubility and thermodynamic properties of the solution were determined. The phase diagrams and the diagrams of thermodynamic properties versus composition were constructed. It turned out that there was one invariant point, two uninvariant curves, and two crystallization regions. In the phase diagram of the ternary system (Na2SO4 + NaH2PO4 + H2O) at 313.15 K, the crystallization region of Na2SO4 was obviously larger than the NaH2PO4·2H2O crystalline region. When Na2SO4 was 11.57 wt % and NaH2PO4 was 44.41 wt %, this system reached saturation at 313.15 K. In the phase diagram of the ternary system (Na2SO4 + NaCl + H2O) at 313.15 K, the crystallization region of Na2SO4 was significantly larger than the crystallization region of NaCl. When NaCl was 22.56 wt % and Na2SO4 was 5.00 wt %, this...

Ingestion of the mushroom containing Amanita phalloides can induce fulminant liver failure and death. There are no specific antidotes. Blood purifications, such as molecular adsorbent recirculating system (MARS) and therapeutic plasma exchange (TPE), are potential therapies. However, the extent to which these technologies avert the deleterious effects of amatoxins remains controversial; the optimal intensity, duration, and initiation criteria have not been determined yet. This study aimed to retrospectively observe the effects of MARS and TPE on nine patients with A. phalloides-induced fulminant liver failure. The survival rate for the nine patients was 66.7%. Both TPE and MARS might remove toxins and improve liver functions. However, a single session of TPE produced immediately greater improvements in alanine aminotransferase (-60% vs. -16.3%), aspartate aminotransferase (-47.6% vs. -15.4%), and total bilirubin (-37.3% vs. -17.1%) (compared with the values of pretreatment, all p < 0.05) than MARS compared with MARS. Early intervention may be more effective than delayed therapy. Additionally, the presence of severe liver failure and renal failure indicated worse outcome. Although these findings are promising, additional case-controlled, randomized studies are required to confirm our results.

Wei Lu, Wenjuan Ma, Jiawei Lu, Xiao Li, Yun Zhao,* Gaojian Chen* ––––––––– W. Lu, J. Lu, X. Li, Prof. G. Chen Center for Soft Condensed Matter Physics and Interdisciplinary Research, Soochow University, Suzhou, 215006, P. R. ChinaCollege of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, P. R China E-mail: gchen@suda.edu.cn W. Ma, Prof. Y. Zhao Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, P. R. China E-mail: zhaoy@suda.edu.cn Wei Lu and Wenjuan Ma contributed equally in this work. ––––––––– Copolymers of 2-(methacrylamido)glucopyranose (MAG) and methacrylic acid (MAA) were synthesized by RAFT polymerization and then used as templates to prepare the glycopolymer-functionalized Ag nanoclusters (Gly-Ag NCs) through microwave irradiation. Polymers and the resulting nanoclusters were characterized by NMR, GPC, UV-Vis, SEM, TEM and fluorescence spectroscopy. The bio-activity of the fluorescent Gly-Ag NCs were further examined using GLUT-1 over-expressing cancer cells K562. Gly-Ag NCs showed efficient binding ability toward K562 cells and inhibited the cell viability in a dose dependent manner (IC50 = 0.65 μg/mL), indicating their potential biological applications for both cancer imaging and targeted cancer therapy.

One-pot system combining multi-reactions is used to synthesize novel porphyrin-glycopolymer conjugates. Sodium mercury amalgam is used to catalyze the reactions: 1) reduction of RAFT polymerized poly(2-(methacrylamido) glucopyranose) (PMAG), 2) converting protoporphyrin to protoporphyrinogen, 3) thiol-ene coupling reaction of PMAG and protoporphyrinogen. The product is oxidized in the same pot to generate the final porphyrin-PMAG conjugates. The resulting conjugates are characterized by NMR, GPC, UV-Vis, and fluorescence spectroscopy. Glycoparticles (≈ 200 nm) bearing glucose units are formed by dissolving the conjugates in water. Glycoparticles show enhanced binding ability toward Con A, bind K562 cells efficiently and kill these cells under light irradiation in dose and light treatment length dependent manners, illustrating the potential biological applications of the conjugates as photosensitizer for cancer imaging and photodynamic therapy.

An efficient and reusable heterogeneous catalytic assembly of PdCl2 held in ionic liquid brushes has been synthesized and an environmentally-friendly procedure was developed for coupling aryl iodides with acrylic acid. These reactions were conducted in water under aerobic conditions with water-insoluble or even solid aryl iodides and they proceeded smoothly and cleanly without any organic co-solvent or other additives. A 0.5 mol% (based on Pd atom) dose of the catalyst was found to be sufficient for Mizoroki–Heck reaction. The catalyst is easily recovered post reaction, via simple filtration, and reused at least eight times without a noticeable loss of activity. The protocol has the advantages of excellent yield, environmental friendliness, and catalyst recyclability. Copyright © 2011 John Wiley & Sons, Ltd.