Search

We report the direct asymmetric synthesis of pyrimido[2,1-b]benzothiazoles using a commercially available chiral amine catalyst. A variety of 2-benzothiazolimines and aldehydes were well tolerated under the reaction conditions and generated the corresponding products in 81-99% yields with excellent diastereoselectivities and enantioselectivities (up to >20:1 dr, 99% ee). Furthermore, the products could be easily converted to other useful chiral building blocks.

A one-pot efficient asymmetric domino annulation of 2-isothiocyanato-1-indanones with tert-butyl 2-hydroxybenzylidenecarbamates in situ generated from 2-hydroxyaryl-substituted α-amido sulfones was developed. This reaction firstly provided a powerful tool for the enantioselective construction of functionalized bridged fused ring hererocycles bearing three adjacent stereogenic centers in high yields with excellent diastereo- and enantioselectivities (up to 91% yield, >20 : 1 dr and 99% ee).

A series of copper thiospinels compounds, CuCo₂S_(4‐x)Se_x (x = 0, 0.2, 0.4, 0.6, 0.8), have been successfully synthesized by solid state reaction and their structure and magnetic properties have been studied. The Rietveld refinements of X‐Ray diffractions indicate that both the lattice constants and the nearest neighbor Cu‐Cu distances increase with increasing selenium doping. A weakly antiferromagnetic transition occurring at about 4 K is observed in CuCo₂S₄. Two antiferromagnetic transitions at about 3.5 K and 6 K are observed in selenium‐doped samples, which suggest that the exchange couplings associated with Cu‐S(Se)‐Cu and Cu‐Se(S)‐Cu, respectively, are responsible for the two antiferromagnetic transitions. Detailed analysis of the experimental results further indicate that the nearest‐neighbor molecular field coefficient is comparable to the next‐neighbor molecular field coefficient. We propose a reasonable model to explain this phenomenon.

Cisplatin is a widely used chemotherapeutic drug in lung cancer treatment. Most cancer patients eventually develop cisplatin resistance, resulting in a poor prognosis. Previously, we identified a novel marker, family with sequence similarity 60A (FAM60A), that was responsible for resistance in cisplatin-resistant human lung adenocarcinoma A549 (A549/DDP) cells. Here, we investigated the biological effects of FAM60A in A549/DDP cells and explored the underlying molecular mechanisms to understand its functional role in cisplatin resistance. Real-time quantitative PCR and western blot analysis were used to determine the expression levels of FAM60A in A549/DDP cells. FAM60A and SKP2 were knockdown with small-interfering RNA (siRNA). Cancer cell viability was analyzed with flow cytometry. The mRNA and protein expression levels of FAM60A increased significantly and dose-dependently in A549/DDP cells following cisplatin treatment. FAM60A overexpression up-regulated MDR1 expression, inhibited caspase 3, cleaved-caspase 3, and caspase 8 expression, and prevented cancer cell death. Microarray analysis of cells transfected with siRNA against the FAM60A transcript and control samples showed that SKP2 expression was positively regulated by FAM60A. SKP2 knockdown using a short-hairpin RNA reversed the functions induced by FAM60A. These results suggest that overexpression of FAM60A in A549/DDP cells led to SKP2 upregulation and enhanced cisplatin resistance in cancer cells. These provide new insights into chemoresistance and may contribute to reversing cisplatin resistance during lung cancer treatment.

An efficient asymmetric and enantio-swithchable organocatalytic [3 + 3] annulation reaction using MBH-2-naphthoates of nitroalkenes and 4-hydroxyquinolin-2(1H)-ones has been developed. Densely substituted tetrahydropyrano[3,2-c]quinolinones scaffolds with two adjacent stereogenic centers are obtained with high yield (up to 95% yield) and good stereoselectivities (up to >20:1 dr and 96% ee) in an enantio-switchable manner. Furthermore, gram scale synthesis was achieved and the nitro group could easily transform into an amino group without any appreciable loss in the diastereo- and enantioselectivity.

We describe herein the first asymmetric total synthesis and biological evaluation of the natural PDE4 inhibitor toddacoumalone and its stereoisomers. The key step of the total synthesis is a formal asymmetric [4 + 2] cycloaddition reaction catalyzed by chiral secondary amine catalysts. A variety of pyranoquinolinones and 3-methylcrotonaldehyde are well tolerated under the optimized reaction conditions, which paved the way for further SAR studies. Further biological evaluation showed 1a' with the best PDE4 inhibitory activity (IC50 = 0.18 μM).

Melatonin (MEL) has been demonstrated to exert a protective effect against subarachnoid hemorrhage (SAH), and nitric oxide (NO) has been shown to play an important role in the pathogenesis of vasospasm. This study aims to explore the underlying molecular mechanisms of MEL in the control of vasospasm following SAH. MEL administration attenuates SAH-induced vasospasm and neurobehavioral deficits. Expressions of H19, eNOS, and miR-675 are low in the SAH group, while expressions of miR-138 and HIF1α are high in the SAH group. Also, MEL treatment upon SAH rats completely restores the dysregulation of H19, eNOS, miR-675, miR-138, and HIF1α to their normal levels. Moreover, MEL dose dependently increases the luciferase activity of H19 promoter and hence the expression of H19. Additionally, H19 directly targets miR-675 and miR-138 to increase miR-675 expression and inhibit miR-138 expression. As virtual target genes of miR-675 and miR-138, respectively, HIF1α and eNOS are also regulated by the treatment with MEL. In particular, MEL treatment increases the expression of miR-675 and eNOS level while decreasing the expression of miR-138 and HIF1α in a dose dependent manner. Our study found that MEL ameliorates post-SAH vasospasm by regulating the expression of eNOS and HIF1α via the H19/miR-138/eNOS/NO and H19/miR-675/HIF1α signaling pathways.

A highly efficient cinchona alkaloid-derived squaramide catalysed asymmetric Michael/cyclization cascade reaction of 4-arylmethylidene-2,3-dioxopyrrolidines with 2-isothiocyanato-1-indanones was successfully developed. This protocol provides an efficient and mild access to indanone-derived spiropyrrolidone scaffolds containing three contiguous stereocenters with two spiroquaternary stereocenters in excellent yields (up to 99%) with high enantio- and diastereoselectivities (up to 99% ee and up to >20 : 1 dr). This method provides an economical and practical approach for the asymmetric synthesis of medicinally relevant molecules.

Chemical modification of a specific amino acid residue on peptides represents an efficient strategy to improve their pharmacokinetics and facilitates the potential to achieve post-synthetic diversification of peptides. Herein, we reported the first Pd-catalyzed late-stage ortho-olefination of Tyr residues on peptides with high chemo- and site-selectivity, by employing the easily attached and removable silanol as a bifunctional protecting group and directing group. Up to hexapeptides with variation on amino acid sequences or locations of the Tyr residue and different olefins were compatible with this protocol, which enriched the chemical toolbox for late-stage modification via C(sp2)–H functionalization. Furthermore, the orthogonal protection strategies of Tyr were also developed and could be applied to SPPS., Efficient Pd-catalyzed ortho-olefination of Tyr residues by employing silanol as a directing group with high chemo- and site-selectivity was developed. Orthogonal protection strategies were also successfully applied to SPPS.

Nickel–cobalt oxide has been given more attention to being used as the supercapacitor's electrode materials due to its two-dimensional layered structure, good electron conductivity, and excellent stability. In this work, NiCo2O4 nanosheets were successfully prepared by the simple solvothermal reaction and the thermal treatment process. Under the three-electrode system, it exhibits a maximum specific capacitance of 978 F/g at 1.5 A/g and good cycle stability. Meanwhile, a freestanding of partially reduced graphene oxides/carbon nanotubes (PRGO/CNTs) film was obtained by the vacuum filter and solvothermal methods, which can provide a wide potential window of − 1 ~ 0 V and a maximum specific capacitance of 236 F/g at 0.5 A/g. Finally, an asymmetric supercapacitor of PRGO/CNTs//NiCo2O4 was assembled, which exhibits good electrochemical performance, such as specific capacitance of 82 F/g at 0.5 A/g, energy density of 18.8 Wh/kg at 0.32 kW/kg, and 99.5% of capacitance retention after 5000 cycles at 5 A/g. This test results reveal that PRGO/CNTs//NiCo2O4 ASC has great potential for practical application in energy storage systems.

Comparative analyses are adopted to examine the influences of Cl− on the degradation of the film on Alloy 690TT in high-temperature water. According to the results of surface analyses and TEM, the composition and structure of the oxide film formed in a chloride solution are determined. Unlike the duplex layer oxide film formed on the sample in pure water, a thinner and monolayer Cr-rich oxide scale with several little corrosion pits on the surface is formed, which is closely related to the adsorption of Cl− ions due to their affinity to material surface and the selective dissolution of Ni-rich oxides.

The molecular of scaffold of thiazole orange has a number of merits for being as a fluorescent dye with tailor-made structure advancement for many useful applications. Structural modification based on 1-methylquinolinium moiety of thiazole orange is able to induce critical effects on fluorescent signal discrimination ability towards certain secondary or tertiary DNA structures. The electronic effect of the substituent on both molecular signaling and binding preference were investigated in the present study. We systematically compared the structural influence on the fluorescence signaling and binding preference towards nucleic acids in vitro through the addition of a number of substituent groups including p-methylstrylyl, p-hydroxylstyryl, p-chlorostyryl, p-bromostyryl, p-fluorostyryl, and (p-fluorobenzyl)-1,3-butadien-1-yl. The dyes synthesized were investigated with 19 nucleic acids for their interaction kinetics and fluorescent signal response with fluorescence titration experiments. The experimental results indicate that both the electronic effect and the molecular size of the dyes show significant influence on achieving higher binding affinity and fluorescent signal discrimination for G-quadruplex DNA. In addition, the dye with the introduction of a p-fluorostyryl substituent exhibits excellent linear relationship of the enhanced signal with respect to the concentration of telo21 DNA in vitro. The limit of detection (LOD) obtained was found to be 9 nM, which is much better than other analogues under the same conditions.

New fluorescent dyes derivatized on a classical thiazole orange framework are able to show unexpectedly strong interaction signal and unusual binding selectivity with different structures of nucleic acid, particularly when bound with double-stranded DNA or G-quadruplex DNA. The present study reveals that these small binding ligands simply bearing an additional amino side group on its parent molecule of thiazole orange have almost no background fluorescence in solution. Conversely, they are able to produce an extremely strong yellow emission signal upon interaction with targeting nucleic acids in live cells. The induced fluorescence intensity was approximately 10–15 times stronger than that of thiazole orange. The dyes are therefore excellent fluorescent stains for bio-sensing and bio-imaging applications. It is particularly suitable for fluorescence microscopy experiments requiring very low working concentration (0.25 μM or less) targeting nucleic acids. This was demonstrated using pu27 G-quadruplex DNA, which has a low limit of detection (LOD = 3–4 nM) while thiazole orange was much higher (LOD = 48.7 nM) under the same conditions. In addition, it was found that structural modification on the quinolinium scaffold of thiazole orange was less effective than modification on the benzothiazole moiety. The findings of the present study provide important information for structural advancement of small molecules based on the widely used thiazole orange skeleton, resulting in analogues that are able to achieve higher sensitivity and selectivity for targeting at a specific class of nucleic acids. Computational docking studies were also conducted to illustrate the interaction behaviors of the dyes with different DNA structures.

Summary: Anterior segment dysgenesis is often associated with cornea diseases, cataracts, and glaucoma. In the anterior segment, the ciliary body (CB) containing inner and outer ciliary epithelia (ICE and OCE) secretes aqueous humor that maintains intraocular pressure (IOP). However, CB development and function remain poorly understood. Here, this study shows that NOTCH signaling in the CB maintains the vitreous, IOP, and eye structures by regulating CB morphogenesis, aqueous humor secretion, and vitreous protein expression. Notch2 and Notch3 function via RBPJ in the CB to control ICE-OCE adhesion, CB morphogenesis, aqueous humor secretion, and protein expression, thus maintaining IOP and eye structures. Mechanistically, NOTCH signaling transcriptionally controls Nectin1 expression in the OCE to promote cell adhesion for driving CB morphogenesis and to directly stabilize Cx43 for controlling aqueous humor secretion. Finally, NOTCH signaling directly controls vitreous protein secretion in the ICE. Therefore, this study provides important insight into CB functions and involvement in eye diseases.

The catalytic asymmetric Mannich-type reaction of 3-hydroxy/3-aminooxindoles with 2-aminoacrylates to afford oxindole-derived acyclic amino acid derivatives bearing vicinal tetrasubstituted stereocenters is reported. (DHQ)

We report the first highly enantio- and diastereoselective three-component Povarov reaction between anilines and aldehydes catalyzed by a chiral amine catalyst. A wide variety of substituted tetrahydroquinolines were obtained with moderate to good yields and excellent enantioselectivity and diastereoselectivity (up to 99% ee and >95:5 dr) under the reaction conditions. Furthermore, the reaction intermediates could be efficiently converted to other valuable building blocks.

In this work, the hybrid nanostructures composed of Ni-Co hydroxide, reduced graphene oxide (rGO) and carbon nanotubes (CNTs) are successfully synthesized and used as a self-supported electrode for supercapacitors. It is found that the hybrid shows a big capacity of 1093 F g−1, excellent rate capability, and superior cycle life (100% capacity maintain after 5000 cycles). One asymmetric supercapacitor (ASC) is developed using Ni-Co hydroxide/rGO/CNTs as positive material and active carbon as negative material. This ASC displays a maximum energy density of 34.7 Wh kg−1 at a high power density of 1.55 kW kg−1 and still keeps 20.7 Wh kg−1 at 15.5 kW kg−1. Moreover, it displays remarkable cycle life with 112.8% capacity retention after 10000 cycles. Such asymmetric supercapacitor demonstrates great potential for practical application in energy storage devices.

Vanadium oxides (V2O5) have been intensely investigated for advanced supercapacitors due to its extensive multifunctional properties of typical layered structure and multiple stable oxide states of vanadium in its oxides. In this study, V2O5 nanosheets are synthesized via V2O5 xerogel solvothermal reaction in ethanol solvent at 200 °C for 12 h. The V2O5 nanosheets facilitate the easy accessibility of ions and can provide more area available for electrochemical reactions. We have achieved the highest specific capacitance of 298 F/g and good rate discharge for V2O5 electrodes. Notably, the capacitance still retains a high retention rate of 85% after 10,000 cycles at 200 mV/s. Furthermore, asymmetric supercapacitors is assembled based on V2O5 nanosheets and active carbon electrode, and a specific capacitance of 13.2 F/g is obtained at 1 A/g, with a energy density of 4.7 Wh/kg at a power density of 0.798 kW/kg and remains 2.28 Wh/kg at 7.992 kW/kg. Based on these results, the asymmetric supercapacitor exhibits a good cycle life with 77.3% capacitance retention after 3000 cycles. It suggests that the V2O5 nanosheets are promising electrode material for electrochemical supercapacitors.

Purpose To investigate the effect of body position on intraocular pressure (IOP) in silicone oil tamponade eyes. Methods This prospective study included 18 eyes from 18 silicone oil tamponade patients and 24 eyes from 24 healthy subjects. Intraocular pressures were measured by Accupen Applanation Tonometer sitting with face forward, sitting with face down, supine, nondependent lateral decubitus, dependent lateral decubitus, and prone positions. The IOPs in each position and the magnitudes of IOP change were compared between the silicone oil and normal groups. Results In both groups, the IOPs in sitting positions were significantly lower than that of each recumbent position. The IOPs were highest in prone among all positions. No significant difference was found between IOPs of each group in each position. Between both groups, the IOP elevations in each position had no statistical difference compared with sitting with face forward. Conclusion The IOP is lowest in the sitting position and highest in the prone position in both silicone oil and normal groups. Between both groups, the amount of IOP elevations is equivalent in each position compared with sitting with face forward. Ophthalmologists should be aware that IOP is higher in the prone position and that it should be monitored accordingly.

Paclitaxel is widely used in the combination chemotherapy for many cancers including esophageal squamous cell carcinoma (ESCC). However, the paclitaxel resistance occurs frequently in treating ESCC and the mechanism is not fully understood yet. The heterogeneity of gene expression within the drug-resistant cancer cells may be one of the major factors contributing to its resistance. In the present study, we successfully induced paclitaxel resistance in ESCC cell line KYSE-30 through low dose and long-term treatment of paclitaxel. Gene expression profiles were measured utilizing population RNA-seq and single-cell RNA-seq (scRNA-seq). 37 single cells from KYSE-30 cells and 73 single cells from paclitaxel resistant KYSE-30 cells (Taxol-R) were subjected to scRNA-seq. Weighted gene co-expression network analysis (WGCNA) of scRNA-seq data revealed two major subpopulations in both KYSE-30 and Taxol-R cancer cells. Two subpopulations based on the KRT19 expression levels in KYSE-30 cells exhibited different paclitaxel sensitivity, suggesting the existence of an intrinsic paclitaxel resistance in KYSE-30 cells. In addition, the Taxol-R cells that acquired the resistance to paclitaxel through induction were characterized with higher expressions of proteasomes but a lower expression of HIF-1 signaling genes. Furthermore, we showed that carfilzomib (CFZ), a proteasome inhibitor, could attenuate the paclitaxel resistance in Taxol-R cancer cells through activating the HIF-1 signaling. Our new finding may pave a way leading to an improvement in the treatment on cancers including ESCC by combining CFZ with paclitaxel as a novel approach for cancer therapy.

The chemical compositions, phases and structures of two oxide films on Alloy 690TT following exposure for 4400 h in pure water with and without lead at 320 °C were studied by surface analysis techniques. The analysis of a lead-doped oxide film prepared by a focused ion beam (FIB) demonstrated that both Cr-rich and Ni-rich oxides were alternatively distributed within the outer layer, whereas the inner layer was porous and poorly protected, causing severe corrosion of the alloy and a thicker film was formed. A duplex film model was proposed for the effects discussion of lead on the oxidation mechanism.

Thiazole orange (TO) stains most nucleic acids giving strong fluorescence signal non-specifically. To resolve the poor discriminating ability of TO among tertiary structures of DNAs, a planar and rotatable π–conjugated small molecule designed by replacing the methylene bridge with an ethylene that slightly increases its structural flexibility, while maintain the crucial conjugated co-planar two-ring system. The study addressed the origin of signal discrimination for the molecule upon binding with different DNA structures and the results demonstrate that the molecule exhibits excellent fluorescence signal discrimination between the DNA G-quadruplexes and other DNA tertiary structures. In a typical staining assay, the molecule induced 30-fold greater fluorescence signal upon binding with Pu27 than that of ssDNA and dsDNA. Molecular modelling studies also support that the flexible ethylene bridge between the two-ring system is the crucial factor for inducing selectivity towards G-quadruplexes. Furthermore, the selectivity, sensitivity, and stability of the molecule were investigated with various techniques. The application of the molecule as a selective staining agent for imaging of G-quadruplex in human prostate cancer cells PC3 and mouse fibroblast L929 was also investigated. The strongly observed green fluorescence signal in the cell nucleus suggests that the molecule is able to enter into the nucleus and then binding with G-quadruplexes.

Brassinosteroid insensitive 1 (BRI1) is a multidomain plant leucine-rich repeat receptor-like kinase (LRR-RLK), belongs to the LRR X subfamily. BRI1 perceives plant hormone brassinosteroids (BRs) through its extracellular domain that constitutes of LRRs interrupted by a 70 amino acid residue island domain (ID), which activates the kinase domain (KD) in its intracellular domain to trigger BR response. Thus, the KD and the ID of BRI1 are highly conserved and greatly contribute to BR functions. In fact, most bri1 mutants are clustered in or surrounded around the ID and the KD. However, the role of the less conserved LRR domains, particularly the first few LRRs after the signal peptide, is elusive. Here, we report the identification of a loss-of-function mutant bri1-235 that carries a mutation in the less conserved fourth LRR of BRI1 extracellular domain in Arabidopsis. This mutant had a base alteration from C to T, resulting in an amino acid substitution from serine to phenylalanine at the 156th position of BRI1. Compared with the wild-type plants, bri1-235 exhibited round leaves, prolonged life span, shorter stature, and approximately normal fertility under light conditions. The bri1-235 mutant was less sensitive to exogenous brassinolide under normal conditions. Importantly, both wild-type BRI1 expression and a sbi1 mutant that activates BRI1 rescued bri1-235 and resembled the wild type. Furthermore, bri1-235 protein was localized in endoplasmic reticulum rather than plasma membrane, suggestive of a cause for reducing BR sensitive in bri1-235. Taken together, our findings provide an insight into the role of the less conserved LRRs of BRI1, shedding light on the role of LRRs in a variety of LRR-RLKs that control numerous processes of plant growth, development, and stress response.

Anterior segment dysgenesis is often associated with cornea diseases, cataracts and glaucoma. The ciliary body (CB) is a part of the anterior segment that secretes aqueous and vitreous humor that nourishes the eye. Although defective Notch signaling in the CB disrupts CB morphogenesis and causes eye degeneration, the underlying mechanisms remain missing. Here, this study shows that NOTCH signaling controls CB morphogenesis by directly regulating Nectin1 expression, and maintains the vitreous and eye structures by regulating the expression of vitreous proteins and gap junction protein Cx43. Genetic inactivation of Rbpj or both Notch2 and Notch3 in the CB not only disrupts CB morphogenesis but also causes CB epithelial detachment and vitreous shrinkage in the developing eye, and eye degeneration in adults. Molecularly, NOTCH signaling transcriptionally controls the expression of adhesion protein Nectin1 known to be essential for CB morphogenesis, and controls eye pressure and the vitreous through stabilizing gap junction protein Cx43 known to be important for CB secretion. Mechanistically, Nectin1 directly binds and stabilizes Cx43. Finally, NOTCH signaling in the CB also directly controls the expression of vitreous proteins. Therefore, this study has provided important mechanistic insight into how NOTCH signaling controls CB morphogenesis and secretion, and also further suggests the potential involvement of CB secretion in various eye diseases, including retinal degeneration.

Background Previous real-world comparative research of MS disease modifying therapies (DMTs) in the overall population has suggested dimethyl fumarate (DMF) to be comparable to fingolimod (FTY) and more efficacious than teriflunomide (TERI) in reducing relapses. However, there is limited comparative evidence in patients switching from platform DMTs in the US. The objective of the study was to compare the annualized relapse rate (ARR) and risk of relapse in MS patients who have switched from a platform therapy to DMF, FTY, or TERI. Methods MS patients (18–65 years old) initiating an oral DMT from June 2013 to March 2015 were identified from the Truven MarketScan® Commercial Claims Database. The index date was the date of first oral DMT fill. Patients were required to have: continuous enrollment in the database for 12 months pre-index date and ≥3 months post-index date; ≥1 MS diagnosis over the pre-index period; discontinuation of a platform DMT with no evidence of oral or infusion DMTs over the pre-index period; and adherence to the index drug for ≥90 days. DMF patients were propensity-score matched (PSM) 3:1 to FTY and to TERI based on age, gender, region, a claims-based MS severity measure, ARR, and number of hospitalizations over the pre-index period. Patients were censored when they dropped out of the database or at the end of the study period (March 31, 2016). Post-index relapses were annualized. Results The database included 20,311 oral DMT users. After applying the study criteria, the PSM yielded 1602:534 switch patients for the DMF–FTY matched cohort. DMF–FTY patients were well-matched on all covariates: age (mean = 44 for both), gender (28% vs. 26% male, respectively), MS severity measure (0.99 vs. 1.08), and baseline ARR (0.40 vs. 0.44). PSM yielded 833:279 switch patients for the DMF–TERI match. DMF–TERI patients were well-matched on all covariates: age (mean = 50), gender (24% vs. 25% male), MS severity measure (0.86 vs. 0.99), and baseline ARR (0.23 vs. 0.30). The standardized differences confirmed balance across all covariates for matched cohorts. The matched DMF–FTY cohorts had comparable post-index ARR (Rate Ratio [RR] = 1.07 [95% Cl: 0.861, 1.328]) and risk of relapse (Hazard Ratio [HR ]= 0.996 [95% CI: 0.803, 1.236]). Post-index ARR was significantly lower with DMF in comparison to TERI (RR = 0.667 [0.486, 0.914]). The risk of relapse was also significantly lower when switching to DMF than TERI (HR = 0.679 [0.503, 0.917]). Conclusion In this analysis, the effectiveness profiles for those oral DMT users specifically switching from platform therapies are consistent with findings from previous research conducted among all oral DMT users, regardless of prior therapy.

The present study investigated the effects of nicorandil on cerebral injury following cardiopulmonary resuscitation (CPR) in a swine model of cardiac arrest. CPR was performed on swine following 4 min induced ventricular fibrillation. Surviving animals were randomly divided into 3 groups: A nicorandil group (n=8), a control group (n=8) and a sham group (n=4). The sham group underwent the same surgical procedure to imitate cardiac arrest, but ventricular fibrillation was not induced. When the earliest observable return of spontaneous circulation (ROSC) was detected, the nicorandil and control groups received injections of nicorandil and saline, respectively. Swine serum was collected at baseline and 5 min, 0.5, 3 and 6 h following ROSC. Serum levels of neuron-specific enolase (NSE), S100β, tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) were measured using ELISA. Animals were euthanized and brain tissue samples were collected and assessed using light and electron microscopy 6 h following ROSC. The expression of aquaporin-4 (AQP-4) in the brain tissue was measured using western blotting. Malondialdehyde (MDA) and glutathione (GSH) levels in the brain tissue were determined using thiobarbituric acid and thiobenzoic acid colorimetric methods, respectively. Serum NSE and S100β were significantly higher in the nicorandil and control groups following CPR, compared with baseline (P

Psoriasis is an autoimmune disease involving the excessive proliferation of keratinocytes mediated by T-cells. Parathyroid hormone (PTH) has been identified as an essential factor in the treatment of psoriasis. In the present study, the mechanism underlying the effect of recombinant human parathyroid hormone (rhPTH) (1-34) in keratinocytes was investigated. The effects of rhPTH (1-34) on cell proliferation, cell cycle, and the secretion and expression of C-X-C motif chemokine 11 (CXCL11) and components of the Hedgehog signaling pathway were examined in HaCaT cells by MTT assay, flow cytometric analysis, ELISA and gene chip analysis. The data showed that rhPTH (1-34) significantly inhibited keratinocyte proliferation at concentrations >8×10−7 mol/l. rhPTH (1-34) induced G1 phase arrest of the cell cycle in the keratinocytes. The secretion of CXCL11 in tumor necrosis factor (TNF)-α-induced keratinocytes was downregulated by rhPTH (1-34) in a dose-dependent manner, compared with that in keratinocytes treated with TNF-α alone. It was also found that rhPTH (1-34) inhibited the expression of CXCL11 in the HaCaT cells. rhPTH (1-34) also affected the Hedgehog signaling pathway specifically by regulating the expression of associated genes. In conclusion, these data suggested that rhPTH (1-34) inhibited cell proliferation, and the secretion and expression of CXCL11 in HaCaTs. rhPTH (1-34) also altered the expression of associated genes in the Hedgehog pathway. Therefore, rhPTH (1-34) can be considered as a novel therapeutic agent for the treatment of psoriasis.

Curcumin is a potent anti-cancer drug in several types of human cancers. Despite of several preclinical and clinical studies of curcumin, the precise mechanism of curcumin in cancer prevention has remained unclear. In our study, we for the first time investigated whole transcriptome alteration in A549 non–small cell lung cancer (NSCLC) cell lines after treatment with curcumin using RNA sequencing. We found that lots of genes and signaling pathways were significantly altered after curcumin treatment in A549 cells. With bioinformatics approaches (gene ontology, Kyoto Encyclopedia of Genes and Genomes, and STRING), we found that those curcumin altered genes were not only the genes that induce cell death but also those extracellular matrix receptors and mitogen-activated protein kinase signaling pathway genes which regulate cell migration and proliferation. Among those significantly altered genes, eight genes ( COL1A1, COL4A1, COL5A1, LAMA5, ITGA3, ITGA2B, DDIT3 , and DUSP1 ) were further examined by quantitative reverse transcription polymerase chain reaction and western blot analysis in four non–small cell lung cancer cell lines. Both in cell lines and in mouse model, the extracellular matrix receptors including the integrin ( ITGA3 and ITGA2B ), collagen ( COL5A1 ), and laminin ( LAMA5 ) were significantly inhibited by curcumin at messenger RNA and protein levels. Functional studies confirmed that curcumin not only induced A549 cell death but also repressed cell proliferation and migration by regulating extracellular matrix receptors. Collectively, our study suggests that curcumin may be used as a promising drug candidate for intervening lung cancer in future studies.

Fatty acid binding protein 3 (H-FABP, FABP3) has been significantly associated with intramuscular fat (IMF) content in pigs, which is positively correlated with palatability of pork. However, its underlying function is not fully elucidated. We have investigated the effects of overexpression of the FABP3 gene on differentiation and adipogenesis of 3T3-L1 preadipocytes in the fat Banna mini-pig inbred line (fBMIL). Eukaryotic vectors that expressed the FABP3 protein were constructed, and stably established in the 3T3-L1 preadipocytes cell line. Cells were induced in a standard differentiation cocktail. Morphological changes and the degree of adipogenesis were measured by Oil Red O staining assay and triacylglycerol content measurement, respectively. mRNA expression levels of triacylglycerol metabolism-related genes were measured by qPCR. FABP3 significantly promoted differentiation of 3T3-L1 cells and enhanced triacylglycerol levels (P < 0.05). mRNA of the peroxisome proliferator-activated receptor γ (PPARγ), adipocyte fatty acid binding protein (422/aP2) and glycerol-3-phosphate dehydrogenase (GPDH) gene increased markedly (P < 0.05). In conclusion, expression of the FABP3 gene enhances adipogenesis in 3T3-L1 preadipocytes primarily by upregulating lipogenic PPARγ, 422/aP2 and GPDH genes.

In this study, uniform MoS2 nanosheets assembling three-dimensional (3D) nanospheres (MoS2 NPs) are developed via a facile hydrothermal procedure with silica (SiO2) nanospheres as a template. The MoS2 NPs catalyst exhibits high hydrogen evolution reaction (HER) performance with low onset overpotential of 87.0 mV, and small Tafel slope of 48.8 mV dec−1, which also exhibits excellent stability even after 30 h potential cycles. The superior HER activity is attributed to the unique 3D hierarchical structure, which provides enriched active edge sites and excellent electrical transport.

Multi-arc ion plating technique was used to fabricate TiN film on the surface of high speed steel (HSS) to improve its wear resistance. The structure and morphology of TiN film were analyzed by XRD and SEM,and the bonding strength between the film and substrate was studied by the scratch tester. The results show that the thin film formed on the surface of the substrate consists of compact TiN. There are some white spots and black spots on the surface of the film. The bonding strength between the film and the substrate reaches 43 N/mm2, which correlates to formation of a pseudo diffusion layer. The tribological experimental results show that plating TiN film can greatly improve wear resistance of HSS.

We investigated whether pancreatitis-associated ascitic fluid (PAAF) could induce the expression of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) in THP-1 cells and the mechanism(s) involved.THP-1 cells were divided into control and PAAF groups. The PAAF group was incubated with different final concentrations of PAAF, whereas the control group was incubated with culture medium. Effects and mechanisms were determined by measuring the levels of TNF-α and IL-6 mRNA expression; phospho-p38-MAPK, nuclear factor κB, peroxisome proliferator-activated receptor γ activation; and the effect on the inhibitory activity of SB203580 and BAY-117082.In response to PAAF, overexpression of TNF-α and IL-6 mRNA was found in THP-1 cells compared with those of the corresponding control (P0.05), and in a dose-dependent manner. The levels of phospho-p38 and nuclear factor κB p65 were also increased in different PAAF groups, whereas low expression of peroxisome proliferator-activated receptor γ was found compared with the control group (P0.05). Furthermore, we presented that the inflammatory response could be partly alleviated by inhibitors SB203580 or BAY-117082, whereas it was markedly inhibited by the simultaneous treatment of 2 inhibitors.Pancreatitis-associated ascitic fluid up-regulated proinflammatory cytokines by interfering with proinflammatory and anti-inflammatory signaling pathways, thus exacerbating activation in acute pancreatitis.

A high-performance liquid chromatography (HPLC) technique was developed for the determination of arctigenin in plasma and various organs of rats after the oral administration of 30, 50 and 70 mgkg(-1) of arctigenin to the Sprague-Dawley rats. Results showed that the validated HPLC method was simple, fast, reproducible and suitable to the determination of arctigenin in rat plasma and organ tissue and one-compartmental model with zero-order absorption process can well describe the changes of arctigenin concentration in the plasma. The concentration of compound was highest in the spleen, less in the liver and the least in the lung.

In order to reveal the influence of oxidization on the properties of AlF3films, single layers of AlF3were deposited at different substrate temperature by thermo evaporation technique with or without oxygen injected into the coating chamber. The chemical composition, total stress, optical properties and laser damage resistance of samples were characterized. Comparative study indicates the AlF3films prepared under higher oxygen pressure have more oxides which result from hydration process in atmosphere. The presence of oxides also reduces total stress and optical absorption of the fluoride coatings.

G-quadruplexes are higher-order DNA and RNA structures formed from guanine-rich sequences. These structures have recently emerged as a new class of potential molecular targets for anticancer drugs. An understanding of the three-dimensional interactions between small molecular ligands and their G-quadruplex targets in solution is crucial for rational drug design and the effective optimization of G-quadruplex ligands. Thus far, rational ligand design has been focused mainly on the G-quartet platform. It should be noted that small molecules can also bind to loop nucleotides, as observed in crystallography studies. Hence, it would be interesting to elucidate the mechanism underlying how ligands in distinct binding modes influence the flexibility of G-quadruplex. In the present study, based on a crystal structure analysis, the models of a tetra-substituted naphthalene diimide ligand bound to a telomeric G-quadruplex with different modes were built and simulated with a molecular dynamics simulation method. Based on a series of computational analyses, the structures, dynamics, and interactions of ligand-quadruplex complexes were studied. Our results suggest that the binding of the ligand to the loop is viable in aqueous solutions but dependent on the particular arrangement of the loop. The binding of the ligand to the loop enhances the flexibility of the G-quadruplex, while the binding of the ligand simultaneously to both the quartet and the loop diminishes its flexibility. These results add to our understanding of the effect of a ligand with different binding modes on G-quadruplex flexibility. Such an understanding will aid in the rational design of more selective and effective G-quadruplex binding ligands.

The pathology of proliferative vitreoretinopathy and proliferative diabetic retinopathy is linked to proliferation, migration, and adhesion of the retinal pigment epithelium. MicroRNA-34a (miR-34a) expression modulates changes in proliferation and migration of retinal pigment epithelial cell line ARPE-19. In this study, we determined that miR-34a interacts with LGR4, identified by bioinformatics using TargetScan Human 5.0, to affect these changes. Double luciferase gene reporter assay confirmed miR-34a involvement in mediating control. miR-34a mimic transfection decreased LGR4 expression. Western blot analysis documented corresponding protein expression inhibition. MTS, Ki67 immunostaining, scratch and transwell testing, along with attachment assay showed that miR-34a upregulation inhibited ARPE-19 cell proliferation, migration and attachment partly through downregulation of LGR4 protein expression. Western blot analysis revealed that both miR-34a upregulation and LGR4 downregulation induced declines in E2F1, p-CDC2, CDK2, CDK4 and CDK6 protein expression. Taken together, miR-34a gene expression upregulation inhibits ARPE-19 cell proliferation, migration and adhesion partly by suppressing LGR4 expression. These results substantiate earlier indications that both miR-34a and LGR4 are potential drug targets to prevent fibrosis in a clinical setting.

The universal fluorescent staining property of thiazole orange (TO) dye was adapted in order to be specific for G-quadruplex DNA structures, through the introduction of a styrene-like substituent at the ortho-position of the TO scaffold. This extraordinary outcome was determined from experimental studies and further explored through molecular docking studies. The molecular docking studies help understand how such a small substituent leads to remarkable fluorescent signal discrimination between G-quadruplex DNA and other types of nucleic acids. The results reveal that the modified dyes bind to the G-quadruplex or duplex DNA in a similar fashion as TO, but exhibit either enhanced or quenched fluorescent signal, which is determined by the spatial length and orientation of the substituent and has never been known. The new fluorescent dye modified with a p-(dimethylamino)styryl substituent offers 10-fold more selectivity toward telomeric G-quadruplexes than double-stranded DNA substrates. In addition, native PAGE experiments, FRET, CD analysis, and live cell imaging were also studied and demonstrated the potential applications of this class of thiazole-orange-based fluorescent probes in bioassays and cell imaging.

The rapid and convenient method for identification of all kinds of G-quadruplex is highly desirable. In the present study, a novel colorimetric indicator for a vast variety of G-quadruplex was designed and synthesized on the basis of thiazole orange and isaindigotone skeleton. Its distinct color change enables label-free visual detection of G-quadruplexes, which is due to the disassembly of dye H-aggregates to monomers. This specific detection of G-quadruplex arises from its end-stacking interaction with G-quartet. On the basis of this universal indicator, a facile approach for large-scale identification of G-quadruplex was developed.

A series of isaindigotone derivatives and analogues were designed, synthesized and evaluated as dual inhibitors of cholinesterases (ChEs) and self-induced β-amyloid (Aβ) aggregation. The synthetic compounds had IC50 values at micro or nano molar range for cholinesterase inhibition, and some compounds exhibited strong inhibitory activity for AChE and high selectivity for AChE over BuChE, which were much better than the isaindigotone derivatives previously reported by our group. Most of these compounds showed higher self-induced Aβ aggregation inhibitory activity than a reference compound curcumin. The structure–activity relationship studies revealed that the derivatives with higher inhibition activity on AChE also showed higher selectivity for AChE over BuChE. Compound 6c exhibiting excellent inhibition for both AChE and self-induced Aβ aggregation was further studied using CD, EM, molecular docking and kinetics.

Anisotropic wet etching is a key processing step for the fabrication of microstructures. In general, convex corner structures and non {111} crystal planes will be undercut during wet anisotropic etching. This characteristic of Si is an obstacle to the fabrication of structures in various applications. Among a number of silicon etchants, TMAH is becoming popular for low toxicity and CMOS compatibility. In this paper, a new design of compensation structure has been proposed to solve the undercutting problem with 25%wt TMAH solution. The new compensation structure is made up by squares which are connected to the convex corner. An empirical expression between the parameters of the new compensation structure and etching depth is derived. The changes of the compensation structure in different etching process are shown by photographs. Experimental results prove the high accuracy of this method. Compared to two widely used compensation structures, the new structure is more space efficient.

A series of quinolino-benzo-[5, 6]-dihydroisoquindolium compounds (3a, 3f, 3g, and 3j) derived from alkaloid berberine were designed and synthesized as novel G-quadruplex ligands. Subsequent biophysical and biochemical evaluation demonstrated that the addition of pyridine ring and amino group into berberine improved the binding ability and selectivity towards G-quadruplex DNA in comparison with the previously reported 9-N-substituted berberine derivatives. Furthermore, qRT-PCR assay showed compound 3j led the down-regulation of c-myc gene transcription in leukemia cell line HL60, while little effect on normal cell line ECV-304, which was consistent with the behavior of an effective G-quadruplex ligand targeting c-myc oncogene.

Quindoline derivatives as telomeric quadruplex ligands have shown good biological activity for telomerase inhibition. In the present study, we used spectroscopic and calorimetric methods to investigate the interactions between a quindoline derivative (5-methyl-11-(2-morpholinoethylamino)-10-H-indolo-[3,2-b]quinolin-5-ium iodide, compound 1) and human telomeric G-quadruplex. The thermodynamic studies using isothermal titration calorimetry (ITC) indicated that their binding process was temperature-dependent and enthalpy-entropy co-driven. The significant negative heat capacity was obtained experimentally from the temperature dependence of enthalpy changes, which was consistent with that from theoretical calculation, and all suggesting significant hydrophobic contribution to the molecular recognition process. Based on the results from UV-vis, ITC, steady-state and time-resolved fluorescence, their binding mode was determined as two ligand molecules stacking on the quartets on both ends of the quadruplex. These results shed light on rational design and development of quindoline derivatives as G-quadruplex binding ligands.

G-quadruplexes are higher-order DNA and RNA structures formed from guanine-rich sequences, and they are attractive anticancer drug targets. Understanding the three-dimensional interactions between a G-quadruplex and its ligand in solution is the key to discovering a drug lead. Hence, from crystallographic or NMR structures, molecular dynamics studies have been performed on six ligand-quadruplex complexes. BRACO-19, BSU6039, daunomycin, RHPS4, MMQ1, and TMPyP4 are the six ligands that bind to the G-quadruplex structures in the studies. Based on molecular dynamics simulations and a series of computational analyses, the results suggest that ions move away from the external G-quartet to let the ligand bind to the quadruplex in aqueous solution. The ligand binding can increase the stability of the Hoogseen hydrogen bonds within the G-quartet. However, the G-quartet binding site can only fit one ligand molecule. The ligand can form hydrogen bonds at the loop or flank of the quadruplex. However, not all the interactions will stabilize the ligand-quadruplex complex in aqueous solution. These findings can assist in the design of selective and potent G-quadruplex ligands.

The time-resolved spectrum of a lightning stepped leader in downward process has been obtained by using a slitless spectrograph. Neutral oxygen and nitrogen spectral lines in the near infrared region are observed in the spectra. The electron density of the lightning stepped leader was calculated by using the Stark broadening of the oxygen spectral lines at 777.4 and 844.6 nm. The evolution characteristic of the electron density with time and channel height of the lightning stepped leader was analysed. The results shown that the electron density of the lightning stepped leader was in the order of 1018 cm-3. The electron density decreased when the lightning stepped leader propagates downward to ground.

Tris)(η5-cyclopentadienyl-μ-carbonyl-iron)-μ3-nitrosyl cluster was obtained from the reaction of cyclopentadienyl dicarbonyliron dimer with nitrogen monoxide in xylane. The cluster was characterised by elemental analyses, IR, MS and 1H NMR. The crystal structure of [(η5-C5H5)(μ-CO)Fe]3(μ3-NO)·C4H8O was determined by X-ray diffraction analysis. It crystallises in the orthorhombic space group Pnma, a=9.063(2), b=10.546(2), c=22.525(4) A, V=2150.3(7) A3, Z=4, Dc=1.68 g·cm−3; structure solution and refinement based on 1141 reflections with I ≥ 3.0σ (I) (MoKα, λ=0.71073 A) converged at R=0.0540. The infrared absorption band at 1325 cm−1 of the μ3-NO in the cluster, which is red shifted, shows that μ3-NO is activated.