In vitro safety signals for potential clinical development of the anti-inflammatory pregnane X receptor agonist FKK6.

Based on the mimicry of microbial metabolites, functionalized indoles were demonstrated as the ligands and agonists of the pregnane X receptor (PXR). The lead indole, FKK6, displayed PXR-dependent protective effects in DSS-induced colitis in mice and in vitro cytokine-treated intestinal organoid cultures. Here, we report on the initial in vitro pharmacological profiling of FKK6. FKK6-PXR interactions were characterized by hydrogen-deuterium exchange mass spectrometry. Screening FKK6 against potential cellular off-targets (G protein-coupled receptors, steroid and nuclear receptors, ion channels, and xenobiotic membrane transporters) revealed high PXR selectivity. FKK6 has poor aqueous solubility but was highly soluble in simulated gastric and intestinal fluids. A large fraction of FKK6 was bound to plasma proteins and chemically stable in plasma. The partition coefficient of FKK6 was 2.70, and FKK6 moderately partitioned into red blood cells. In Caco2 cells, FKK6 displayed high permeability (A-B: 22.8 × 10-6 cm.s-1) and no active efflux. These data are indicative of essentially complete in vivo absorption of FKK6. The data from human liver microsomes indicated that FKK6 is rapidly metabolized by cytochromes P450 (t1/2 5 min), notably by CYP3A4. Two oxidized FKK6 derivatives, including DC73 (N6-oxide) and DC97 (C19-phenol), were detected, and these metabolites had 5-7 × lower potency as PXR agonists than FKK6. This implies that despite high intestinal absorption, FKK6 is rapidly eliminated by the liver, and its PXR effects are predicted to be predominantly in the intestines. In conclusion, the PXR ligand and agonist FKK6 has a suitable pharmacological profile supporting its potential preclinical development.

Knockdown of pseudogene derived from lncRNA DUXAP10 inhibits cell proliferation, migration, invasion, and promotes apoptosis in pancreatic cancer.

Current evidence suggests that pseudogene derived lncRNAs may be important players in human cancer progression. Our previous study showed that DUXAP10 could promote cell proliferation in colorectal cancer. However, the clinical significance and potential role of DUXAP10 in human pancreatic cancer (PC) has not been uncovered. In this study, we found that DUXAP10 was overexpressed in PC tissues compared with normal tissues. DUXAP10 expression was significantly higher in patients with an advanced TNM stage and positive lymph node metastasis. Bioinformatic analysis showed that cell cycle progression was increased in patients with high DUXAP10 expression. In vitro and in vivo assays of DUXAP10 alterations revealed a complex integrated phenotype affecting cell growth, apoptosis, migration, and invasion. Mechanistic studies revealed that DUXAP10 has a crucial role in G2/M arrest. We further showed that DUXAP10 regulated PC cell proliferation through interact with RNA-binding protein EZH2 and LSD1. Overall, our findings indicates that DUXAP10 is an oncogenic lncRNA that promotes PC proliferation and metastasis.

Coexistence of peripheral myelin protein 22 and dystrophin mutations in a chinese boy.

INTRODUCTION: We describe a 10-year-old Chinese boy with features of Charcot-Marie-Tooth disease (CMT) and Duchenne muscular dystrophy (DMD). METHODS: Case report. RESULTS: Weakness and mild sensory loss in the distal extremities, pes cavus, and nerve conduction findings suggested demyelinating neuropathy, while moderate calf pseudohypertrophy, proximal muscle weakness, a myopathic pattern on electromyography, and deficiency of dystrophin immunohistochemical staining on muscle biopsy indicated DMD. Genetic testing revealed a large deletion spanning exon 50 in the gene coding for dystrophin and duplications in the gene coding for peripheral myelin protein 22. CONCLUSIONS: This is an interesting and very rare case of CMT type 1A comorbid with DMD. This results in an unusual phenotype and rapid deterioration of motor function. Usage of both target region capture and next generation sequencing is a powerful tool for predicting precisely the range of the large DNA fragment deletion in DMD.

Facile preparation and enhanced capacitance of the polyaniline/sodium alginate nanofiber network for supercapacitors.

A porous and mat-like polyaniline/sodium alginate (PANI/SA) composite with excellent electrochemical properties was polymerized in an aqueous solution with sodium sulfate as a template. Ultraviolet-visible spectra, X-ray diffraction pattern, and Fourier transform infrared spectra were employed to characterize the PANI/SA composite, indicating that the PANI/SA composite was successfully prepared. The PANI/SA nanofibers with uniform diameters from 50 to 100 nm can be observed on scanning electron microscopy. Cyclic voltammetry and galvanostatic charge/discharge tests were carried out to investigate the electrochemical properties. The PANI/SA nanostructure electrode exhibits an excellent specific capacitance as high as 2093 F g(-1), long cycle life, and fast reflect of oxidation/reduction on high current changes. The remarkable electrochemical characteristic is attributed to the nanostructured electrode materials, which generates a high electrode/electrolyte contact area and short path lengths for electronic transport and electrolyte ion. The approach is simple and can be easily extended to fabricate nanostructural composites for supercapacitor electrode materials.

Natural Clay-Based Materials for Energy Storage and Conversion Applications.

Among various energy storage and conversion materials, functionalized natural clays display significant potentials as electrodes, electrolytes, separators, and nanofillers in energy storage and conversion devices. Natural clays have porous structures, tunable specific surface areas, remarkable thermal and mechanical stabilities, abundant reserves, and cost-effectiveness. In addition, natural clays deliver the advantages of high ionic conductivity and hydrophilicity, which are beneficial properties for solid-state electrolytes. This review article provides an overview toward the recent advancements in natural clay-based energy materials. First, it comprehensively summarizes the structure, classification, and chemical modification methods of natural clays to make them suitable in energy storage and conversion devices. Then, the particular attention is focused on the application of clays in the fields of lithium-ion batteries, lithium-sulfur batteries, zinc-ion batteries, chloride-ion batteries, supercapacitors, solar cells, and fuel cells. Finally, the possible future research directions are provided for natural clays as energy materials. This review aims at facilitating the rapid developments of natural clay-based energy materials through a fruitful discussion from inorganic and materials chemistry aspects, and also promotes the broad sphere of clay-based materials for other utilization, such as effluent treatment, heavy metal removal, and environmental remediation.

Chemical methods for the detection of protein N-homocysteinylation via selective reactions with aldehydes.

Elevated blood levels of homocysteine (Hcy), hyperhomocysteinemia or homocystinuria, have been associated with various diseases and conditions. Homocysteine thiolactone (Hcy TL) is a metabolite of Hcy and reacts with amine groups in proteins to form stable amides, homocystamides, or N-homocysteinylated proteins. It has been proposed that protein N-homocysteinylation contributes to the cytotoxicity of elevated Hcy. Due to its heterogeneity and relatively low abundance, detection of this posttranslational modification remains challenging. On the other hand, the gamma-aminothiol group in homocystamides imparts different chemical reactivities than the native proteins. Under mildly acidic conditions, gamma-aminothiols irreversibly and stoichiometrically react with aldehydes to form stable 1,3-thiazines, whereas the reversible Schiff base formation between aldehydes and amino groups in native proteins is markedly disfavored due to protonation of amines. As such, we have developed highly selective chemical methods to derivatize N-homocysteinylated proteins with various aldehyde tags, thereby facilitating the subsequent analyses. For instance, fluorescent or biotin tagging coupled with gel electrophoresis permits quantification and global profiling of complex biological samples, such as hemoglobin and plasma from rat, mouse and human; affinity enrichment with aldehyde resins drastically reduces sample complexity. In addition, different reactivities of lysine residues in hemoglobin toward Hcy TL were observed.

A diacetate ketone-catalyzed asymmetric epoxidation of olefins.

A fructose-derived diacetate ketone has been shown to be an effective catalyst for asymmetric epoxidation. High ee values have been obtained for a variety of trans and trisubstituted olefins including electron-deficient alpha,beta-unsaturated esters as well as certain cis olefins.

Use of dynamic rheological behavior to estimate the dispersion of carbon nanotubes in carbon nanotube/polymer composites.

Well-dispersed multiwalled carbon nanotube (MWNT)/polystyrene composites have been prepared. Transmission and scanning electron microscopy were employed to observe the distribution of the MWNTs in the composites in a microscopic scale, indicating a nanotube network formed in the matrix. The dispersion of the nanotubes in the polymer was monitored by oscillatory rheology. It was found that the addition of MWNTs in the polymer had a drastic influence on the rheological behavior of the composites. As the MWNT loading increased, Newtonian behavior disappeared at low frequency, suggesting a transition from liquid-like to solid-like viscoelastic behavior. A more homogeneous dispersion or a greater loading of the nanotubes in the matrix produced stronger solid-like and nonterminal behavior, and the composites exhibited less temperature dependence at elevated temperature, compared to the matrix melt.

Preparation and characterization of chitosan based injectable hydrogels enhanced by chitin nano-whiskers.

The objective of current study was to prepare an injectable hydrogel with great mechanical properties and biological compatibility, which could be more suitable to be applied as tissue engineering scaffold. Chitin nano-whiskers (CNWs) were introduced into chitosan/ß-glycerophosphate disodium salt (CS/GP) injectable hydrogel. The effects of CNWs contents and gelation temperatures on gelation speed and mechanical properties of the composite hydrogels were characterized and discussed. The maximum values of tensile strength and elongation at break were both more than 4 times larger than that of neat CS/GP hydrogel. The gelation time of injectable hydrogel with 5% CNWs content (formed at 37°C) was 25 seconds, which was much shorter than that (6038 seconds) of the neat CS/GP hydrogel. In combination with results of Fourier transform infrared spectroscopy (FT-IR), it was proved that CNWs functioned as a cross-linker through hydrogen bond interaction in the gel formation process, which might be the main reason for mechanical enhancement. Meanwhile, gels formed with higher CNWs content and gelation temperature had lower equilibrium swelling ratio and drug release rate. Cytotoxicity of hydrogel in vitro was studied by MTT method with a result of indicating a good biocompatibility of CNWs enhanced hydrogel.

Synthesis and characterization of a chitosan based nanocomposite injectable hydrogel.

The aim of the current study was to enhance the mechanical property of chitosan/ß-glycerophosphate disodium salt (CS/GP) injectable hydrogels. A novel nanocomposite injectable hydrogel was prepared by introducing attapulgite (ATP) nano particles into the CS/GP hydrogels. The mechanical properties of the composite hydrogels with two different water contents were characterized by tensile test, the results shown that the tensile strength and elongation at break of composite hydrogels both increased obviously with increasing of ATP content. And, in our testing range, the maximum values of tensile strength and elongation at break were both more than 5 times larger than that of neat CS/GP hydrogel. We discussed this enhancement effect in detail by Scanning electron microscope observations (SEM) and Fourier transform infrared spectroscopy testing (FT-IR). The SEM images of composite hydrogels shown quite different from the neat CS/GP hydrogel, where the pores were more tightly and with some uniform and smaller holes dispersed on the wall. FT-IR test results revealed that the introduction of ATP increased the cross-link density because of the hydrogen bonds formation between ATP nanoparticles and CS molecules. Also, we studied the impact of ATP introduction on gelation speed through tracking the dynamic process of the sol-gel transition by means of rheological measurement, and the results shown that the reaction rate increased significantly with the increase of ATP concentration.

Trefoil factor family 2 expression inhibits gastric cancer cell growth and invasion in vitro via interactions with the transcription factor Sp3.

The trefoil factor family (TFF) is a group of short secretory peptides of gastric mucous neck cells. The loss of TFF2 protein expression enhances gastric inflammation and occurs in gastric cancer. In this study, we examined the effect of TFF2 on gastric cancer cell lines in vitro and characterized the interaction between TFF2 and Sp3, including the mechanisms that mediate this interaction, using genomics and proteomics approaches, as well as genetics techniques, such as RNA interference and gene knockdown. Assays were performed to examine the role of TFF2 and Sp3 in cancer cell proliferation, invasion and migration. We found that TFF2 expression inhibited the proliferation and invasion capacity of gastric cancer cells, and induced apoptosis. TFF2 interacted with the Sp3 protein, as shown by immunofluorescence staining and immunoprecipitation with western blot analysis. Sp3 knockdown in gastric cancer cells antagonized TFF2 antitumor activity. Additionally, TFF2 upregulated the expression of pro-apoptotic proteins, such as Bid, but downregulated the expression of NF-κB and the anti-apoptotic proteins, Bcl-xL and Mcl­1. By contrast, Sp3 knockdown significantly blocked TFF2 activity, affecting the expression of these proteins. The data from our study demonstrate that the antitumor activity of TFF2 is mediated by an interaction with the Sp3 protein in gastric cancer cells. Additional in vivo and ex vivo warrned in order to fully characterize this interaction.

Preparation, properties, and synthetic potentials of novel boronates in a fluorous version (fluorous boronates).

[reaction: see text] A series of boronic acids were attached to a fluorous tag by esterification. Functional transformations of these boronates together with the fluorous Suzuki coupling reaction illustrated their usefulness in fluorous-phase techniques.

Synthesis of (pyridin-2-yl)hydrazine conjugates as bifunctional chelates using the Suzuki-Miyaura reaction.

Palladium catalyzed C-C couplings were used to connect (pyridin-2-yl)hydrazine to organic substrates, including a phenylalanine derivative, providing a new method for introducing this important ligand.

Preparation and characterization of a novel stimuli-responsive nanocomposite hydrogel with improved mechanical properties.

A novel stimuli-responsive organic/inorganic nanocomposite hydrogel (NC hydrogel) with excellent mechanical properties was synthesized by in situ polymerization of 2-(2-methoxyethoxy) ethyl methacrylate (MEO(2)MA), oligo (ethylene glycol) methacrylate (OEGMA) and acrylic acid (AAc), as the polymeric matrix (PMOA), and fibrillar attpulgite (AT), as the reinforcer and cross-linker. The effect of the AT content on the mechanical properties for the swollen and dried NC hydrogels was determined by tensile testing and dynamic mechanical analysis (DMA), respectively. The tensile testing results showed that the incorporation of AT nanoparticles significantly enhanced the mechanical properties of NC hydrogels. As the content of AT increased, the tensile strength, tensile modulus and effective cross-linked chain density increased. The DMA results showed that the storage modulus of AT/PMOA NC hydrogels was increased and the glass transition temperatures shifted to higher temperature compared to the pure PMOA hydrogel, which further indicated that the enhancement of mechanical property depended upon the presence and content of AT. In addition, the faster swelling rates of the NC hydrogels were observed in comparison with the corresponding physically cross-linked PMOA hydrogel, except for 1% AT/PMOA sample. However, the deswelling kinetics of NC hydrogels was obviously retarded.

Grafting poly(methyl methacrylate) onto polyimide nanofibers via "click" reaction.

Surface modification of azide-decorated polyimide (PI) nanofibers with well-defined alkyne-terminated poly(methyl methacrylate) (PMMA) was accomplished via the combination of atom transfer radical polymerization (ATRP) and "click" chemistry. In this work, PI nanofibers were prepared via electrospun polyamic acid (PAA), followed by thermal imidization. Grafting of PMMA onto PI nanofibers was accomplished in three steps: (1) choloromethylation and azidization of PI nanofibers; (2) preparation of alkyne-terminated PMMA by ATRP of methyl methacrylate in toluene using propargyl 2-bromopropionate as initiator; (3) click coupling between the azidized PI nanofibers and the alkyne-terminated PMMA under the catalysis of Cu(I)Br/N,N,N',N''-pentamethyldiethylenetriamine (PMDETA). Gel permeation chromatography (GPC), (1)H NMR, and Fourier transform infrared (FT-IR) all confirmed the structure of alkyne-terminated poly(methyl methacrylate). The modified surface was characterized by X-ray photoelectron spectroscopy (XPS) after each modification stage. XPS and scanning electron microscope (SEM) were utilized to confirm PMMA-functionalized PI nanofibers, showing polymer coatings present on the surface of PI nanofibers. PI-g-PMMA nanofibers exhibited a more significant reinforcing effect compared to that with ungrafted PI nanofibers.