Three-dimensional pharmacophore modeling of liver-X receptor agonists

High cholesterol levels contribute to hyperlipidemia. Liver X receptors (LXRs) are the drug targets. LXRs regulate the cholesterol absorption, biosynthesis, transportation, and metabolism. Novel agonists of LXR, especially LXRβ, are attractive solutions for treating hyperlipidemia. In order to discover novel LXRβ agonists, a three-dimensional pharmacophore model was built based upon known LXRβ agonists. The model was validated with a test set, a virtual screening experiment, and the FlexX docking approach. Results show that the model is capable of predicting a LXRβ agonist activity. Ligand-based virtual screening results can be refined by cross-linking by structure-based approaches. This is because two ligands that are mapped in the same way to the same pharmacophore model may have significantly different binding behaviors in the receptor's binding pocket. This paper reports our approach to identify reliable pharmacophore models through combining both ligand- and structure-based approaches.     

Peptide Amphiphile Supramolecular Nanostructures as a Targeted Therapy for Atherosclerosis

The rising prevalence of cardiovascular disease worldwide necessitates novel therapeutic approaches to manage atherosclerosis. Intravenously administered nanostructures are a promising noninvasive approach to deliver therapeutics that reduce plaque burden. The drug liver X receptor agonist GW3965 (LXR) can reduce atherosclerosis by promoting cholesterol efflux from plaque but causes liver toxicity when administered systemically at effective doses, thus preventing its clinical use. The ability of peptide amphiphile nanofibers containing apolipoprotein A1–derived targeting peptide 4F to serve as nanocarriers for LXR delivery (ApoA1‐LXR PA) in vivo is investigated here. These nanostructures are found to successfully target atherosclerotic lesions in a mouse model within 24 h of injection. After 8 weeks of intravenous administration, the nanostructures significantly reduce plaque burden in both male and female mice to a similar extent as LXR alone in comparison to saline‐treated controls. Furthermore, they do not cause increased liver toxicity in comparison to LXR treatments, which may be related to more controlled release by the nanostructure. These findings demonstrate the potential of supramolecular nanostructures as safe, effective drug nanocarriers to manage atherosclerosis.     

Structural development of liver X receptor (LXR) antagonists derived from thalidomide-related glucosidase inhibitors

Following our previous discovery of LXR antagonistic activity of 2'-substituted phenylphthalimides derived from thalidomide-related glucosidase inhibitors, structure-activity studies and further structural development led to 5-chloro-N-2'-n-pentylphenyl-1,3-dithiophthalimide (5CPPSS-50), with IC50 values of about 10 and 13 microM for LXRalpha and LXRbeta, respectively.     

A Multitarget Approach to Evaluate the Efficacy of Aquilaria sinensis Flower Extract against Metabolic Syndrome

Aquilaria sinensis (Lour.) Spreng is known for its resinous secretion (agarwood), often secreted in defense against injuries. We investigated the effects of A. sinensis flower extract (AF) on peroxisome proliferator-activated receptors alpha and gamma (PPARα and PPARγ), liver X receptor (LXR), glucose uptake, and lipid accumulation (adipogenesis). Activation of PPARα, PPARγ and LXR was determined in hepatic (HepG2) cells by reporter gene assays. Glucose uptake was determined in differentiated muscle (C2C12) cells using 2-NBDG (2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose). Adipogenesis was determined in adipocytes (3T3-L1 cells) by Oil red O staining. At a concentration of 50 µg/mL, AF caused 12.2-fold activation of PPARα and 5.7-fold activation of PPARγ, while the activation of LXR was only 1.7-fold. AF inhibited (28%) the adipogenic effect induced by rosiglitazone in adipocytes and increased glucose uptake (32.8%) in muscle cells at 50 μg/mL. It was concluded that AF acted as a PPARα/γ dual agonist without the undesired effect of adipogenesis and exhibited the property of enhancing glucose uptake. This is the first report to reveal the PPARα/γ dual agonistic action and glucose uptake enhancing property of AF along with its antiadipogenic effect, indicating its potential in ameliorating the symptoms of metabolic syndrome.     

Exogenous Addition of 25-Hydroxycholesterol Reduces Level of Very Long-Chain Fatty Acids in X-Linked Adrenoleukodystrophy

X-Linked adrenoleukodystrophy (X-ALD) is a severe metabolic disorder characterized by the accumulation of very long-chain fatty acids (VLCFAs). Recently, we demonstrated that levels of 25-hydroxycholesterol (25-HC) and cholesterol 25-hydroxylase (CH25H) were found to be elevated in X-ALD. Herein, we report that the exogenous addition of 25-HC significantly reduces C26:0 levels in X-ALD patient-derived fibroblasts and oligodendrocytes differentiated from induced pluripotent stem cells (iPSCs) derived from X-ALD patients. Moreover, 25-HC treatment was found to down-regulate the expression of ELOVL1, a key enzyme for the synthesis of C26. In addition, activation of liver X receptor (LXR), a molecular target of endogenous 25-HC, also reduced C26:0 level. The reduction of C26:0 levels by 25-HC treatment might result, at least partially, from the decrease of ELOVL1 expression as well as the activation of LXR. Our findings could provide a better understanding of the role of 25-HC in X-ALD and useful information to find therapeutic agents to treat X-ALD.     

Identification of novel liver X receptor activators by structure-based modeling

Liver X receptors (LXRs) are members of the nuclear receptor family. Activators of LXRs are of high pharmacological interest as LXRs regulate cholesterol, fatty acid, and carbohydrate metabolism as well as inflammatory processes. On the basis of different X-ray crystal structures, we established a virtual screening workflow for the identification of novel LXR modulators. A two-step screening concept to identify active compounds included 3D-pharmacophore filters and rescoring by shape alignment. Eighteen virtual hits were tested in vitro applying a reporter gene assay, where concentration-dependent activity was proven for four novel lead structures. The most active compound 10, a 1,4-naphthochinone, has an estimated EC?? of around 5 μM.     

Single-molecule detection of DNA via sequence-specific links between F1-ATPase motors and gold nanorod sensors

We report the construction of a novel biosensing nanodevice to detect single, sequence-specific target DNA molecules. Nanodevice assembly occurs through the association of an immobilized F1-ATPase molecular motor and a functionalized gold nanorod via a single 3',5'-dibiotinylated DNA molecule. Target-dependent 3',5'-dibiotinylated DNA bridges form by combining ligation and exonucleation reactions (LXR), with a specificity capable of selecting against a single nucleotide polymorphism (SNP). Using dark field microscopy to detect gold nanorods, quantitation of assembled nanodevices is sufficient to distinguish the presence of as few as 1800 DNA bridges from nonspecifically bound nanorods. The rotary mechanism of F1-ATPase can drive gold nanorod rotation when the nanorod is attached via the DNA bridge. Therefore, rotation discriminates fully assembled devices from nonspecifically bound nanorods, resulting in a sensitivity limit of one zeptomole (600 molecules).     

Am(III) adsorption on oxides of aluminium and silicon: effects of humic substances,pH, and ionic strength

The adsorption of Am(III) (total concentration 10(-9) mol/l) on alumina, silica, and hematite was studied by a batch technique. The effects of pH, ionic strength, and humic substances on the adsorption of Am(III) on alumina and silica were investigated, and the adsorption isotherms of Am(III) on alumina and silica at different pH values were determined. It was found that compared with the adsorption of Am(III) on alumina, the adsorbability of silica on the basis of mass is less, the relative adsorption rate on silica is slower, the sensitivity of adsorption on silica to ionic strength is less, the dependence of adsorption on silica on pH is gentler, and consequently that the adsorption characteristics of Am(III) on alumina and silica are distinctly different. The negative effect of fulvic acid on the adsorption on silica and the positive effect of humic acid on the adsorption on alumina were found. In contrast to the Am(III) adsorption on alumina and silica, a tremendously high adsorbability of Am(III) on hematite was found. The sequence of adsorbabilities of Am(III) on the basis of mass is Fe2O3 > Al2O3 > SiO2.     

Anionic Graft Copolymers. III. Hydrogenation of Polydienes Grafted with Vinylaromatics

A new method is described to prepare graft copolymers of polystyrene and polyvinylcyclohexane on polyethylene and poly (ethylene, butene-1). Hydrogenation of the butadiene moieties of graft copolymers of polystyrene on poly-1, 4-butadiene and high vinyl polybutadiene forms graft copolymers of polystyrene on polyethylene and on poly (ethylene, butene-1). Graft copolymers of polyvinylcyclohexane on polyethylene and on poly (ethylene, butene-1) are prepared by completely hydrogenating graft copolymers of polystyrene on poly-1, 4-butadiene and on high vinyl polybutadiene. The physical properties of these polymer systems depend on composition and graft level, resulting in either tough polymers or elastomers.     

Resonance Raman spectra of polyacetylene on zeolite and alumina surfaces

Raman spectra are reported for polyacetylene on exchanged zeolites and on alumina. The polymerization of acetylene on zeolites is found to depend on the zeolitic cation size and on surface coverage. Mean chain lengths of about fifteen CC bonds are formed on alumina.     

Recent progress in experiments for sessile droplet wetting on structured surfaces

Wetting of a sessile droplet on structured or patterned surface can be found in a broad range of applications. The researchers have been promoted to keep working on the topic. The review is on the basis of the recent experimental advances on the sessile droplet wetting on the hydrophobic, hydrophilic, or combined hydrophobic and hydrophilic surfaces under isothermal conditions, and on heating or cooling substrates having nonisothermal conditions. More attention has been paid on the wetting configuration between the sessile droplet and the structured substrate; the research gap has been discussed on identifying the three-phase line shape. Further, the three-dimensional measurement for the sessile droplets on the patterned surfaces with focusing more on the contact line of sessile droplets might reveal new physical insights. This review targets at building a holistic overview on the sessile droplet wetting behaviors on the structured substrate in the past 2 years.     

环取代基对金属化聚苯胺衍生物膜修饰电极性能的影响

通过比较聚2，5－二甲氧基苯胺（PDMAn）、聚邻甲基苯胺（POT）和聚间氯苯胺（PmClAn）膜修饰电极的氧化还原电位、沉积在这3种聚合物上的铂微粒的表面形态与晶面取向以及异丙醇在分散Pt微粒的聚苯胺膜修饰电极上的氧化行为，从电子效应和立体效应探讨了聚合物电化学性质与环取代基的关系以及不同聚合基质对Pt沉积机理和有催化性能的影响,结果表明，在硫酸溶液中PDMAn膜修饰电极的氧化还原电位最负、POT次之、PmClAn最正，Pt在PDMAn和POT膜上的电沉积机理与在PmClAn膜上的不同，聚合物膜上沉积的Pt微粒呈现（200)晶面择优取向，其中POT膜上择优取向度最大，PDMAn次之，Pm-ClAn最小，异丙醇在金属化聚合物膜电极上的氧化电位取决于聚苯胺的本质，在POT膜修饰电极上异丙醇的电氧化主要发生在POT的活性电位区，而在PDMAn与PmClAn膜上的电氧化则主要发生在Pt上的氧化电位区，说明聚合物膜不仅作为Pt微粒的分散介质，而且本身有产生催化作用。     

A Comparative Study of Electrochemical Reduction of 4‐Nitrophenyl Covalently Grafted on Gold and Carbon

4‐Nitrophenyl layers were grafted on gold and glassy carbon surfaces by electrochemical reductive adsorption of the corresponding diazonium salt. Electrochemical conversion efficiencies of 4‐nitrophenyl moieties to 4‐aminophenyl moieties on gold versus on glassy carbon in a protic medium were investigated using X‐ray photoelectron spectroscopy (XPS). In total contrast to all previous comparative studies showing greater electrochemical reactivity of aryl diazonium salt‐derived layers on gold than on glassy carbon, a much lower rate of conversion to 4‐aminophenyl was observed on gold than on glassy carbon by both cyclic voltammetry (CV) and chronoamperometry (CA) methods. The lower electron transfer rate during conversion observed on gold versus glassy carbon was proposed to be due to a mechanism related to the molecular structure rearrangement of 4‐nitrophenyl during the process on glassy carbon. However, whilst complete conversion of 4‐nitrophenyl to 4‐aminophenyl on gold by chronoamperometry was achieved, on glassy carbon complete reduction could not be achieved under the same conditions.     

Dewetting of liquids on ceramic surfaces at high temperatures.

The influence of surface structure and chemistry on high-temperature dewetting of silicate liquids on ceramic surfaces has been investigated. Model systems based on well-defined crystallography and known chemistry have been used to illustrate the effect of surface roughness and chemistry on the dewetting process. Reconstructed ceramic surfaces provide ideal substrates to study effects of surface roughness. It has been shown that the morphology of dewet droplets depend on the length scale and the crystallography of the facets on the surface. Complex pattern formation due to solute redistribution during dewetting is illustrated in the case of SiO2 dewetting on (001) rutile substrates. The role of kinetics on the dewetting process has also been clarified.     

Layer-selective epitaxial self-assembly of porphyrins on ultrathin insulators

Copper-Octaethyl Porphyrin self-assembly has been studied on NaCl islands, 1–3 monolayers thick, grown on metal substrates. Extended ordered molecular monolayers are observed for the first time on ultrathin insulator films. The assembly occurs in hierarchical fashion, starting on the metal substrate, then followed by assembly on the first and second NaCl layers, clearly demonstrating a decrease in adsorption energy for increasing insulator layer thickness. The underlying mechanisms are discussed on the basis of molecule–substrate interactions. Voltage-dependent STM images reveal differences of the electronic structure for molecules adsorbed on metal and NaCl/metal areas.     

Influence of the precursors on the properties of alumina supported rhodium particles

The effect of chlorine on the properties of Rh particles supported on alumina was studied using the hydroconversion of alkanes as a molecular probe. Chloride ions on the alumina have little influence on the Rh particles. Chlorine adsorbed on the Rh particles decreases the chemisorption capacity and increases the metal-support interaction, which results in modifications of their catalytic properties. Depending on the alkane processed, specific activity can be depressed up to four orders of magnitude.     

Determination of complex reaction mechanisms. Analysis of chemical, biological and genetic networks

We present several methods of determining, not guessing, complex chemical reaction mechanisms and their functions. One method is based on the theory of correlation functions of measured time series of concentrations of chemical species; another is on measurements of temporal responses of concentrations to various perturbations of arbitrary magnitude; a third deals with the analysis of oscillatory systems; a fourth is on the use of genetic algorithms to determine functions of chemical reaction networks. All methods are applicable to chemical, biochemical, and biological reaction systems and to genetic networks and systems biology. The methods depend on the design of appropriate experiments on the whole system and corresponding theories for interpretation that lead to information on the causal chemical connectivity of species, on reaction pathways, on reaction mechanisms, on control centers in the system, and on functions of the system. The first three methods require no assumption of a model or hypothesis, nor extensive calculations, unlike the interpretation of measurements made on a gene network at only one time.