硫前列酮影响小鼠代谢的NMR研究

前列腺素E2（PGE2）作为一种体内广泛分布的活性物质,通过与其特异性受体EP1,EP2,EP3和EP4结合实现信号跨膜转导,参与许多重要的生理病理过程. 硫前列酮作为PGE2的类似物,通过激活EP1和EP3受体发挥其生理作用,但相关的代谢基础还不甚清楚. 该研究运用基于核磁共振（NMR）技术的代谢组学方法研究了EP1和EP3受体激活剂硫前列酮对小鼠血清和肝脏代谢组的影响. 结果表明,中高剂量硫前列酮处理32天会导致小鼠肝脏代谢组中的烟酰胺腺嘌呤二核苷酸磷酸、烟酰胺腺嘌呤二核苷酸、二磷酸尿苷、磷酸腺苷和胆汁酸的明显增加,同时肝糖原、葡萄糖、苯丙氨酸、酪氨酸、尿苷、肌苷、烟碱酸和氧化型谷胱甘肽明显减少. 恢复3周后,高剂量硫前列酮处理小鼠会导致肝脏代谢组中的胆碱水平比对照组高. 这些结果表明EP1和EP3受体激活剂硫前列酮会对小鼠肝脏的糖、核酸和氨基酸等代谢产生影响. 同时,未发现硫前列酮对血清代谢组产生明显影响,这可能与血液循环系统维持机体内环境相对稳定有关. 以上研究结果为认识PGE2- EP1/3信号通路在代谢中的作用提供了基础数据.     

Identification of furo[3′, 2′:3,4]naphtho[1,2-d]imidazole derivatives as orally active and selective inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1)

This study describes the synthesis and anti-inflammatory effects of furo[3', 2':3,4]naphtho[1,2-d] imidazole derivatives. Among these furo[3', 2':3,4]naphtho[1,2-d]imidazole derivatives, 2-(4-methoxyphenyl)furo [3', 2':3,4]naphtho[1,2-d]imidazole (12) exhibited a strong inhibitory activity against LPS-induced PGE(2) production, with an IC(50) value of 47?nM. Compound 12 is then further examined for its inhibitory effects in the protein expression of COX-2 and microsomal prostaglandin E(2) synthase-1 (mPGES-1) in Raw 264.7 cells. Our results indicate that compound 12 was capable against inhibiting LPS-induced mPGES-1 protein expression at a concentration of 1.0?μM and no inhibitory effect in COX-2 expression. The sepsis-induced PGE(2) production in rat serum decreased ~250% by the pretreatment of 12 at 10?mg/kg. These results are especially important since compound 12 exhibited good oral bioavailability (72%) and was not cytotoxic at a concentration of 10.0?μM. Therefore, compound 12 is a highly selective mPGES-1 inhibitor that can serve as a lead for the development of novel oral anti-inflammatory drug candidates.     

Glycine receptors expression in rat spinal cord and dorsal root ganglion in prostaglandin E2 intrathecal injection models

Background

Glycine receptors (GlyRs) are involved in the development of spinal pain sensitization. The GlyRα3 subunit has recently emerged as a key factor in inflammatory pain pathways in the spinal cord dorsal horn (DH). Our study is to identify the extent of location and cell types expressing different GlyR subunits in spinal cord and dorsal root ganglion (DRGs). To tease out the possible actions of GlyRs on pain transmission, we investigate the effects produced by GlyRs on acute inflammatory pain by behavioral testing using prostaglandin E2 (PGE2) intrathecal injection models. Furthermore, we investigate the changes of GlyR expression in DRGs and spinal cord in rats after the induction of acute inflammatory pain.

Results

Compared to the vehicle administration, the PGE2 intrathecal injection model produced significantly higher hyperalgesia, which started 3 h after PGE2 injection and lasted more than 5 h. PGE2 intrathecal injection significantly decreased GlyRα1 and GlyRα3 protein expressions in the L5 DH at 1 h and lasted to 5 h, and similar results were observed in the L5 DRG at 5 h. Confocal microscopic images showed the co-existence of punctate gephyrin and GlyRα3 immunoreactivity (IR) throughout the gray matter of the spinal cord, mainly in DH laminae I–III neurons and in ventral horn neurons. It also showed the co-existence of punctate gephyrin and GlyRα3 IR in DRG neurons.

Conclusions

In this study, PGE2 intrathecal injection significantly decreased protein expression of gephyrin, GlyRα1 and GlyRα3 in spinal cord DH and DRG. The gephyrin and GlyRα3 were localized on neuron cells both in the DH and DRG.

     

Antiproliferative and antiinflammatory coxib–combretastatin hybrids suppress cell cycle progression and induce apoptosis of MCF7 breast cancer cells

In our study, some newly synthesized aryl-substituted pyrazole derivatives mimicking cis-diphenylethylene scaffold of two apoptotic inducing agents celecoxib and combretastatin A-4 were found to have strong antiproliferative as well as antiinflammatory activities. Among these coxib–combretastatin hybrids, two lead compounds 8 and 6c simultaneously inhibited prostaglandin E2 (PGE2) production in LPS-activated murine macrophage RAW 264.7 cells and suppressed cell cycle progression of MCF7 cells at G2/M or G0/G1 phases, but only compound 8 induced apoptosis via caspase-3 activation. Both the lead compounds showed good docking energies with both protein targets COX-2 and tubulin in the molecule interaction modeling. The cis-diphenylethylene scaffold of celecoxib or combretastatin A-4 as well as functional groups such as the ethyl ester group and the sulfonamide could be considered as potential key features for the dual activity of studied compounds meanwhile the trimethoxybenzene remained the crucial characterization of the newly derived compounds of combretastatins.

     

Sonochemical degradation of ethyl paraben in environmental samples: Statistically important parameters determining kinetics,by-products and pathways

The sonochemical degradation of ethyl paraben (EP), a representative of the parabens family, was investigated. Experiments were conducted at constant ultrasound frequency of 20 kHz and liquid bulk temperature of 30 °C in the following range of experimental conditions: EP concentration 250–1250 μg/L, ultrasound (US) density 20–60 W/L, reaction time up to 120 min, initial pH 3–8 and sodium persulfate 0–100 mg/L, either in ultrapure water or secondary treated wastewater.A factorial design methodology was adopted to elucidate the statistically important effects and their interactions and a full empirical model comprising seventeen terms was originally developed. Omitting several terms of lower significance, a reduced model that can reliably simulate the process was finally proposed; this includes EP concentration, reaction time, power density and initial pH, as well as the interactions (EP concentration) × (US density), (EP concentration) × (pH_o) and (EP concentration) × (time).Experiments at an increased EP concentration of 3.5 mg/L were also performed to identify degradation by-products. LC–TOF–MS analysis revealed that EP sonochemical degradation occurs through dealkylation of the ethyl chain to form methyl paraben, while successive hydroxylation of the aromatic ring yields 4-hydroxybenzoic, 2,4-dihydroxybenzoic and 3,4-dihydroxybenzoic acids. By-products are less toxic to bacterium V. fischeri than the parent compound.     

Exploring surface processes by coaxial impact-collision ion scattering spectroscopy and time-of-flight elastic recoil detection analysis

The usefulness of coaxial impact-collision ion scattering spectroscopy and time-of-flight elastic recoil detection analysis for in situ surface analysis, especially for elucidation of surface processes, is demonstrated by taking the following studies as examples: (1) self-restoration processes of oxygen vacancies at vacuum-annealed TiO₂(1 1 0) surface, (2) effects of Mn incorporation on MBE growth of GaMnN film, (3) growth process in hydrogen-surfactant mediated epitaxy of Ge/Si(0 0 1), and (4) structure analysis of the Si(0 0 1)2×3-Ag surface.     

Effects of genetic deficiency of cyclooxygenase-1 or cyclooxygenase-2 on functional and histological outcomes following traumatic brain injury in mice

Background  

Neuroinflammation contributes to the pathophysiology of acute CNS injury, including traumatic brain injury (TBI). Although prostaglandin lipid mediators of inflammation contribute to a variety of inflammatory responses, their importance in neuroinflammation is not clear. There are conflicting reports as to the efficacy of inhibiting the enzymes required for prostaglandin formation, cyclooxygenase (COX) -1 and COX-2, for improving outcomes following TBI. The purpose of the current study was to determine the role of the COX isoforms in contributing to pathological processes resulting from TBI by utilizing mice deficient in COX-1 or COX-2.     

Anti-metastatic and pro-apoptotic effects elicited by combination photodynamic therapy with sonodynamic therapy on breast cancer both in vitro and in vivo

Sono-Photodynamic therapy (SPDT), a new modality for cancer treatment, is aimed at enhancing anticancer effects by the combination of sonodynamic therapy (SDT) and photodynamic therapy (PDT). In this study, we investigated the antitumor effect and possible mechanisms of Chlorin e6 (Ce6) mediated SPDT (Ce6-SPDT) on breast cancer both in vitro and in vivo. MTT assay revealed that the combined therapy markedly enhanced cell viability loss of breast cancer cell lines (MDA-MB-231, MCF-7 and 4T1) compared with SDT and PDT alone. Propidium iodide/hoechst33342 double staining reflected that 4T1 cells with apoptotic morphological characteristics were significantly increased in groups given combined therapy. Besides, the combined therapy caused obvious mitochondrial membrane potential (MMP) loss at early 1 h post SPDT treatment. The generation of intracellular reactive oxygen species (ROS) detected by flow cytometry was greatly increased in 4T1 cells treated with the combination therapy, and the loss of cell viability and MMP could be effectively rescued by pre-treatment with the ROS scavenger N-acetylcysteine (NAC). Further, Ce6-SPDT markedly inhibited the tumor growth (volume and weight) and lung metastasis in 4T1 tumor-bearing mice, but had no effect on the body weight. Hematoxylin and eosin staining revealed obvious tissue destruction with large spaces in the Ce6-SPDT groups, and TUNEL staining indicated tumor cell apoptosis after treatment. Immunohistochemistry analysis showed that the expression level of VEGF and MMP were significantly decreased in the combined groups. These results indicated that Ce6-mediated SPDT enhanced the antitumor efficacy on 4T1 cells compared with SDT and PDT alone, loss of MMP and generation of ROS might be involved. In addition, Ce6-mediated SPDT significantly inhibited tumor growth and metastasis in mouse breast cancer 4T1 xenograft model, in which MMP-9 and VEGF may play a crucial role.     

Electrochemical and catalytic investigations of epinephrine,acetaminophen and folic acid at the surface of titanium dioxide nanoparticle-modified carbon paste electrode

In the present paper, the use of a carbon paste electrode modified with 1-(4-(1, 3-dithiolan-2-yl)-6, 7-dihydroxy-2-methyl-6, 7-dihydrobenzofuran-3-yl)ethanone (DDE) and TiO₂ nanoparticles prepared by a simple and rapid method was described. The modified electrode showed excellent properties for electrocatalytic oxidization of epinephrine (EP), acetaminophen (AC) and folic acid (FA). The apparent charge transfer rate constant, k _s?=?1.14 s^?1, and transfer coefficient, α?=?0.54, for electron transfer between the modifier and carbon paste electrode were calculated. It has been found that under optimum condition (pH?=?7.0) in cyclic voltammetry, the oxidation of EP occurs at a potential about 280 mV less positive than that of an unmodified carbon paste electrode. The values of transfer coefficients (α?=?0.46), catalytic rate constant (k?=?1.2?×?10⁴ M^?1 s^?1) and diffusion coefficient (D?=?2.70?×?10^?5 cm² s^?1) were calculated for EP. Differential pulse voltammetry (DPV) exhibited two linear dynamic ranges of 0.5 to 50.0 μM and 50.0 to 1,000 μM for EP. This modified electrode is quite effective not only for the detection of EP, AC and FA but also for the simultaneous determination of these species in a mixture. The limit of detection for EP, AC and FA is 0.10, 1.80 and 2.36 μM, respectively.     

Interaction of the mu-opioid receptor with GPR177 (Wntless) inhibits Wnt secretion: potential implications for opioid dependence

Background  

Opioid agonist drugs produce analgesia. However, long-term exposure to opioid agonists may lead to opioid dependence. The analgesic and addictive properties of opioid agonist drugs are mediated primarily via the mu-opioid receptor (MOR). Opioid agonists appear to alter neuronal morphology in key brain regions implicated in the development of opioid dependence. However, the precise role of the MOR in the development of these neuronal alterations remains elusive. We hypothesize that identifying and characterizing novel MOR interacting proteins (MORIPs) may help to elucidate the underlying mechanisms involved in the development of opioid dependence.     

The roles of zinc selenide sandwiched between organic layers and its applications in white light-emitting diodes

In this paper, the roles of zinc selenide (ZnSe) sandwiched between organic layers, i.e. organic/ZnSe/aluminum quinoline (Alq₃), have been studied by varying device structure. A broad band emission was observed from ITO/poly(N-vinylcarbazole)(PVK)(80 nm)/ZnSe(120 nm)/ Alq₃(15 nm)/Al under electric fields and it combined the emissions from the bulk of PVK, ZnSe and Alq₃, however, emission from only Alq₃ was observed from trilayer device ITO/N,N^′-bis-(1-naphthyl)-N,N^′-diphenyl-1, 1^′-biphenyl-4, 4^′-diamine (NPB) (40 nm)/ZnSe(120 nm)/ Alq₃(15 nm)/Al. Consequently the luminescence mechanism in the ZnSe layer is suggested to be charge carrier injection and recombination. By thermal co-evaporating Alq₃ and 4-(dicyanomethylene)-2-t-butyl-6-(1,1,7,7-tetramethyljulolidyl-9-enyl)-4H-pyran (DCJTB), we get white light emission with a Commission Internationale de l’E clairage (C.I.E) co-ordinates of (0.32, 0.38) from device ITO/PVK(80 nm)/ZnSe(120 nm)/ Alq₃:DCJTB(0.5 wt% DCJTB)(15 nm)/Al at 15 V and the device performs stably with increasing applied voltages.     

Upconversion of photoluminescence due to subband resonances in a GaAs/AlAs multiple quantum well structure

We have investigated the upconversion of photoluminescence (PL) due to subband resonances in a simple GaAs(15.3 nm)/AlAs(4.5 nm) multiple quantum well embedded in a p–i–n diode structure. The systematic measurements of the PL spectra and the calculated results of the interband transition energies as a function of electric field strength reveal that the PL bands from the electron subbands with n=3 (E3) and n=4 (E4) sharply appear under the first-nearest-neighbor resonance conditions between the E1 and E3 subbands and the E1 and E4 subbands, respectively, owing to the carrier injection to the E3 and E4 subbands from the E1 subband. This result indicates that the resonant tunneling due to the subband resonance is a dominant mechanism for the carrier population in the higher lying subbands. Utilizing these subband resonances, we have demonstrated the upconversion of PL from the E3 and E4 subbands under the excitation condition of the fundamental interband transition between the E1 and the n=1 heavy-hole subbands.     

Cellular toxicity following application of adeno-associated viral vector-mediated RNA interference in the nervous system

Background  

After a spinal cord lesion, axon regeneration is inhibited by the presence of a diversity of inhibitory molecules in the lesion environment. At and around the lesion site myelin-associated inhibitors, chondroitin sulfate proteoglycans (CSPGs) and several axon guidance molecules, including all members of the secreted (class 3) Semaphorins, are expressed. Interfering with multiple inhibitory signals could potentially enhance the previously reported beneficial effects of blocking single molecules. RNA interference (RNAi) is a tool that can be used to simultaneously silence expression of multiple genes. In this study we aimed to employ adeno-associated virus (AAV) mediated expression of short hairpin RNAs (shRNAs) to target all Semaphorin class 3 signaling by knocking down its receptors, Neuropilin 1 (Npn-1) and Neuropilin 2 (Npn-2).     

Effects of prostaglandin E<Subscript>2</Subscript> on the electrical properties of thermally classified neurons in the ventromedial preoptic area of the rat hypothalamus

Background  

Physiological and morphological evidence suggests that activation of the ventromedial preoptic area of the hypothalamus (VMPO) is an essential component of an intravenous LPS-dependent fever. In response to the endogenous pyrogen prostaglandin E₂ (PGE₂), the majority of temperature insensitive neurons in the VMPO show an increase in firing rate, while warm sensitive neurons are inhibited. We have hypothesized that these PGE₂ dependent effects on firing rate are due to changes in the inherent electrical properties of VMPO neurons, which are regulated by the activity of specific ionic currents.     

Performance of lithium-ion cells using 1 M LiPF<Subscript>6</Subscript> in EC/DEC (<Emphasis Type="Italic">v</Emphasis>/<Emphasis Type="Italic">v</Emphasis> = 1/2) electrolyte with ethyl propionate additive

In this work, 1 M LiPF₆:EC:DEC (v/v = 1/2) was used as a baseline electrolyte where EC is ethylene carbonate and DEC is diethyl carbonate. Ethyl propionate (EP) was used as an additive. The conductivity of the liquid electrolyte was obtained at ambient and elevated temperatures. The highest room temperature conductivity was observed at (8.05 ± 0.16) mS cm⁻¹ for the electrolyte containing 28.6 vol.% EP. Viscosity of the baseline and EP added baseline electrolytes have been measured at room and elevated temperatures. The electrolyte was also characterized by linear sweep voltammetry. The highest conducting electrolyte with 28.6 vol.% EP and the baseline electrolyte were used to fabricate several batteries. The batteries were charged and discharged at room temperature and at −20°C.     

Damping,Thermal, and Mechanical Properties of Polycaprolactone-Based PU/EP Graft IPNs: Effects of Composition and Isocyanate Index

A series of polycaprolactone (PCL)-based polyurethane (PU)/epoxy resin (EP) graft interpenetrating polymer networks (IPNs) were prepared and their damping propertiesand thermal stability, as well as mechanical properties, were systematically studied in terms of composition and the values of the PU isocyanate index (R). The morphologies of the PU/EP IPNs were observed by scanning electron microscope (SEM) and atomic force microscope (AFM) characterization and the relationship between the morphologies and the properties is also discussed. The damping properties and thermal stability measurements revealed that the formation of PU/EP IPNs could significantly improve not only the damping properties but also the thermal stability. Meanwhile, the mechanical tests showed that the tensile strengths of the IPNs decreased, while their impact strengths increased with increasing PU content. The value of the PU isocyanate index also had significant impacts on the properties of the IPNs when the PU to EP ratio was fixed, which could be an effective means for manipulating the fabrication of PU/EP IPNs. From the results obtained, the PCL-based PU/EP IPNs hold promise for use in structural damping materials.     

HIV-1 neutralization by monoclonal antibody against conserved region 2 and patterns of epitope exposure on the surface of native viruses

Background  

Conserved neutralizing epitopes are considered to be a key role for eliciting broadly neutralizing antibody (NAb). Previously, two conserved neutralizing epitopes of HIV-1 CRF01_AE envelope were identified at amino acid 93-112 of the C1 (C1E) and at 218-239 of the C2 (C2E) regions. To access the potency of antibody directed against conserved epitopes, a monoclonal antibody (MAb) specific to the C2E region was developed and characterized.     

Non-faradaic electrochemical modification of the catalytic activity for propane combustion of Pt/YSZ and Rh/YSZ catalyst-electrodes

The effect of non-faradaic electrochemical modification of catalytic activity (NEMCA effect) or electrochemical promotion (EP) was investigated in the total oxidation of propane on porous Pt and Rh catalyst-electrode films interfaced to 8 mol% Y₂O₃-stabilized-ZrO₂ (or YSZ), in the temperature range 425–520 °C and for sub-stoichiometric O₂ to propane ratios. Application of either positive or negative overpotentials resulted in non-faradaic increase of the catalytic rate, by up to a factor of 4 in the case of Rh and by up to a factor of 1350 in the case of Pt. The rate increase observed in the case of Pt is among the highest ones reported so far in NEMCA studies with oxygen ion conductors as active supports.     

Single-pulse shock-tube study on the pyrolysis of small esters (ethyl and propyl propanoate,isopropyl acetate) and methyl isopropyl carbonate

Single-pulse shock-tube experiments were used to study the thermal decomposition of selected oxygenated hydrocarbons: Ethyl propanoate (C₂H₅OC(O)C₂H₅; EP), propyl propanoate (C₃H₇OC(O)C₂H₅; PP), isopropyl acetate ((CH₃)₂HCOC(O)CH₃; IPA), and methyl isopropyl carbonate ((CH₃)₂HCOC(O)OCH₃; MIC) The consumption of reactants and the formation of stable products such as C₂H₄ and C₃H₆ were measured with gas chromatography/mass spectrometry (GC/MS). Depending on the considered reactant, the temperatures range from 716–1102 K at pressures between 1.5 and 2.0 bar. Rate-coefficient data were obtained from first-order analysis. All reactants primarily decompose by six-center eliminations: EP → C₂H₄ + C₂H₅COOH (propionic acid); PP → C₃H₆ + C₂H₅COOH; IPA → C₃H₆ + CH₃COOH (acetic acid); MIC → C₃H₆ + CH₃OC(O)OH (methoxy formic acid). Experimental rate-coefficient data can be well represented by the following Arrhenius expressions: k(EP → products) = 10^13.49±0.16 exp(−214.95±3.25 kJ/mol/RT) s⁻¹; k(PP → products) = 10^12.21±0.16 exp(–191.21±2.79 kJ/mol/RT) s⁻¹; k(IPA → products) = 10^13.10±0.31 exp(–186.38±5.10 kJ/mol/RT) s⁻¹; k(MIC → products) = 10^12.43±0.29 exp(–165.25±4.46 kJ/mol/RT) s⁻¹. The determination of rate coefficients was based on the amount of C₂H₄ or C₃H₆ formed. The potential energy surface (PES) of the thermal decomposition of these four reactants was determined with the G4 composite method. A master-equation analysis was conducted based on energies and molecular properties from the G4 computations. The results indicate that the length of a linear alkyl substituent does not significantly influence the rate of six-center eliminations, whereas the change from a linear to a branched alkyl substituent results in a significant reactivity increase. The comparison between rate-coefficient data also shows that alkyl carbonates have higher reactivity towards decomposition by six-center elimination than esters. The results are discussed in in the context of reactivity patterns of carbonyl compounds.     

Electrical sterilization of Escherichia coli by electrostatic atomization with a photo-chemical catalyst

The inactivation of Escherichia coli (E. coli) was studied to find the optimal sterilization conditions using electrostatic atomization with a near ultraviolet light-emitting diode (near UV-LED) and TiO₂ nanofiber films. Three types of near UV-LEDs of different wavelengths (365 nm, 375 nm, 385 nm) were used in this investigation. In order to enhance the LED performances, TiO₂ nanofiber films were utilized for the production of a photo-chemical catalytic effect. In these studies, the flow rate condition of the E. coli mixture was varied from 2 ml/h to 10 ml/h for the purposes of measuring the capabilities of the proposed sterilization method. During these electrostatic atomization experiments, Each LED irradiated a TiO₂ nanofiber film and atomized E. coli mixture. The results of these experiments were compared with electrostatic atomization performed without the use of photo-chemical catalyst effects. The experimental result shows that the optimal sterilization effect of E. coli is 375 nm wavelength with a TiO₂ nanofiber employed during electrostatic atomization.