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Cholestasis is a major cause of a series of bile flow malfunction-related liver diseases. Pregnane X receptor (PXR) is a key regulator in endo- and xeno-biotics metabolism, which has been considered as a promising therapeutic target for cholestasis. In this study we conducted human PXR (hPXR) agonistic screening using dual-luciferase reporter gene assays, which led to discovering a series of potent hPXR agonists from a small Euphorbiaceae diterpenoid library, containing 35 structurally diverse diterpenoids with eight different skeleton types. The most active compound 6, a lathyrane diterpenoid (5/11/3 ring system), dose-dependently activated hPXR with a high selectivity, and significantly upregulated the expression of hPXR downstream genes CYP3A4 and UGT1A1. In LCA-induced cholestasis mouse model, administration of compound 6 (50 mg· kg

The remarkable advancement of top-down proteomics in the past decade is driven by the technological development in separation, mass spectrometry (MS) instrumentation, novel fragmentation, and bioinformatics. However, the accurate identification and quantification of proteoforms, all clearly-defined molecular forms of protein products from a single gene, remain a challenging computational task. This is in part due to the complicated mass spectra from intact proteoforms when compared to those from the digested peptides. Herein, pTop 2.0 is developed to fill in the gap between the large-scale complex top-down MS data and the shortage of high-accuracy bioinformatic tools. Compared with pTop 1.0, the first version, pTop 2.0 concentrates mainly on the identification of the proteoforms with unexpected modifications or a terminal truncation. The quantitation based on isotopic labeling is also a new function, which can be carried out by the convenient and user-friendly "one-key operation," integrated together with the qualitative identifications. The accuracy and running speed of pTop 2.0 is significantly improved on the test data sets. This chapter will introduce the main features, step-by-step running operations, and algorithmic developments of pTop 2.0 in order to push the identification and quantitation of intact proteoforms to a higher-accuracy level in top-down proteomics.

Ovarian cancer (OV) is the most lethal gynecologic malignancy. One major reason of the high mortality of the disease is due to platinum-based chemotherapy resistance. Increasing evidence reveal the important biological functions and clinical significance of zinc finger proteins (ZNFs) in OV. In the present study, the relationship between the zinc finger protein 76 (ZNF76) and clinical outcome and platinum resistance in patients with OV was explored. We further analyzed ZNF76 expression via multiple gene expression databases and identified its functional networks using cBioPortal. RT-qPCR and IHC assay shown that the ZNF76 mRNA and protein expression were significantly lower in OV tumor than that in normal ovary tissues. A strong relationship between ZNF76 expression and platinum resistance was determined in patients with OV. The low expression of ZNF76 was associated with worse survival in OV. Multivariable analysis showed that the low expression of ZNF76 was an independent factor predicting poor outcome in OV. The prognosis value of ZNF76 in pan-cancer was validated from multiple cohorts using the PrognoScan database and GEPIA 2. A gene-clinical nomogram was constructed by multivariate cox regression analysis, combined with clinical characterization and ZNF76 expression in TCGA. Functional network analysis suggested that ZNF76 was involved in several biology progressions which associated with OV. Ten hub genes (CDC5L, DHX16, SNRPC, LSM2, CUL7, PFDN6, VARS, HSD17B8, PPIL1, and RGL2) were identified as positively associated with the expression of ZNF76 in OV. In conclusion, ZNF76 may serve as a promising prognostic-related biomarker and predict the response to platinum in OV patients.

Ovarian cancer (OV) is the main cause of deaths worldwide in female reproductive system malignancies. Enhancer RNAs (eRNAs) are derived from the transcription of enhancers and has attracted increasing attention in cancers recently. However, the biological functions and clinical significance of eRNAs in OV have not been well described presently. We used an integrated data analysis to identify prognostic-related eRNAs in OV. Tissue-specific enhancer-derived RNAs and their regulating genes were considered as putative eRNA–target pairs using the computational pipeline PreSTIGE. Gene expression profiles and clinical data of OV and 32 other cancer types were obtained from the UCSC Xena platform. Altogether, 71 eRNAs candidates showed significant correlation with overall survival (OS) of OV samples (Kaplan–Meier log-rank test, P 0.3, P

Although thousands of intact proteins have been feasibly identified in recent years, global quantification of intact proteins is still challenging. Herein, we develop a high-throughput strategy for global intact protein quantification based on chemical isotope labeling. The isotope incorporation efficiency is as high as 99.2% for complex intact protein samples extracted from HeLa cells. Further, the pTop 2.0 software is developed for automated quantification of intact proteoforms in a high-throughput manner. The high quantification accuracy and reproducibility of this strategy have been demonstrated for both standard and complex cellular protein samples. A total of 2283 intact proteoforms originated from 660 protein accessions are successfully quantified under anaerobic and aerobic conditions and the differentially expressed proteins are observed to be involved in the important biological processes such as stress response.

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RNA-seq analysis was used to identify differentially expressed genes (DEGs) at the genetic level in the longissimus dorsi muscle from two pigs to investigate the genetic mechanisms underlying the difference in meat quality between Debao pigs and Landrace pigs. Then, these DEGs underwent functional annotation, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein–protein interaction (PPI) analyses. Finally, the expression levels of specific DEGs were assessed using qRT-PCR. The reference genome showed gene dosage detection of all samples which showed that the total reference genome comprised 22342 coding genes, including 14743 known and 190 unknown genes. For detection of the Debao pig genome, we obtained 14168 genes, including 13994 known and 174 unknown genes. For detection of the Landrace pig genome, we obtained 14404 genes, including 14223 known and 181 unknown genes. GO analysis and KEGG signaling pathway analysis show that DEGs are significantly related to metabolic regulation, amino acid metabolism, muscular tissue, muscle structure development etc. We identified key genes in these processes, such as FOS, EGR2, and IL6, by PPI network analysis. qRT-PCR confirmed the differential expression of six selected DEGs in both pig breeds. In conclusion, the present study revealed key genes and related signaling pathways that influence the difference in pork quality between these breeds and could provide a theoretical basis for improving pork quality in future genetic thremmatology.

Isoquinoline alkaloids possess a wide range of structural features and pharmaceutical activities and are promising drug candidates. Ten water-soluble catecholic isoquinolines were isolated from the medicinal plant Portulaca oleracea, including three new (1–3) and seven known compounds (4–10), along with the known catecholamines 11 and 12 and four other known compounds (13–16). A method of polyamide column chromatography using EtOAc–MeOH as the mobile phase was developed for the isolation of catecholic isoquinolines. Alkaloids 1–12 exhibited anti-inflammatory activities (EC50 = 18.0–497.7 μM) through inhibition of NO production in lipopolysaccharide-induced murine macrophage RAW 264.7 cells. Among these compounds, 11, 2, 5, 4, and 8 were more potent than was the positive control, 3,4-dihydroxybenzohydroxamic acid (EC50 = 82.4 μM), with EC50 values of 18.0, 18.1, 35.4, 36.3, and 58.7 μM, respectively. Additionally, at 100 μM, compounds 1–12 showed different degrees of β2-adrenergic receptor (β2-AR) agonist ...

Mo-V-Ti catalysts of low temperature denitrification were prepared by dipping method. In order to study the activity of selective catalytic reduction, the catalyst was placed in a fixed bed reactor. Industrial flue gas was simulated with cylinder gas. The experimental condition is NO: 500ppm, NH3:500ppm, O2:8%, SO2:100ppm, N2: equilibrium gas, space velocity: 36000h-1. Results indicate that the catalyst prepared by dipping method had good denitrification activity and sulfur resistance at low temperature. The optimum ratio of catalyst was 3V2O5-6MoO3-91TiO2 (wt %). The conversion efficiency of NO was 80~93%, and the conversion efficiency of SO2 was less than 1% at 180~260 °C.

Mg-Mo-V-Ti catalysts of low temperature denitrification were prepared by dipping method. In order to study the activity of selective catalytic reduction, the catalyst was placed in a fixed bed reactor. Industrial flue gas was simulated with cylinder gas. Results indicate that the 0.1wt% content of MgO catalyst has good performance on denitration activity and sulfur resistance. The effects of oxygen content, space velocity and reaction temperature on the activity of the 0.1MgO-6MoO3-3V2O5-TiO2 wt% catalyst were investigated. With the increase of oxygen concentration, the denitrification efficiency increases when the oxygen concentration is less than 8%. When the oxygen content is greater than 8%, the denitrification efficiency is almost the same. The denitrification efficiency decreases with the increase of space velocity. The removal efficiency of NO 0.1MgO-6MoO3-3V2O5-TiO2 wt% catalyst over increases first and then becomes stable with the increase of temperature, and the conversion efficiency of SO2 is less than or equal to 2.2% at 120~240 °C.

The aim of this study was to investigate the topographical distribution of dopamine transporter (DAT), dopamine D2 receptor, and glucose metabolism in Parkinson's disease (PD) using PET/computed tomography (CT) scanning and statistical parametric mapping (SPM) analysis.Seventy-four patients (58 PD patients and 16 normal controls) underwent DAT, D2 receptor, and glucose brain PET/CT scans using C-methyl-N-2-β-carbomethoxy-3-β-(4-fluorophenyl) tropane (C-β-CFT), C-raclopride (C-RAC), and fluorine-18-fluorodeoxyglucose (F-FDG) radiotracers for the respective scans. All three PET/CT procedures were performed in each participant. The uptake patterns were analyzed using SPM software.Striatal DAT binding was lower in PD patients than in controls, whereas D2 receptor binding did not differ between PD patients and controls. D2 receptor binding was increased in the putamen in only the 12 drug-naive patients. Glucose uptake was also slightly lower in the cingulate gyrus of PD patients than in the controls.Suite PET/CT scans using the ligands C-β-CFT, C-RAC, and F-FDG PET/CT are valuable for diagnosing PD. SPM-based analysis of static PET/CT scan data is potentially of great clinical use.

To investigate the prognostic evaluation value of fluorodeoxyglucose (FDG) interim positron emission tomography/computed tomography (PET/CT) for diffuse large B cell lymphoma (DLBCL).Two hundred and twenty-seven patients with pathologically diagnosed DLBCL underwent 18F-FDG scans at baseline and before 3 cycles of a rituximab-containing chemotherapy regimen. The Visual Deauville score (DS) and changes in maximum standard uptake values (ΔSUVmax) were calculated for tracer for the predominant lesion of each patient, for prediction of progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier method and COX regression.The median follow-up period was 71 months. Receiver operating characteristic analysis indicated that the best ΔSUV cut-off values for FDG (ΔSUVFDG) was 71%. The sensitivity, specificity and accuracy of DS and ΔSUVmax were 86.9%, 74.3%, 82.8% and 77.8%, 63.5%, 73.1%, respectively in response assessment. Kaplan-Meier analysis showed DS, ΔSUVmax and IPI had significance for prediction of PFS and OS (P = 0.001). The DS 4-5 and IPI 3-5 were independent risk factors of poor prognosis by COX regression analysis.Interim PET/CT is important predictor for evaluation therapeutic response and prognosis in DLBCL patients.

The core value of finance is to provide "services" which is provide decision-making information to middle and senior leaders of the company, provide financial support and business management to business departments, provide specified statements to government regulators and provide financial reports to stakeholders, etc. Therefore, improving service quality, service efficiency and service satisfaction are the core elements of establishing financial Shared service center. This paper expounds the core idea and several construction modes of Financial Shared Service Center (FSSC), and analyzes and studies the problems, additional values and existing difficulties of FSSC.

There has been tremendous progress in top-down proteomics (TDP) in the past 5 years, particularly in intact protein separation and high-resolution mass spectrometry. However, bioinformatics to deal with large-scale mass spectra has lagged behind, in both algorithmic research and software development. In this study, we developed pTop 1.0, a novel software tool to significantly improve the accuracy and efficiency of mass spectral data analysis in TDP. The precursor mass offers crucial clues to infer the potential post-translational modifications co-occurring on the protein, the reliability of which relies heavily on its mass accuracy. Concentrating on detecting the precursors more accurately, a machine-learning model incorporating a variety of spectral features was trained online in pTop via a support vector machine (SVM). pTop employs the sequence tags extracted from the MS/MS spectra and a dynamic programming algorithm to accelerate the search speed, especially for those spectra with multiple post-translational modifications. We tested pTop on three publicly available data sets and compared it with ProSight and MS-Align+ in terms of its recall, precision, running time, and so on. The results showed that pTop can, in general, outperform ProSight and MS-Align+. pTop recalled 22% more correct precursors, although it exported 30% fewer precursors than Xtract (in ProSight) from a human histone data set. The running speed of pTop was about 1 to 2 orders of magnitude faster than that of MS-Align+. This algorithmic advancement in pTop, including both accuracy and speed, will inspire the development of other similar software to analyze the mass spectra from the entire proteins.

Isoquinoline alkaloids possess a wide range of structural features and pharmaceutical activities and are promising drug candidates. Ten water-soluble catecholic isoquinolines were isolated from the medicinal plant Portulaca oleracea, including three new (1-3) and seven known compounds (4-10), along with the known catecholamines 11 and 12 and four other known compounds (13-16). A method of polyamide column chromatography using EtOAc-MeOH as the mobile phase was developed for the isolation of catecholic isoquinolines. Alkaloids 1-12 exhibited anti-inflammatory activities (EC

We present a sequence-tag-based search engine, Open-pFind, to identify peptides in an ultra-large search space that includes coeluting peptides, unexpected modifications and digestions. Our method detects peptides with higher precision and speed than seven other search engines. Open-pFind identified 70-85% of the tandem mass spectra in four large-scale datasets and 14,064 proteins, each supported by at least two protein-unique peptides, in a human proteome dataset.

It remains unclear whether autophagy affects hippocampal neuronal injury in vascular dementia. In the present study, we investigated the effects of autophagy blockade on hippocampal neuronal injury in a rat model of vascular dementia. In model rats, hippocampal CA1 neurons were severely damaged, and expression of the autophagy-related proteins beclin-1, cathepsin B and microtubule-associated protein 1 light chain 3 was elevated compared with that in sham-operated animals. These responses were suppressed in animals that received a single intraperitoneal injection of wortmannin, an autophagy inhibitor, prior to model establishment. The present results confirm that autophagy and autophagy-related proteins are involved in the pathological changes of vascular dementia, and that inhibition of autophagy has neuroprotective effects.

Study of LMS control method on active engine mount is carried out for ride quality improvement. Take an active engine mount which is based and developed from a hydraulic mount with decoupled disc-membrane as a module, the characteristic of vibration isolation of active engine mount is simulated and analyzed. The results indicated that active engine mount could reduce the vertical vibration effectively with LMS Control method.

Due to high efficiency and good scalability, hierarchical hybrid P2P architecture has drawn more and more attention in P2P streaming research and application fields recently. The problem about super peer selection, which is the key problem in hybrid heterogeneous P2P architecture, is becoming highly challenging because super peers must be selected from a huge and dynamically changing network. A distributed super peer selection (SPS) algorithm for hybrid heterogeneous P2P streaming system based on evolutionary game is proposed in this paper. The super peer selection procedure is modeled based on evolutionary game framework firstly, and its evolutionarily stable strategies are analyzed. Then a distributedQ-learning algorithm (ESS-SPS) according to the mixed strategies by analysis is proposed for the peers to converge to the ESSs based on its own payoff history. Compared to the traditional randomly super peer selection scheme, experiments results show that the proposed ESS-SPS algorithm achieves better performance in terms of social welfare and average upload rate of super peers and keeps the upload capacity of the P2P streaming system increasing steadily with the number of peers increasing.

In this paper, we study the approximation of identity operator and the convolution integral operator Bm by Fourier partial sum operators, Fejer operators, Vallee-Poussin operators, Cesaro operators and Abel mean operators, respectively, on the periodic Wiener space (C1(ℝ),Wℴ) and obtain the average error estimations.

To design Keap1-tat peptide and explore its neuroprotective role on hipocampal CA1 neuron, as well as the effect on spacial learning and memory function following global cerebral ischemia.Adult male Sprague Dawley (SD) rats were subjected to global cerebral ischemia (GCI) by four-vessel occlusion for 15 min and randomly divided into five groups: sham, sham+Keap1-tat, ischemia/reperfusion (I/R), Keap1-tat peptide- and vehicle-administrated groups. For Keap1-tat or vehicle groups, the rats were treated with Keap1-tat (30, 50, 100 μg in 5 μL 0.9% saline) or the same volume vehicle by intracerebroventricular injection (icv) 30 min prior to ischemia. Cresyl violet staining was used to observe the surviving neurons and 4-hydroxy-2-noneal (4-HNE) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) immunostaining were used to detect the change of markers response to oxidative stress in hippocampal CA1 region. The spatial learning and memory function of the rats was evaluated using Morris water maze.Compared with sham group, the number of surviving neurons in ischemia-reperfusion and vehicle groups significantly decreased in the hippocampal CA1 region (P0.05), while administration of Keap1-tat significantly decreased the damage following GCI (P0.05), and the dose of 50 μg existed the most effective neuroprotective role. Furthermore, immunostaining intensity of 4-HNE and 8-OHdG, markers of oxidative stress damage attenuated by Keap1-tat peptide as compared with vehicle group in CA1 region. Of significant interest, the time of finding underwater platform in Keap1-tat group animals was significantly short, and after removing the platform, the probe time of Keap1-tat group animals in the original quadrant where the platform was significantly increased compared with that of vehicle and I/R group animals (P0.05).Keap1-tat peptide can effectively attenuate neuronal damage in hippocampal CA1 region and improve learning and memory function, which might bedue to the attenuation of oxidative stress caused by GCI.

Objective We explored the clinical values of 11 C-choline ( 11 C-CHO) PET in optimization of target volume delineation and treatment regimens in postoperative radiotherapy for brain gliomas. Methods Sixteen patients with the pathological confirmation of the diagnosis of gliomas prior to receiving radiotherapy (postoperative) were included, and on whom both MRI and CHO PET scans were performed at the same position for comparison of residual tumors with the two techniques. 11 C-CHO was used as the tracer in the PET scan. A plain T1-weighted, T2-weighted and contrast-enhanced T1-weighted imaging scans were performed in the MRI scan sequence. The gliomas' residual tumor volume was defined as the area with CHO-PET high-affinity uptake and metabolism ( V CHO ) and one with MRI T1-weighted imaging high signal intensity ( V Gd ), and was determined by a group of experienced professionals and clinicians. Results (1) In CHO-PET images, the tumor target volume, i.e., the highly metabolic area with a high concentration of isotopes (SUV 1.016–4.21) and the corresponding contralateral normal brain tissues (SUV0.1–0.62), was well contrasted, and the boundary between lesions and surrounding normal brain tissues was better defined compared with MRI and 18 F-FDG PET images. (2) For patients with brain gliomas of WHO Grade II, the SUV was 1.016–2.5; for those with WHO Grades III and IV, SUVs were >26–4.2. (3) Both CHO PET and MRI were positive for 10 patients and negative for 2 patients. The residual tumor consistency between these two studies was 75%. Four of the 10 CHO-PET-positive patients were negative on MRI scans. The maximum distance between V Gd and V CHO margins was 1.8 cm. (4) The gross tumor volumes (GTVs) and the ensuing treatment regimens were changed for 31.3% (5/16) of patients based on the CHO-PET high-affinity uptake and metabolism, in which the change rate was 80% (4/5), 14.3 % (1/7) and 0% (0/4) for patients with WHO Grade II III, and IV gliomas, respectively. Conclusion Our data demonstrate that difference exists between CHO PET and MRI by which to judge and identify residual tumor for patients with brain gliomas. CHO PET is considered to be a supplementary diagnostic approach for MRI. Biological tumor target volume (BTV) displayed in the CHO PET images is useful in determining or delineating the radiotherapy target volume and making decisions in selecting treatment regimens. Tumor target volume may be defined more accurately and rationally when the CHO PET is combined with MRI.

Background/Aims: The aim of this study was to assess the prevalence and related factors of different types of urinary incontinence (UI) among Hebei women in China. Methods: A total of 2,500 women aged 20 years or more were sampled and interviewed face-to-face by well-trained interviewers. Results: Among these women, 35.2% (862/2,448) had UI. The prevalence of stress, urge, and mixed UI was 26.4% (647/2,448), 1.9% (47/2,448), and 6.9% (168/2,448), respectively. In multivariable logistic regression, age, constipation, pelvic organ prolapse, number of abortions, and cesarean sections were associated with both stress and mixed UI; body mass index, dysmenorrhea, vaginitis and cervicitis, fetal weight, and dystocia were associated with stress UI only; age of menarche and dystocia were associated with urge UI only, and living in a city or countryside, a history of pelvic operation, urinary infection, diseases of the respiratory system, heart disease, and alcohol consumption with mixed UI. Conclusions: UI is a highly prevalent condition among women in Hebei Province, PR China. Stress, urge, and mixed UI not only have some related factors in common but also have some different ones. Economic condition and a lack of UI-related knowledge are factors keeping patients from seeing a doctor.

Serum chemokine CXC Ligand 16 (CXCL16) concentration is associated with atherosclerosis and CXCL16 expression may be influenced by the polymorphism, A181V. We established whether serum CXCL16 concentration or the A181V genotype is more strongly associated with atherosclerotic stroke and its associated risk factor, carotid atherosclerosis.PCR-RFLP was used to genotype 244 atherosclerotic stroke patients (AS group), 153 stroke-free controls (patient controls) and 167 healthy controls. Serum CXCL16 concentration was determined for a subset of patients (n=135) and all controls. The same subset of patients was then examined using ultrasound to evaluate their carotid atherosclerotic lesions, including intima-media thickness (IMT), plaque stability and carotid plaque area (CPA).Compared with the patient controls and healthy controls, serum CXCL16 concentration was significantly increased in the AS group (P0.05, and 0.01). It was also strongly associated with increased IMT, vulnerable plaque and increased CPA (P0.05,0.001, and0.01). However, the CXCL16 A181V genotype distribution and allele frequencies showed no differences between AS and control groups, nor did it influence serum CXCL16 concentration.Serum CXCL16 concentration is significantly associated with atherosclerotic stroke and carotid atherosclerosis, suggesting that this biochemical test may be useful to identify patients at increased risk of atherosclerosis.

A new type of composite material, stainless steel fiber and carbon fiber-reinforced polyether-ether-ketone (PEEK), was investigated to study its friction and wear properties and mechanisms. The friction materials containing 11 ingredients were hot-pressed and tested using a pad-on-disc type wear tester under unlubricated sliding friction and wear conditions at a constant sliding speed. The worn surface morphology was observed by Field-emission Scanning Electron Microscope (FE-SEM) and Atomic Force Microscope (AFM). The role of transfer film was studied using X-ray photoelectron spectroscopy (XPS) to investigate the thermal decomposition of the friction material. The fade ratio of the composites was only 4.8%, the recovery ratio 107%, and the total wear ratio was as low as 0.99 × 10−7 cm3(N m)−1, showing the perfect properties of heat stability and recovery, as well as high antiwear ability of the composites. Adherence abrasion and particle abrasion take place at higher temperature. A transfer film is formed, which may improve abrasive resistant performance to get stable friction coefficient and low abrasion value for composite friction materials.

Model and simulation are good tools for design optimization of fuel cell systems. This paper proposes a new hybrid model of proton exchange membrane fuel cell (PEMFC). The hybrid model includes physical component and black-box component. The physical component represents the well-known part of PEMFC, while artificial neural network (ANN) component estimates the poorly known part of PEMFC. The ANN model can compensate the performance of the physical model. This hybrid model is implemented on Matlab/Simulink software. The hybrid model shows better accuracy than that of the physical model and ANN model. Simulation results suggest that the hybrid model can be used as a suitable and accurate model for PEMFC.

The Raman spectra of unintentionally doped gallium nitride (GaN) and Mg-doped GaN films were investigated and compared at room temperature and low temperature. The differences of E2 and A1(LO) mode in two samples are discussed. Stress relaxation is observed in Mg-doped GaN, and it is suggested that Mg-induced misfit dislocation and electron–phonon interaction are the possible origins. A peak at 247 cm−1 is observed in both the Raman spectra of GaN and Mg-doped GaN. Temperature-dependent Raman scattering experiment of Mg-doped GaN shows the frequency and intensity changes of this peak with temperature. This peak is attributed to the defect-induced vibrational mode.

We investigated the expression and subcellular localization of the multidomain protein POSH (plenty of SH3s) by immunohistochemistry and western blot analysis, as well as its role in the selective activation of mixed-lineage kinases (MLKs) 3, MAP kinase kinase (MKK) 4, c-Jun N-terminal kinases (JNKs) and the c-Jun signalling cascade in the rat hippocampal CA1 region following cerebral ischaemia. Our results indicated that the cytosol immunoreactivity of POSH was strong in the CA1-CA3 pyramidal cell but weak in the DG granule cell of the rat hippocampus both in sham control and after reperfusion. Co-immunoprecipitation experiments showed that the interactions of MLK3, MKK4 and phospho-JNKs with POSH were persistently enhanced during the early (30 min) and the later reperfusion period (from 1 to 3 days) compared with sham controls. Consistently, MLK3-MKK4-JNK activation was rapidly increased with peaks both at 30 min and 3 days of reperfusion. Intracerebroventricular infusion of POSH antisense oligodeoxynucleotides (AS-ODNs) not only significantly reduced the protein level of POSH, markedly decreased its interactions with MLK3, MKK4 and phospho-JNKs, but also attenuated the activation of the JNK signalling pathway. In addition, infusion of POSH AS-ODNs significantly increased the neuronal density in the CA1 region at 5 days of reperfusion. Our results suggest that POSH might serve as a scaffold mediating JNK signalling activation in the hippocampal CA1 region following cerebral ischaemia, and POSH AS-ODNs exerts its protective effects on ischaemic injury through a mechanism of inhibition of the MLK3-MKK4-JNK signalling pathway, involving c-Jun and caspase 3 activation.

Mitogen-activated protein kinase kinase (MKK) 7, a specific upstream activator of Jun N-terminal kinases (JNKs) in the stress-activated protein kinase (SAPK)/JNK signaling pathway, plays an important role in response to global cerebral ischemia. We investigated the subcellular localization of activated (phosphorylated) MKK (p-MKK) 7 using western blotting, immunoprecipitation and immunohistochemistry analysis in rat hippocampus. Transient forebrain ischemia was induced by the four-vessel occlusion method on Sprague-Dawley rats. Our results showed that both protein expression and activation of MKK7 were increased rapidly with peaks at 10 min of reperfusion in the nucleus of the hippocampal CA1 region. Simultaneously, in the cytosol activated MKK7 enhanced gradually and peaked at 30 min of reperfusion. In addition, we also detected JNK-interacting protein (JIP) 1, which accumulated in the perinuclear region of neurons at 30 min of reperfusion. Interestingly, at the same time-point the binding of JIP-1 to p-MKK7 reached a maximum. Consequently, we concluded that MKK7 was rapidly activated and then translocated from the nucleus to the cytosol depending on its activation in the hippocampal CA1 region. To further elucidate the possible mechanism of MKK7 activation and translocation, the antioxidant N-acetylcysteine was injected into the rats 20 min before ischemia. The result showed that the levels of MKK7 activation, translocation and binding of p-MKK7 to JIP-1 were obviously limited by N-acetylcysteine in the cytosol at 30 min after reperfusion. The findings suggested that MKK7 activation, translocation and binding to JIP-1 were closely associated with reactive oxygen species and might play a pivotal role in the activation of the JNK signaling pathway in brain ischemic injury.

Activation (phosphorylation) and the possible mechanism of extracellular signal-regulated kinase 5 (ERK5) were evaluated after cerebral ischemia-reperfusion (I/R) in the hippocampus in a four-vessel occlusion model of Sprague-Dawley rats. Western blotting showed that ERK5 was strongly activated from 10 min to 1 day and peaked at 30 min of reperfusion after 15 min ischemia. Pretreatment with N-acetylcysteine, a free radical scavenger, effectively inhibited ERK5 activation in a dose-dependent manner. Consistently, ERK5 activation was significantly suppressed by genistein (protein-tyrosine kinase inhibitor), PP2 (specific inhibitor of Src family kinases), nifedipine (L-VGCC blocker) and dextromethorphan (NMDA receptor antagonist), but not 6,7-dinitroquinoxaline-2, 3(1H, 4H)-dione (AMPA receptor antagonist). These results suggested that ERK5 could be significantly activated by I/R, which might be mediated by NMDA receptor and L-VGCC through Src kinase pathway involving oxidative stress in rat hippocampus.

Purpose: To prepare and characterize a formulation containing an ethanol extract of Camellia ptilophylla leaves (cocoa tea), with a focus on antihyperlipidemic and anti-obesity activities. Methods: An aloe vera–based formulation of an ethanol extract of cocoa tea ( C. ptilophylla ) was prepared. The formulation was given orally at 400 mg/kg daily to obese (high-fat diet–induced) mice for 1 month, and body weight as well as total cholesterol, triglyceride, HDL cholesterol, LDL cholesterol, and VLDL cholesterol levels were determined and compared with those of control and standard groups (the latter mice received atorvastatin at 400 mg/kg daily). Results: At the end of treatment, the standard group exhibited 64.65 % reduction in body weight gain and the test group exhibited 48.87 % reduction, compared with control. The group that received the formulation had significantly lower levels of serum total cholesterol, triglycerides, and LDL cholesterol, and a higher level of HDL cholesterol. Conclusion: The formulation of an ethanolic extract of cocoa tea leaves seems to exert antihyperlipidemic and anti-obesity activities comparable to those of a modern lipid-lowering agent (atorvastatin) in mice. Thus, this natural remedy has the potential to prevent or delay hyperlipidemia and the cardiovascular complications associated with diet-induced obesity. Keywords: Obesity, Lipid profile, Cocoa tea ( Camellia ptilophylla ) leaves, Weight management, Herbal formulation, Antihyperlipidemic, Anti-obesity

A new fluorescent Zn2+ chemosensor (3) based on functionalized 8-hydroxylquinoline has been synthesized and characterized. Compound 3 shows weak fluorescence in CH3CN–HEPES buffer solution (50 mM, pH 7.2 v/v = 1:9), but the fluorescence is significantly enhanced upon binding to Zn2+ through a zinc(II)-catalyzed ester hydrolysis reaction to form a highly emissive zinc(II) complex. This suggests that 3 can be served as a typical “switch–on” chemosensor with high selectivity for Zn2+ over other metal ions.

To investigate whether N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) can inhibit the differentiation of pulmonary fibroblasts into myofibroblasts by regulating Rho-associated coiled-coil forming protein kinase (ROCK) pathway mediated by transforming growth factor-β1 (TGF-β1).Primary culture of pulmonary fibroblasts was performed by trypsinization method. Four generations of pulmonary fibroblasts were divided into control group, TGF-β-induced differentiation group, Y-27632 treatment group, and Ac-SDKP treatment group. The intracellular distributions of ROCK, serum response factor (SRF), and α-smooth muscle actin (α-SMA) were observed by confocal laser scanning microscopy. The protein expression of ROCK, SFR, α-SMA, and type I and type III collagen in pulmonary fibroblasts was measured by Western blot. The mRNA expression of ROCK, SFR, and α-SMA was measured by real-time quantitative PCR.Compared with the control group, the pulmonary fibroblasts stimulated by TGF-β1 had a lot of α-SMA antibody-labeled myofilaments in parallel or cross arrangement, as observed by confocal laser scanning microscopy, and the mRNA and protein expression of ROCK, SRF, and α-SMA and protein expression of type I and type III collagen increased significantly after 6, 12, and 24 h of stimulation (P0.05). Compared with the TGF-β1-induced differentiation group, the Y-27632 treatment group and Ac-SDKP treatment group had significantly decreased mRNA and protein expression of ROCK, SRF, and α-SMA and protein expression of type I and type III collagen at the same time point (P0.05).Ac-SDKP can inhibit the differentiation of pulmonary fibroblasts into myofibroblasts and the synthesis of collagen in rats by regulating the ROCK pathway mediated by TGF-β1. That may be one of the mechanisms by which Ac-SDKP acts against (silicotic) pulmonary fibrosis.

Solid pseudopapillary tumors (SPT) are rare, unique pancreatic tumors with benign entity and low malignant potential. Limited information is available in the literature reporting their accumulation of fluorine-18 fluoro deoxyglucose ((18)F-FDG) using positron emission tomography/computed tomography (PET/CT). The aim of this retrospective study was to define t he uptake-accumulation of (18)F-FDG PET/CT in a comparatively large cohort of SPT, and to compare their uptake with the uptake of (18)F-FDG in pancreatic ductal adenocarcinomas (PAC) and neuroendocrine tumors (PNET). Between June 2007 and January 2013, 18 pathologically proven SPT were identified from the total of patients studied by PET/CT in our Center, including 13 women and 5 men, aging from 23 to 56 years old (mean age, 38.5 years). Malignant SPT was histologically classified using the WHO criteria. Eighty-six PAC patients and 28 PNET patients were also identified and included in this study for comparison. Positron emission tomography results were considered as positive if focal accumulation of (18)F-FDG exceeded the surrounding normal pancreatic tissue. Regions of interest were drawn on the pancreatic lesions, and the maximal standardized uptake values (SUVmax values) were calculated. The mean values of SUVmax were compared with independent-samples t test or with the nonparametric Mann-Whitney U method. Correlation of SUVmax values and tumor size were analyzed in cases of SPT. Receiver operating characteristics (ROC curve) were used to study the efficiency of SUV values for the differential diagnosis between SPT versus (vs) PAC and SPT vs PNET. A value of P0.05 was considered statistically significant. All SPT cases were (18)F-FDG-PET positive, with SUVmax values ranging from 3.5-18.3. The SUVmax values of SPT had poor correlation with tumor size, and no significant difference by gender and age. Areas under the curve ROC were 0.619 and 0.526, respectively for the differentiation of SPT from PNET and PAC tumors. Five SPT tumors were malignant, and exhibited relatively low (18)F-FDG uptake (SUVmax range, 3.0-4.5) except a tumor after recurrence (SUVmax 17.7). Images of CT were of low dose and thus were not evaluated. In conclusion, our results suggest that SPT benign or malignant are consistently hyperaccumulating (18)F-FDG above SUVmax 3. Differentiation from PAC and PNET if only based on the higher SUVmax values was not possible but if based on lower SUVmax, of ≤2.6 (in 14%) and ≤2.5 (in 21,4%) of PAC and PNET, respectively, these pancreatic tumors could be differentiated from SPT.