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1.  Exosomes derived from atorvastatin-modified bone marrow dendritic cells ameliorate experimental autoimmune myasthenia gravis by up-regulated levels of IDO/Treg and partly dependent on FasL/Fas pathway 
Background
Previously, we have demonstrated that spleen-derived dendritic cells (DCs) modified with atorvastatin suppressed immune responses of experimental autoimmune myasthenia gravis (EAMG). However, the effects of exosomes derived from atorvastatin-modified bone marrow DCs (BMDCs) (statin-Dex) on EAMG are still unknown.
Methods
Immunophenotypical characterization of exosomes from atorvastatin- and dimethylsulfoxide (DMSO)-modified BMDCs was performed by electron microscopy, flow cytometry, and western blotting. In order to investigate whether statin-DCs-derived exosomes (Dex) could induce immune tolerance in EAMG, we administrated statin-Dex, control-Dex, or phosphate-buffered saline (PBS) into EAMG rats via tail vein injection. The tracking of injected Dex and the effect of statin-Dex injection on endogenous DCs were performed by immunofluorescence and flow cytometry, respectively. The number of Foxp3+ cells in thymuses was examined using immunocytochemistry. Treg cells, cytokine secretion, lymphocyte proliferation, cell viability and apoptosis, and the levels of autoantibody were also carried out to evaluate the effect of statin-Dex on EAMG rats. To further investigate the involvement of FasL/Fas in statin-Dex-induced apoptosis, the underlying mechanisms were studied by FasL neutralization assays.
Results
Our data showed that the systemic injection of statin-Dex suppressed the clinical symptoms of EAMG rats. These statin-Dex had immune regulation functions in immune organs, such as the spleen, thymus, and popliteal and inguinal lymph nodes. Furthermore, statin-Dex exerted their immunomodulatory effects in vivo by decreasing the expression of CD80, CD86, and MHC class II on endogenous DCs. Importantly, the therapeutic effects of statin-Dex on EAMG rats were associated with up-regulated levels of indoleamine 2,3-dioxygenase (IDO)/Treg and partly dependent on FasL/Fas pathway, which finally resulted in decreased synthesis of anti-R97–116 IgG, IgG2a, and IgG2b antibodies.
Conclusions
Our data suggest that atorvastatin-induced immature BMDCs are able to secrete tolerogenic Dex, which are involved in the suppression of immune responses in EAMG rats. Importantly, our study provides a novel cell-free approach for the treatment of autoimmune diseases.
doi:10.1186/s12974-016-0475-0
PMCID: PMC4710023  PMID: 26757900
Atorvastatin; Exosomes; Experimental autoimmune myasthenia gravis; IDO; FasL
2.  Minor Prenylated Flavonoids from the Twigs of Macarangaadenantha and Their Cytotoxic Activity 
Three new minor prenylated flavonoids, named macadenanthins A–C (1–3), together with three known ones (4–6), were isolated from the twigs of Macaranga adenantha. Their structures were elucidated on the basis of extensive spectroscopic analysis including NMR, UV and MS. The prenyl moieties in compounds 1–3 were further modified by cyclization and hydroxylation. The new compounds were tested for their cytotoxicity against four cancer cell lines (MCF-7, Hep G2, Hela and P388) and showed IC50 values in the range of 13.76–22.27 μM.
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-015-0059-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s13659-015-0059-1
PMCID: PMC4402582  PMID: 25858705
Macaranga adenantha; Prenylated Flavonoids; Macadenanthins A–C; Cytotoxicity
3.  Minor Prenylated Flavonoids from the Twigs of Macarangaadenantha and Their Cytotoxic Activity 
Three new minor prenylated flavonoids, named macadenanthins A–C (1–3), together with three known ones (4–6), were isolated from the twigs of Macaranga adenantha. Their structures were elucidated on the basis of extensive spectroscopic analysis including NMR, UV and MS. The prenyl moieties in compounds 1–3 were further modified by cyclization and hydroxylation. The new compounds were tested for their cytotoxicity against four cancer cell lines (MCF-7, Hep G2, Hela and P388) and showed IC50 values in the range of 13.76–22.27 μM.
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-015-0059-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s13659-015-0059-1
PMCID: PMC4402582  PMID: 25858705
Macaranga adenantha; Prenylated Flavonoids; Macadenanthins A–C; Cytotoxicity
4.  Co-activation of nAChR and mGluR induces γ oscillation in rat medial septum diagonal band of Broca slices 
Acta Pharmacologica Sinica  2014;35(2):175-184.
Aim:
To examine whether co-activation of nAChR and mGluR1 induced γ oscillation (20–60 Hz) in rat medial septum diagonal band of Broca (MSDB) slices.
Methods:
Rat brain sagittal slices containing the MSDB were prepared. Extracellular field potentials were recorded with glass microelectrodes. The nAChR and mGluR1 agonists were applied to the slices to induce network activity. Data analysis was performed off-line using software Spike 2.
Results:
Co-application of the nAChR agonist nicotine (1 μmol/L) and the mGluR1 agonist dihydroxyphenylglycine (DHPG, 25 μmol/L) was able to induce γ oscillation in MSDB slices. The intensity of nAChR and mGluR1 activation was critical for induction of network oscillation at a low (θ oscillation) or high frequency (γ oscillation): co-application of low concentrations of the two agonists only increased the power and frequency of oscillation within the range of θ, whereas γ oscillation mostly appeared when high concentrations of the two agonists were applied.
Conclusion:
Activation of mGluR1 and nAChR is able to program slow or fast network oscillation by altering the intensity of receptor activation, which may provide a mechanism for modulation of learning and memory.
doi:10.1038/aps.2013.138
PMCID: PMC4651216  PMID: 24389946
nAChR; mGluR1; DHPG; nicotine; θ oscillation; γ oscillation; the medial septum diagonal band of Broca; learning and memory
5.  Epigenetic and metabolic regulation of breast cancer stem cells*  
Breast cancer has a relatively high mortality rate in women due to recurrence and metastasis. Increasing evidence has identified a rare population of cells with stem cell-like properties in breast cancer. These cells, termed cancer stem cells (CSCs), which have the capacity for self-renewal and differentiation, contribute significantly to tumor progression, recurrence, drug resistance and metastasis. Clarifying the mechanisms regulating breast CSCs has important implications for our understanding of breast cancer progression and therapeutics. A strong connection has been found between breast CSCs and epithelial mesenchymal transition (EMT). In addition, recent studies suggest that the maintenance of the breast CSC phenotype is associated with epigenetic and metabolic regulation. In this review, we focus on recent discoveries about the connection between EMT and CSC, and advances made in understanding the roles and mechanisms of epigenetic and metabolic reprogramming in controlling breast CSC properties.
doi:10.1631/jzus.B1400172
PMCID: PMC4288940  PMID: 25559951
Cancer stem cells (CSCs); Epithelial mesenchymal transition (EMT); Epigenetic modification; Metabolic reprogramming; Breast cancer
6.  A two-layer integration framework for protein complex detection 
BMC Bioinformatics  2016;17:100.
Background
Protein complexes carry out nearly all signaling and functional processes within cells. The study of protein complexes is an effective strategy to analyze cellular functions and biological processes. With the increasing availability of proteomics data, various computational methods have recently been developed to predict protein complexes. However, different computational methods are based on their own assumptions and designed to work on different data sources, and various biological screening methods have their unique experiment conditions, and are often different in scale and noise level. Therefore, a single computational method on a specific data source is generally not able to generate comprehensive and reliable prediction results.
Results
In this paper, we develop a novel Two-layer INtegrative Complex Detection (TINCD) model to detect protein complexes, leveraging the information from both clustering results and raw data sources. In particular, we first integrate various clustering results to construct consensus matrices for proteins to measure their overall co-complex propensity. Second, we combine these consensus matrices with the co-complex score matrix derived from Tandem Affinity Purification/Mass Spectrometry (TAP) data and obtain an integrated co-complex similarity network via an unsupervised metric fusion method. Finally, a novel graph regularized doubly stochastic matrix decomposition model is proposed to detect overlapping protein complexes from the integrated similarity network.
Conclusions
Extensive experimental results demonstrate that TINCD performs much better than 21 state-of-the-art complex detection techniques, including ensemble clustering and data integration techniques.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-016-0939-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12859-016-0939-3
PMCID: PMC4765032  PMID: 26911324
Protein complex; Protein interaction data; Co-complex matrix; Consensus matrix; Matrix fusion; Matrix decomposition
7.  Caspase-1 inhibitor ameliorates experimental autoimmune myasthenia gravis by innate dendric cell IL-1-IL-17 pathway 
Background
IL-1β has been shown to play a pivotal role in autoimmunity. Cysteinyl aspartate-specific proteinase-1 (caspase-1) inhibitor may be an important drug target for autoimmune diseases. However, the effects of caspase-1 inhibitor on myasthenia gravis (MG) remain undefined.
Methods
To investigate the effects of caspase-1 inhibitor on experimental autoimmune myasthenia gravis (EAMG), an animal model of MG, caspase-1 inhibitor was administered to Lewis rats immunized with region 97–116 of the rat AChR α subunit (R97-116 peptide) in complete Freund’s adjuvant. The immunophenotypical characterization by flow cytometry and the levels of autoantibody by ELISA were carried out to evaluate the neuroprotective effect of caspase-1 inhibitor.
Results
We found that caspase-1 inhibitor improved EAMG clinical symptom, which was associated with decreased IL-17 production by CD4+ T cells and γδ T cells, lower affinity of anti-R97-116 peptide IgG. Caspase-1 inhibitor decreased expression of CD80, CD86, and MHC class II on DCs, as well as intracellular IL-1β production from DCs. In addition, caspase-1 inhibitor treatment inhibited R97-116 peptide-specific cell proliferation and decreased follicular helper T cells relating to EAMG development.
Conclusions
Our results suggest that caspase-1 inhibitor ameliorates experimental autoimmune myasthenia gravis by innate DC IL-1-IL-17 pathway and provides new evidence that caspase-1 is an important drug target in the treatment of MG and other autoimmune diseases.
doi:10.1186/s12974-015-0334-4
PMCID: PMC4470006  PMID: 26071315
Caspase-1 inhibitor; IL-1β; Dendric cell; Th17 cell; Follicular helper T cell; Experimental autoimmune myasthenia gravis
8.  Autophagy induction contributes to the resistance to methotrexate treatment in rheumatoid arthritis fibroblast-like synovial cells through high mobility group box chromosomal protein 1 
Background
Rheumatoid arthritis fibroblast-like synovial cells (RA-FLS) show resistance to methotrexate (MTX) treatment. To better understand the mechanisms of this resistance, RA-FLS and osteoarthritis fibroblast-like synovial cells (OA-FLS) were isolated and exposed to MTX. We analyzed the autophagy induced by MTX in vitro and its relationship to apoptosis.
Methods
Cell viability was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was detected by flow cytometry and Western blot analysis. Autophagy was determined by transmission electron microscopy as well as Western blot analysis. The expression levels of Beclin-1, LC3, Akt, p-Akt, mammalian target of rapamycin (mTOR), p-mTOR, high mobility group box chromosomal protein 1 (HMGB1), and an 85 kDa caspase cleaved fragment of poly(ADP-ribose) polymerase were measured by Western blotting.
Results
MTX-induced apoptosis was increased in OA-FLS compared with RA-FLS. However, MTX stimulated the autophagy response in RA-FLS by inducing autophagosome formation, but not in OA-FLS. In RA-FLS, transfection with Beclin-1 small interfering RNA inhibited autophagy and increased susceptibility to MTX, which induces cell death. MTX upregulated autophagy through its ability to enhance the expression of HMGB1 and Beclin-1 rather than through the Akt/mTOR pathway.
Conclusions
Autophagy induction contributes to resistance to MTX treatment in fibroblasts from patients with rheumatoid arthritis.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0892-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-015-0892-y
PMCID: PMC4718027  PMID: 26702616
Rheumatoid arthritis; Fibroblast-like synovial cells; Methotrexate; Autophagy; Apoptosis
9.  Discovery of Protein Complexes with Core-Attachment Structures from Tandem Affinity Purification (TAP) Data 
Journal of Computational Biology  2012;19(9):1027-1042.
Abstract
Many cellular functions involve protein complexes that are formed by multiple interacting proteins. Tandem Affinity Purification (TAP) is a popular experimental method for detecting such multi-protein interactions. However, current computational methods that predict protein complexes from TAP data require converting the co-complex relationships in TAP data into binary interactions. The resulting pairwise protein-protein interaction (PPI) network is then mined for densely connected regions that are identified as putative protein complexes. Converting the TAP data into PPI data not only introduces errors but also loses useful information about the underlying multi-protein relationships that can be exploited to detect the internal organization (i.e., core-attachment structures) of protein complexes. In this article, we propose a method called CACHET that detects protein complexes with Core-AttaCHment structures directly from bipartitETAP data. CACHET models the TAP data as a bipartite graph in which the two vertex sets are the baits and the preys, respectively. The edges between the two vertex sets represent bait-prey relationships. CACHET first focuses on detecting high-quality protein-complex cores from the bipartite graph. To minimize the effects of false positive interactions, the bait-prey relationships are indexed with reliability scores. Only non-redundant, reliable bicliques computed from the TAP bipartite graph are regarded as protein-complex cores. CACHET constructs protein complexes by including attachment proteins into the cores. We applied CACHET on large-scale TAP datasets and found that CACHET outperformed existing methods in terms of prediction accuracy (i.e., F-measure and functional homogeneity of predicted complexes). In addition, the protein complexes predicted by CACHET are equipped with core-attachment structures that provide useful biological insights into the inherent functional organization of protein complexes. Our supplementary material can be found at http://www1.i2r.a-star.edu.sg/∼xlli/CACHET/CACHET.htm; binary executables can also be found there. Supplementary Material is also available at www.liebertonline.com/cmb.
doi:10.1089/cmb.2010.0293
PMCID: PMC3440013  PMID: 21777084
algorithms; gene clusters; gene networks
10.  Effects of nicotine stimulation on spikes, theta frequency oscillations, and spike-theta oscillation relationship in rat medial septum diagonal band Broca slices 
Acta Pharmacologica Sinica  2013;34(4):464-472.
Aim:
Spiking activities and neuronal network oscillations in the theta frequency range have been found in many cortical areas during information processing. The aim of this study is to determine whether nicotinic acetylcholine receptors (nAChRs) mediate neuronal network activity in rat medial septum diagonal band Broca (MSDB) slices.
Methods:
Extracellular field potentials were recorded in the slices using an Axoprobe 1A amplifier. Data analysis was performed off-line. Spike sorting and local field potential (LFP) analyses were performed using Spike2 software. The role of spiking activity in the generation of LFP oscillations in the slices was determined by analyzing the phase-time relationship between the spikes and LFP oscillations. Circular statistic analysis based on the Rayleigh test was used to determine the significance of phase relationships between the spikes and LFP oscillations. The timing relationship was examined by quantifying the spike-field coherence (SFC).
Results:
Application of nicotine (250 nmol/L) induced prominent LFP oscillations in the theta frequency band and both small- and large-amplitude population spiking activity in the slices. These spikes were phase-locked to theta oscillations at specific phases. The Rayleigh test showed a statistically significant relationship in phase-locking between the spikes and theta oscillations. Larger changes in the SFC were observed for large-amplitude spikes, indicating an accurate timing relationship between this type of spike and LFP oscillations. The nicotine-induced spiking activity (large-amplitude population spikes) was suppressed by the nAChR antagonist dihydro-β-erythroidine (0.3 μmol/L).
Conclusion:
The results demonstrate that large-amplitude spikes are phase-locked to theta oscillations and have a high spike-timing accuracy, which are likely a main contributor to the theta oscillations generated in MSDB during nicotine receptor activation.
doi:10.1038/aps.2012.180
PMCID: PMC4002786  PMID: 23474704
medial septum diagonal band of Broca; theta oscillations; spike; LFP; nicotinic acetylcholine receptor; nicotine; dihydro-β-erythroidine; brain slice; electrophysiology
11.  Nondestructive detection of lead chrome green in tea by Raman spectroscopy 
Scientific Reports  2015;5:15729.
Raman spectroscopy was first adopted for rapid detecting a hazardous substance of lead chrome green in tea, which was illegally added to tea to disguise as high-quality. 160 samples of tea infusion with different concentrations of lead chrome green were prepared for Raman spectra acquirement in the range of 2804 cm−1–230 cm−1 and the spectral intensities were calibrated with relative intensity standards. Then wavelet transformation (WT) was adopted to extract information in different time and frequency domains from Raman spectra, and the low-frequency approximation signal (ca4) was proved as the most important information for establishment of lead chrome green measurement model, and the corresponding partial least squares (PLS) regression model obtained good performance in prediction with Rp and RMSEP of 0.936 and 0.803, respectively. To further explore the important wavenumbers closely related to lead chrome green, successive projections algorithm (SPA) was proposed. Finally, 8 characteristic wavenumbers closely related to lead chrome green were obtained and a more convenient and fast model was also developed. These results proved the feasibility of Raman spectroscopy for nondestructive detection of lead chrome green in tea quality control.
doi:10.1038/srep15729
PMCID: PMC4623710  PMID: 26508516
12.  Three-dimensional poly-(ε-caprolactone) nanofibrous scaffolds directly promote the cardiomyocyte differentiation of murine-induced pluripotent stem cells through Wnt/β-catenin signaling 
BMC Cell Biology  2015;16:22.
Background
Environmental factors are important for stem cell lineage specification, and increasing evidence indicates that the nanoscale geometry/topography of the extracellular matrix (ECM) directs stem cell fate. Recently, many three-dimensional (3D) biomimetic nanofibrous scaffolds resembling many characteristics of the native ECM have been used in stem cell-based myocardial tissue engineering. However, the biophysical role and underlying mechanism of 3D nanofibrous scaffolds in cardiomyocyte differentiation of induced pluripotent stem cells (iPSCs) remain unclear.
Results
Here, we fabricated a 3D poly-(ε-caprolactone) (PCL) nanofibrous scaffold using the electrospinning method and verified its nanotopography and porous structure by scanning electron microscopy. We seeded murine iPSCs (miPSCs) directly on the 3D PCL nanofibrous scaffold and initiated non-directed, spontaneous differentiation using the monolayer method. After the 3D PCL nanofibrous scaffold was gelatin coated, it was suitable for monolayer miPSC cultivation and cardiomyocyte differentiation. At day 15 of differentiation, miPSCs differentiated into functional cardiomyocytes on the 3D PCL nanofibrous scaffold as evidenced by positive immunostaining of cardiac-specific proteins including cardiac troponin T (cTnT) and myosin light chain 2a (MLC2a). In addition, flow cytometric analysis of cTnT-positive cells and cardiac-specific gene and protein expression of cTnT and sarcomeric alpha actinin (α-actinin) demonstrated that the cardiomyocyte differentiation of miPSCs was more efficient on the 3D PCL nanofibrous scaffold than on normal tissue culture plates (TCPs). Furthermore, early inhibition of Wnt/β-catenin signaling by the selective antagonist Dickkopf-1 significantly reduced the activity of Wnt/β-catenin signaling and decreased the cardiomyocyte differentiation of miPSCs cultured on the 3D PCL nanofibrous scaffold, while the early activation of Wnt/β-catenin signaling by CHIR99021 further increased the cardiomyocyte differentiation of miPSCs.
Conclusion
These results indicated that the electrospun 3D PCL nanofibrous scaffolds directly promoted the cardiomyocyte differentiation of miPSCs, which was mediated by the activation of the Wnt/β-catenin signaling during the early period of differentiation. These findings highlighted the biophysical role of 3D nanofibrous scaffolds during the cardiomyocyte differentiation of miPSCs and revealed its underlying mechanism involving Wnt/β-catenin signaling, which will be helpful in guiding future stem cell- and scaffold-based myocardium bioengineering.
Electronic supplementary material
The online version of this article (doi:10.1186/s12860-015-0067-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12860-015-0067-3
PMCID: PMC4558999  PMID: 26335746
Poly-(ε-caprolactone); Nanofibrous scaffold; Induced pluripotent stem cell; Cardiomyocyte differentiation
13.  Changed Synaptic Plasticity in Neural Circuits of Depressive-Like and Escitalopram-Treated Rats 
Background:
Although progress has been made in the detection and characterization of neural plasticity in depression, it has not been fully understood in individual synaptic changes in the neural circuits under chronic stress and antidepressant treatment.
Methods:
Using electron microscopy and Western-blot analyses, the present study quantitatively examined the changes in the Gray’s Type I synaptic ultrastructures and the expression of synapse-associated proteins in the key brain regions of rats’ depressive-related neural circuit after chronic unpredicted mild stress and/or escitalopram administration. Meanwhile, their depressive behaviors were also determined by several tests.
Results:
The Type I synapses underwent considerable remodeling after chronic unpredicted mild stress, which resulted in the changed width of the synaptic cleft, length of the active zone, postsynaptic density thickness, and/or synaptic curvature in the subregions of medial prefrontal cortex and hippocampus, as well as the basolateral amygdaloid nucleus of the amygdala, accompanied by changed expression of several synapse-associated proteins. Chronic escitalopram administration significantly changed the above alternations in the chronic unpredicted mild stress rats but had little effect on normal controls. Also, there was a positive correlation between the locomotor activity and the maximal synaptic postsynaptic density thickness in the stratum radiatum of the Cornu Ammonis 1 region and a negative correlation between the sucrose preference and the length of the active zone in the basolateral amygdaloid nucleus region in chronic unpredicted mild stress rats.
Conclusion:
These findings strongly indicate that chronic stress and escitalopram can alter synaptic plasticity in the neural circuits, and the remodeled synaptic ultrastructure was correlated with the rats’ depressive behaviors, suggesting a therapeutic target for further exploration.
doi:10.1093/ijnp/pyv046
PMCID: PMC4648155  PMID: 25899067
Synapse; plasticity; depression; rat
14.  Chemical constituents from the aerial parts of Euphorbia sikkimensis and their bioactivities 
Phytochemical investigation of the aerial parts of Euphorbia sikkimensis led to the isolation of one new diterpenoids, named sikkimenoid E (1), together with thirteen other known compounds (2–14). Their structures were established by means of spectroscopic methods. Compound 2 was identified to be a trinortriterpenoid, and derived for the first time from a natural source. In this paper we reveal for the first time its comprehensive spectral data and NMR spectral assignment. Compound 4 showed antiangiogenic activity with an IC50 value of 5.66 µM in a zebrafish model, and compounds 5 and 6 exhibited cytotoxicity toward A549 cell line with IC50 values of 12.12 and 6.45 µM, respectively.
Electronic Supplementary Material
Supplementary material is available for this article at 10.1007/s13659-013-0006-y and is accessible for authorized users.
doi:10.1007/s13659-013-0006-y
PMCID: PMC4131670
Euphorbia sikkimensis; ingenol; trinortriterpenoid; tocopherol derivatives; bioactivities
15.  Erlotinib Plus Capecitabine as First-Line Treatment for Older Chinese Patients With Advanced Adenocarcinoma of the Lung (C-TONG0807) 
Medicine  2015;94(2):e249.
Abstract
Preclinical studies have shown synergism between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and antifolates in solid tumors. This study is to investigate the efficacy and tolerability of erlotinib plus capecitabine as first-line treatment in older Chinese patients (≥ 65 years) with lung adenocarcinoma.
This is an open-label, single arm, multicenter phase II clinical trial. Sixty- two patients with previously untreated stage IIIB/IV adenocarcinoma and age 65 years or above were enrolled at four tertiary teaching hospitals and 2 provincial hospitals in China; 58 patients fulfilled the study requirements. Erlotinib (150 mg/day) and capecitabine (1000 mg/m2 twice daily on days 1–14) were administered during every 21-day cycle. The primary endpoint was the non-progression rate at 12 weeks. EGFR and K-ras mutation rates were determined using PCR. Tumor expression of different biomarkers was assessed using immunohistochemistry.
In a cohort of 58 patients, 34 patients had no disease progression at 12 weeks following treatment. The objective response rate was 29.3%, and the disease control rate was 75.9%. The objective response rate was significantly higher in patients with EGFR mutations than in those with wild-type EGFR. Patients with thymidine phosphorylase-negative tumors had significantly longer overall survival after one year than patients with thymidine phosphorylase-positive tumors. Forty-four patients had at least one primary adverse events (AEs), including skin rash (n = 30), grade 3 AEs (n = 17), and grade 4 AEs (n = 7).
This is the first phase II clinical trial to assess erlotinib plus capecitabine combination therapy as first-line treatment in older patients with lung adenocarcinoma. Erlotinib/capecitabine chemotherapy was significantly better in patients with EGFR mutations and in those with thymidine phosphorylase-negative tumors. The use of fluorouracil derivatives for the treatment of lung adenocarcinoma warrants further study.
doi:10.1097/MD.0000000000000249
PMCID: PMC4602552  PMID: 25590835
16.  Hyperspectral Imaging for Mapping of Total Nitrogen Spatial Distribution in Pepper Plant 
PLoS ONE  2014;9(12):e116205.
Visible/near-infrared (Vis/NIR) hyperspectral imaging was employed to determine the spatial distribution of total nitrogen in pepper plant. Hyperspectral images of samples (leaves, stems, and roots of pepper plants) were acquired and their total nitrogen contents (TNCs) were measured using Dumas combustion method. Mean spectra of all samples were extracted from regions of interest (ROIs) in hyperspectral images. Random frog (RF) algorithm was implemented to select important wavelengths which carried effective information for predicting the TNCs in leaf, stem, root, and whole-plant (leaf-stem-root), respectively. Based on full spectra and the selected important wavelengths, the quantitative relationships between spectral data and the corresponding TNCs in organs (leaf, stem, and root) and whole-plant (leaf-stem-root) were separately developed using partial least-squares regression (PLSR). As a result, the PLSR model built by the important wavelengths for predicting TNCs in whole-plant (leaf-stem-root) offered a promising result of correlation coefficient (R) for prediction (RP = 0.876) and root mean square error (RMSE) for prediction (RMSEP = 0.426%). Finally, the TNC of each pixel within ROI of the sample was estimated to generate the spatial distribution map of TNC in pepper plant. The achievements of the research indicated that hyperspectral imaging is promising and presents a powerful potential to determine nitrogen contents spatial distribution in pepper plant.
doi:10.1371/journal.pone.0116205
PMCID: PMC4280196  PMID: 25549353
17.  Chemical constituents from Munronia sinica and their bioactivities 
Two new minor constituents, musinisins A (1) and B (2), together with five known compounds (3–7), were isolated from the aerial parts of Munronia sinica. Their structures were established by means of spectroscopic methods and the absolute stereochemistry of 1 was determined by single crystal X-ray experiment. Compound 4 showed antiangiogenic activity evaluated by a zebrafish model and apoptosis-inducing effect on A549 lung cancer cells.
Electronic Supplementary Material
Supplementary material is available for this article at 10.1007/s13659-012-0001-8 and is accessible for authorized users.
doi:10.1007/s13659-012-0001-8
PMCID: PMC4131585
Munronia sinica; chemical constituent; musinisin; antiangiogenic activity
18.  Detecting temporal protein complexes from dynamic protein-protein interaction networks 
BMC Bioinformatics  2014;15(1):335.
Background
Proteins dynamically interact with each other to perform their biological functions. The dynamic operations of protein interaction networks (PPI) are also reflected in the dynamic formations of protein complexes. Existing protein complex detection algorithms usually overlook the inherent temporal nature of protein interactions within PPI networks. Systematically analyzing the temporal protein complexes can not only improve the accuracy of protein complex detection, but also strengthen our biological knowledge on the dynamic protein assembly processes for cellular organization.
Results
In this study, we propose a novel computational method to predict temporal protein complexes. Particularly, we first construct a series of dynamic PPI networks by joint analysis of time-course gene expression data and protein interaction data. Then a Time Smooth Overlapping Complex Detection model (TS-OCD) has been proposed to detect temporal protein complexes from these dynamic PPI networks. TS-OCD can naturally capture the smoothness of networks between consecutive time points and detect overlapping protein complexes at each time point. Finally, a nonnegative matrix factorization based algorithm is introduced to merge those very similar temporal complexes across different time points.
Conclusions
Extensive experimental results demonstrate the proposed method is very effective in detecting temporal protein complexes than the state-of-the-art complex detection techniques.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2105-15-335) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2105-15-335
PMCID: PMC4288635  PMID: 25282536
Dynamic protein-protein interaction; Gene expression; Stable interaction; Transient interaction; Protein complex
19.  PLW: Probabilistic Local Walks for detecting protein complexes from protein interaction networks 
BMC Genomics  2013;14(Suppl 5):S15.
Background
Many biological processes are carried out by proteins interacting with each other in the form of protein complexes. However, large-scale detection of protein complexes has remained constrained by experimental limitations. As such, computational detection of protein complexes by applying clustering algorithms on the abundantly available protein-protein interaction (PPI) networks is an important alternative. However, many current algorithms have overlooked the importance of selecting seeds for expansion into clusters without excluding important proteins and including many noisy ones, while ensuring a high degree of functional homogeneity amongst the proteins detected for the complexes.
Results
We designed a novel method called Probabilistic Local Walks (PLW) which clusters regions in a PPI network with high functional similarity to find protein complex cores with high precision and efficiency in O (|V| log |V| + |E|) time. A seed selection strategy, which prioritises seeds with dense neighbourhoods, was devised. We defined a topological measure, called common neighbour similarity, to estimate the functional similarity of two proteins given the number of their common neighbours.
Conclusions
Our proposed PLW algorithm achieved the highest F-measure (recall and precision) when compared to 11 state-of-the-art methods on yeast protein interaction data, with an improvement of 16.7% over the next highest score. Our experiments also demonstrated that our seed selection strategy is able to increase algorithm precision when applied to three previous protein complex mining techniques.
Availability
The software, datasets and predicted complexes are available at http://wonglkd.github.io/PLW
doi:10.1186/1471-2164-14-S5-S15
PMCID: PMC3852146  PMID: 24564427
20.  PIMT Prevents the Apoptosis of Endothelial Cells in Response to Glycated Low Density Lipoproteins and Protective Effects of Grape Seed Procyanidin B2 
PLoS ONE  2013;8(7):e69979.
Background
The development of diabetic angiopathy is associated with profound vascular endothelial cells (VEC) dysfunction and apoptosis. Glycated low density lipoproteins (gly-LDL) continuously produced in the setting of diabetic patients play an important role in causing VEC dysfunction and apoptosis. However, the underlying molecular mechanism remains largely elusive. Protein L-isoaspartyl methyltransferase (PIMT) is a widely expressed protein repair enzyme by multiple cell types of arterial wall including VEC. Our previous proteomic studies showed that the expression of PIMT was significantly decreased in the aorta of diabetic rats as compared with control rats and treatment with grape seed procyanidin extracts significantly increased the PIMT expression in diabetic rats. We hypothesized that PIMT plays a critical role in gly-LDL induced VEC apoptosis; grape seed procyanidin B2 (GSPB2) protect against gly-LDL induced VEC apoptosis through PIMT regulation.
Methods and Results
HUVEC transfected negative control and PIMT siRNA were treated with or without GSPB2 (10 µmol/L) for 48 h. Moreover, HUVEC of PIMT overexpression were stimulated by gly-LDL (50 µg/ml) in the presence or absence of GSPB2 (10 µmol/L) for 48 h. Our results showed that gly-LDL downregulated PIMT expression and PIMT overexpression or GSPB2 significantly attenuated gly-LDL induced VEC apoptosis. PIMT siRNA increased VEC apoptosis with up-regulation of p53, cytochrome c release, caspase-9 and caspase-3 activation. Mechanistically, overexpression of PIMT or GSPB2 increased the phosphorylation of ERK1/2 and GSK3β in the gly-LDL induced VEC.
Conclusion
In summary, our study identified PIMT as a key player responsible for gly-LDL induced VEC apoptosis and GSPB2 protect against gly-LDL induced VEC apoptosis by PIMT up-regulation. Targeting PIMT including use of GSPB2 could be turned into clinical application in the fighting against diabetic vascular complications.
doi:10.1371/journal.pone.0069979
PMCID: PMC3724603  PMID: 23922881
21.  Stress and Temperature Sensitivity of Photonic Crystals Resonant Cavity 
The Scientific World Journal  2013;2013:805470.
The temperature and stress characteristic of photonic band gap structure resonant cavities with square and graphite lattice have been studied by finite-difference time-domain method. The results show that the resonant cavities, both square and graphite lattice, have more and more resonant frequency with the cavity enlarging. And the curves between the resonant frequency and stress have better linearity. When the cavity enlarges enough, the curve between resonant frequency and temperature will become sectionalized line from nonlinear curve. Especially, the temperature sensitivity will be descending as the cavity is enlarging. Nevertheless, once some structures are put in the center of the cavity, the temperature sensitivity will be rising fast for this kind of cavity. Obviously, this character is convenient for us to achieve the specification measurement for temperature and stress.
doi:10.1155/2013/805470
PMCID: PMC3725802  PMID: 23935434
22.  Modulation of Brain Electroencephalography Oscillations by Electroacupuncture in a Rat Model of Postincisional Pain 
The present study aimed to investigate how ongoing brain rhythmical oscillations changed during the postoperative pain and whether electroacupuncture (EA) regulated these brain oscillations when it relieved pain. We established a postincisional pain model of rats with plantar incision to mimic the clinical pathological pain state, tested the analgesic effects of EA, and recorded electroencephalography (EEG) activities before and after the EA application. By analysis of power spectrum and bicoherence of EEG, we found that in rats with postincisional pain, ongoing activities at the delta-frequency band decreased, while activities at theta-, alpha-, and beta-frequency bands increased. EA treatment on these postincisional pain rats decreased the power at high-frequency bands especially at the beta-frequency band and reversed the enhancement of the cross-frequency coupling strength between the beta band and low-frequency bands. After searching for the PubMed, our study is the first time to describe that brain oscillations are correlated with the processing of spontaneous pain information in postincisional pain model of rats, and EA could regulate these brain rhythmical frequency oscillations, including the power and cross-frequency couplings.
doi:10.1155/2013/160357
PMCID: PMC3655616  PMID: 23710210
23.  Prevalence of and risk factors for aspirin resistance in elderly patients with coronary artery disease 
Objective
To assess the prevalence of and related risk factors for aspirin resistance in elderly patients with coronary artery disease (CAD).
Methods
Two hundred and forty-six elderly patients (75.9 ± 7.4 years) with CAD who received daily aspirin therapy (≥ 75 mg) over one month were recruited. The effect of aspirin was assessed using light transmission aggregometry (LTA) and thrombelastography platelet mapping assay (TEG). Aspirin resistance was defined as ≥ 20% arachidonic acid (AA)-induced aggregation and ≥ 70% adenosine diphosphate (ADP)-induced aggregation in the LTA assay. An aspirin semi-responder was defined as meeting one (but not both) of the criteria described above. Based on the results of TEG, aspirin resistance was defined as ≥ 50% aggregation induced by AA.
Results
As determined by LTA, 23 (9.3%) of the elderly CAD patients were resistant to aspirin therapy; 91 (37.0%) were semi-responders. As determined by TEG, 61 patients (24.8%) were aspirin resistant. Of the 61 patients who were aspirin resistant by TEG, 19 were aspirin resistant according to LTA results. Twenty-four of 91 semi-responders by LTA were aspirin resistant by TEG. Multivariate logistic regression analysis revealed that elevated fasting serum glucose level (Odds ratio: 1.517; 95% CI: 1.176–1.957; P = 0.001) was a significant risk factor for aspirin resistance as determined by TEG.
Conclusions
A significant number of elderly patients with CAD are resistant to aspirin therapy. Fasting blood glucose level is closely associated with aspirin resistance in elderly CAD patients.
doi:10.3969/j.issn.1671-5411.2013.01.005
PMCID: PMC3627718  PMID: 23610570
Aspirin resistance; Coronary artery disease; Risk factors
24.  Effects of phlorizin on diabetic retinopathy according to isobaric tags for relative and absolute quantification–based proteomics in db/db mice 
Molecular Vision  2013;19:812-821.
Purpose
Diabetic retinopathy (DR) is a leading cause of vision loss in working-age people. To retard the development and progression of retina lesions, effective therapeutic strategies directed toward key molecular targets are desired. Phlorizin is effective in treating diabetic complications, but little is known about functional protein changes that may mediate its actions. The aim of this study was to identify retinal proteomic alterations in db/db mice treated with phlorizin.
Methods
We used C57BLKS/J db/db mice as a type 2 diabetic animal model, while C57BLKS/J db/m mice were selected as the control. Phlorizin (20 mg/kg bodyweight /d) was administrated to db/db mice for ten weeks. Serum fasting blood glucose and advanced glycation end products were determined. Meanwhile, retina cell apoptosis was determined with terminal transferase dUTP nick end labeling. Isobaric tags for relative and absolute quantification and subsequent liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to identify and profile retinal proteins among control, untreated diabetic, and phlorizin-treated db/db mice. The expression of glial fibrillary acidic protein was measured in retinas using western blotting analysis.
Results
Phlorizin treatment significantly reduced fasting blood glucose and levels of advanced glycation end products (p<0.05) and remarkably inhibited retina cell apoptosis and the expression of glial fibrillary acidic protein in the retinas of db/db mice. In addition, we identified 1,636 proteins from retina tissue in total, of which 348 proteins were differentially expressed in db/db mice compared with the controls. Only 60 proteins in the retinas of the db/db mice were found to be differentially changed following phlorizin treatment, including 33 proteins that were downregulated and 27 proteins that were upregulated. Most of these differentially changed proteins were involved in oxidative stress, apoptosis, energy metabolism, and signaling transduction.
Conclusions
Our study revealed the expression of proteins differentially changed after phlorizin therapy. These proteins are most likely to participate in the development and recovery of DR. Our findings help expand understanding of the mechanism underlying the onset and progression of DR, and provide novel targets for evaluating the effects of phlorizin therapy.
PMCID: PMC3626294  PMID: 23592918
25.  Proteomic Analysis of Aorta and Protective Effects of Grape Seed Procyanidin B2 in db/db Mice Reveal a Critical Role of Milk Fat Globule Epidermal Growth Factor-8 in Diabetic Arterial Damage 
PLoS ONE  2012;7(12):e52541.
Background
Atherosclerosis is one of the major complications of type 2 diabetic patients (T2DM), leading to morbidity and mortality. Grape seed procyanidin B2 (GSPB2) has demonstrated protective effect against atherosclerosis, which is believed to be, at least in part, a result of its antioxidative effects. The aim of this study is to identify the target protein of GSPB2 responsible for the protective effect against atherosclerosis in patients with DM.
Methods and Results
GSPB2 (30 mg/kg body weight/day) were administrated to db/db mice for 10 weeks. Proteomics of the aorta extracts by iTRAQ analysis was obtained from db/db mice. The results showed that expression of 557 proteins were either up- or down-regulated in the aorta of diabetic mice. Among those proteins, 139 proteins were normalized by GSPB2 to the levels comparable to those in control mice. Among the proteins regulated by GSPB2, the milk fat globule epidermal growth factor-8 (MFG-E8) was found to be increased in serum level in T2DM patients; the serum level of MFG-E8 was positively correlated with carotid-femoral pulse wave velocity (CF-PWV). Inhibition of MFG-E8 by RNA interference significantly suppressed whereas exogenous recombinant MFG-E8 administration exacerbated atherogenesis the db/db mice. To gain more insights into the mechanism of action of MFG-E8, we investigated the effects of MFG-E8 on the signal pathway involving the extracellular signal-regulated kinase (ERK) and monocyte chemoattractant protein-1 (MCP-1). Treatment with recombinant MFG-E8 led to increased whereas inhibition of MFG-E8 to decreased expression of MCP-1 and phosphorylation of ERK1/2.
Conclusion
Our data suggests that MFG-E8 plays an important role in atherogenesis in diabetes through both ERK and MCP-1 signaling pathways. GSPB2, a well-studied antioxidant, significantly inhibited the arterial wall changes favoring atherogenesis in db/db mice by down-regulating MFG-E8 expression in aorta and its serum level. Measuring MFG-E8 serum level could be a useful clinical surrogate prognosticating atherogenesis in DM patients.
doi:10.1371/journal.pone.0052541
PMCID: PMC3528673  PMID: 23285083

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