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1.  Enhanced hepatic delivery of siRNA and microRNA using oleic acid based lipid nanoparticle formulations 
Many cationic lipids have been developed for lipid-based nanoparticles (LNPs) for delivery of siRNA and microRNA (miRNA). However, less attention has been paid to “helper lipids”. Here, we investigated several “helper lipids” and examined their effects on the physicochemical properties such as particle size and zeta potential, as well as cellular uptake and transfection efficiency. We found that inclusion of oleic acid (OA), an unsaturated fatty acid; into the LNP formulation significantly enhanced the delivery efficacy for siRNA and miRNA. For proof-of-concept, miR-122, a liver-specific microRNA associated with many liver diseases, was used as a model agent to demonstrate the hepatic delivery efficacy both in tumor cells and in animals. Compared to Lipofectamine 2000, a commercial transfection agent, OA containing LNPs delivered microRNA-122 in a more efficient manner with a 1.8-fold increase in mature miR-122 expression and a 20% decrease in Bcl-w, a target of microRNA-122. In comparison with Invivofectamine, a commercial transfection agent specifically designed for hepatic delivery, OA containing LNPs showed comparable liver accumulation and in vivo delivery efficiency. These findings demonstrated the importance of “helper lipid” components of the LNP formulation on the cellular uptake and transfection activity of siRNA and miRNA. OA containing LNPs are a promising nanocarrier system for the delivery of RNA-based therapeutics in liver diseases.
doi:10.1016/j.jconrel.2013.09.027
PMCID: PMC4307782  PMID: 24121065
Cationic lipid nanoparticles; Helper lipids; siRNA; microRNA; Hepatic delivery
2.  Detection of ALK protein expression in lung squamous cell carcinomas by immunohistochemistry 
Background
The echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene rearrangements occur in approximately 5% of lung adenocarcimomas (ACA), leading to ALK overexpression and predicting response to targeted therapy. To the present, few studies have been focused on the expression of ALK protein in lung squamous cell carcinomas (SqCC). Only several cases of lung SqCC were reported expression of ALK protein. No clinical study has been published to explicit the relationship between ALK expression and the response to targeted therapy in SqCC.
Methods
In this study, we analyzed ALK protein expression with a specific rabbit monoclonal Ig antibody (D5F3 clone) in 207 cases of lung SqCC. The positive cases were confirmed with ALK fluorescence in situ hybridization (FISH) and RT-PCR.
Results
We found that 3 out of 207 (1.4%) cases of lung SqCC were ALK positive detected by IHC staining, which were confirmed by ALK FISH and RT-PCR.
Conclusions
Our results indicate that ALK protein expression is not a rare molecular event in SqCC. Although the frequency of EML4-ALK rearrangements is lower in lung SqCC than that in lung adenocarcinomas, their presence may provide additional treatment options in lung SqCC. The response of SqCC patients with ALK expression to target therapy of crizotinib should be explored.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-014-0109-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13046-014-0109-2
PMCID: PMC4304180  PMID: 25527865
Anaplastic lymphoma kinase; Lung squamous cell carcinoma; IHC; D5F3 clone
3.  Overexpression of CDX2 in gastric cancer cells promotes the development of multidrug resistance 
Modulator of multidrug resistance (MDR) gene is a direct transcriptional target of CDX2. However, we still speculate whether CDX2 affects MDR through other ways. In this study, a cisplatin-resistant (SGC7901/DDP) and a 5-fluoro-2, 4(1h,3h)pyrimidinedione-resistant (BGC823/5-FU) gastric cancer cell line with stable overexpression of CDX2 were established. The influence of overexpression of CDX2 on MDR was assessed by measuring IC50 of SGC7901/DDP and BGC823/5-FU cells to cisplatin, doxorubicin, and 5-fluorouracil, rate of doxorubicin efflux, apoptosis, and cell cycle progression detected by flow cytometry. In addition, we determined the in vivo effects of CDX2-overexpression lentiviral vector (LV-CDX2-GFP) on tumor size, and apoptotic cells in tumor tissues were detected by deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling and hematoxylin and eosin staining. Results showed that LV-CDX2-GFP led to up-regulation of CDX2 mRNA and protein expression. It significantly inhibited the sensitivity of SGC7901/DDP and BGC823/5-FU cells to cisplatin, doxorubicin, and 5-fluorouracil. Flow cytometry confirmed that the percentage of apoptotic cells decreased after CDX2 up-regulation. This notion was further supported by the observation that up-regulation of CDX2 blocked entry into the M-phase of the cell cycle. Furthermore, up-regulation of CDX2 significantly decreased intracellular accumulation of doxorubicin. In molecular studies, quantitative reverse-transcriptase real-time polymerase chain reaction and western blotting revealed that CDX2 up-regulation could suppress expression of Caspase-3, Caspase-9 and PTEN, and increased the expression of MDR1, MRP, mTOR, HIF-1α.
PMCID: PMC4300718  PMID: 25628941
Homeobox gene CDX2; lentiviral vector; gastric cancer; drug resistance; murine model
4.  Detection of extracellular RNAs in cancer and viral infection via tethered cationic lipoplex nanoparticles containing molecular beacons 
Analytical chemistry  2013;85(23):11265-11274.
Non-invasive early detection methods have the potential to reduce mortality rates of both cancer and infectious diseases. Here, we present a novel assay by which tethered cationic lipoplex nanoparticles containing molecular beacons (MBs) can capture cancer cell-derived exosomes or viruses, and identify encapsulated RNAs in a single step. A series of ultracentrifugation and Exoquick™ isolation kit were first used to isolate exosomes from the cell culture medium and human serum respectively. Cationic lipoplex nanoparticles linked onto the surface of a thin glass plate capture negatively charged viruses or cell-secreted exosomes by electrostatic interactions to form larger nanoscale complexes. Lipoplex/virus or lipoplex/exosome fusion leads to the mixing of viral/exosomal RNAs and MBs within the lipoplexes. After the target RNAs specially bind to the MBs, exosomes enriched in target RNAs are readily identified by the fluorescence signals of MBs. The in situ detection of target extracellular RNAs without diluting the samples leads to high detection sensitivity not achievable by existing methods, e.g. qRT-PCR. Here we demonstrate this concept using lentivirus and serum from lung cancer patients.
doi:10.1021/ac401983w
PMCID: PMC4121114  PMID: 24102152
lipoplex nanoparticles; exosome; extracellular RNA; cancer detection; viral infection
5.  Overexpression of E2F1 in human gastric carcinoma is involved in anti-cancer drug resistance 
BMC Cancer  2014;14(1):904.
Background
Routine chemotherapy often cannot achieve good therapeutic effects because of multidrug resistance (MDR). MDR is frequently caused by the elevated expression of the MDR1 gene encoding P-glycoprotein (P-gp). E2F1 is a frequently overexpressed protein in human tumor cells that increases the activity of the MDR1 promoter, resulting in higher P-gp levels. The upregulation of P-gp might contribute to the survival of tumor cells during chemotherapy. E2F1 confers anticancer drug resistance; however, we speculate whether E2F1 affects MDR through other pathways. This study investigated the possible involvement of E2F1 in anticancer drug resistance of gastric carcinoma in vitro and in vivo.
Methods
A cisplatin-resistant SGC7901/DDP gastric cancer cell line with stable overexpression of E2F1 was established. Protein expression levels of E2F1, MDR1, MRP, TAp73, GAX, ZEB1, and ZEB2 were detected by western blotting. The influence of overexpression of E2F1 on anticancer drug resistance was assessed by measuring IC50 of SGC7901/DDP cells to cisplatin, doxorubicin, and 5-fluorouracil, as well as the rate of doxorubicin efflux, apoptosis, and cell cycle progression detected by flow cytometry. We determined the in vivo effects of E2F1-overexpression on tumor size in nude mice, and apoptotic cells in tumor tissues were detected by deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling and hematoxylin and eosin staining.
Results
The SGC7901/DDP gastric cancer cell line stably overexpressing E2F1 exhibited significantly inhibited sensitivity to cisplatin, doxorubicin, and 5-fluorouracil. Flow cytometry confirmed that the percentage of apoptotic cells decreased after E2F1 upregulation, and that upregulation of E2F1 potentiated S phase arrest of the cell cycle. Furthermore, upregulation of E2F1 significantly decreased intracellular accumulation of doxorubicin. Western blot revealed that E2F1 upregulation suppressed expression of GAX, and increased the expression of MDR1, MRP, ZEB1, TAp73, and ZEB2.
Conclusions
Overexpression of E2F1 promotes the development of MDR in gastric carcinoma, suggesting that E2F1 may represent an efficacious target for gastric cancer therapy.
doi:10.1186/1471-2407-14-904
PMCID: PMC4258940  PMID: 25466554
E2F1 transcription factor; Lentiviral vector; Gastric carcinoma; Drug resistance; Murine model
6.  Lidocaine Potentiates the Deleterious Effects of Triamcinolone Acetonide on Tenocytes 
Background
Local anesthetics are commonly used for the treatment of a variety of tendinopathies in combination with corticosteroids injection. The goal of this study was to evaluate the effects of lidocaine and triamcinolone acetonide (TA) on cultured rat tenocytes and to determine whether there is a synergistic effect.
Material/Methods
Rat patellar tendon-derived tenocytes were cultured with or without TA and lidocaine, and the culture without any additive served as the control. Cell morphology and cell viability were evaluated. Expressions of tenocyte-related genes were measured by qRT-PCR.
Results
TA, when exposed to tenocytes in vitro, significantly decreased cell viability. The cells cultured with TA had a flattened shape. Moreover, the expressions of tenocyte-related genes in tenocytes were markedly decreased in the TA-treated group. We found that 1% lidocaine synergistically increased the deleterious effects of TA.
Conclusions
Our data provide evidence of the detrimental effects of these drugs on tendon tissues. Injection of TA in combination with 1% lidocaine should be used with caution.
doi:10.12659/MSM.891116
PMCID: PMC4259563  PMID: 25433272
Cell Survival; Lidocaine; Patellar Ligament; Triamcinolone Acetonide
7.  Genome Sequence of Tumebacillus flagellatus GST4, the First Genome Sequence of a Species in the Genus Tumebacillus 
Genome Announcements  2014;2(6):e01189-14.
We present here the first genome sequence of a species in the genus Tumebacillus. The draft genome sequence of Tumebacillus flagellatus GST4 provides a genetic basis for future studies addressing the origins, evolution, and ecological role of Tumebacillus organisms, as well as a source of acid-resistant amylase-encoding genes for further studies.
doi:10.1128/genomeA.01189-14
PMCID: PMC4241674  PMID: 25395648
8.  In Vivo Diagnosis of Plaque Erosion and Calcified Nodule in Patients with Acute Coronary Syndrome by Intravascular Optical Coherence Tomography 
Journal of the American College of Cardiology  2013;62(19):10.1016/j.jacc.2013.05.071.
Objectives
To characterize the morphological features of plaque erosion and calcified nodule in patients with acute coronary syndrome (ACS) by optical coherence tomography (OCT).
Background
Plaque erosion and calcified nodule have not been systematically investigated in vivo.
Methods
One hundred and twenty-six patients with ACS who had undergone pre-intervention OCT imaging were included. The culprit lesions were classified as plaque rupture (PR), erosion (OCT-erosion), calcified nodule (OCT-CN), or others using a new set of diagnostic criteria for OCT.
Results
The incidences of PR, OCT-erosion, and OCT-CN were 43.7%, 31.0%, and 7.9%, respectively. Patients with OCT-erosion were the youngest compared with those with PR and OCT-CN (53.8±13.1 years vs. 60.6±11.5 years, 65.1±5.0 years, p=0.005). Compared with patients with PR, presentation with non-ST-segment elevation ACS (NSTE-ACS) was more common in patients with OCT-erosion (61.5% vs. 29.1%, p=0.008) and OCT-CN (100% vs. 29.1%, p<0.001). OCT-erosion had a lower frequency of lipid plaque (43.6% vs. 100%, p<0.001), thicker fibrous cap (169.3±99.1 μm vs. 60.4±16.6 μm, p<0.001), and smaller lipid arc (202.8±73.6° vs. 275.8±60.4°, p<0.001) than PR. The diameter stenosis was least severe in OCT-erosion followed by OCT-CN and PR (55.4±14.7% vs. 66.1±13.5% vs. 68.8±12.9%, p<0.001).
Conclusions
OCT is a promising modality for identifying OCT-erosion and OCT-CN in vivo. OCT-erosion is a frequent finding in patients with ACS, especially in those with NSTE-ACS and younger patients. OCT-CN is the least common etiology for ACS and is more common in older patients.
doi:10.1016/j.jacc.2013.05.071
PMCID: PMC3874870  PMID: 23810884
plaque erosion; calcified nodule; plaque rupture; acute coronary syndrome; optical coherence tomography
9.  Cationic Lipid Nanoparticles for Therapeutic Delivery of siRNA and miRNA to Murine Liver Tumor 
Nanomedicine : nanotechnology, biology, and medicine  2013;9(8):10.1016/j.nano.2013.05.007.
miR-122, a liver-specific tumor suppressor microRNA, is frequently downregulated in hepatocellular carcinoma (HCC). LNP-DP1, a cationic lipid nanoparticle formulation, was developed as a vehicle to restore deregulated gene expression in HCC cells by miR-122 delivery. LNP-DP1 consists of 2-dioleyloxy-N,N-dimethyl-3-aminopropane (DODMA), egg phosphatidylcholine, cholesterol and cholesterol-polyethylene glycol. In vitro, LNP-DP1-mediated transfection of a miR-122 mimic to HCC cells downregulated miR-122 target genes by >95%. In vivo, siRNAs/miRNAs encapsulated in LNP-DP1 were preferentially taken up by hepatocytes and tumor cells in a mouse HCC model. The miR-122 mimic in LNP-DP1 was functional in HCC cells without causing systemic toxicity. To demonstrate its therapeutic potential, LNP-DP1 encapsulating miR-122 mimic was intratumorally injected and resulted in ~50% growth suppression of HCC xenografts within 30 days, which correlated well with suppression of target genes and impairment of angiogenesis. These data demonstrate the potential of LNP-DP1-mediated microRNA delivery as a novel strategy for HCC therapy.
doi:10.1016/j.nano.2013.05.007
PMCID: PMC3815988  PMID: 23727126
Cationic lipid nanoparticle; miR-122; microRNA; HCC
10.  Experimental Optimal Single Qubit Purification in an NMR Quantum Information Processor 
Scientific Reports  2014;4:6857.
High quality single qubits are the building blocks in quantum information processing. But they are vulnerable to environmental noise. To overcome noise, purification techniques, which generate qubits with higher purities from qubits with lower purities, have been proposed. Purifications have attracted much interest and been widely studied. However, the full experimental demonstration of an optimal single qubit purification protocol proposed by Cirac, Ekert and Macchiavello [Phys. Rev. Lett. 82, 4344 (1999), the CEM protocol] more than one and half decades ago, still remains an experimental challenge, as it requires more complicated networks and a higher level of precision controls. In this work, we design an experiment scheme that realizes the CEM protocol with explicit symmetrization of the wave functions. The purification scheme was successfully implemented in a nuclear magnetic resonance quantum information processor. The experiment fully demonstrated the purification protocol, and showed that it is an effective way of protecting qubits against errors and decoherence.
doi:10.1038/srep06857
PMCID: PMC4215327  PMID: 25358758
11.  Single Prolonged Stress induces ATF6 alpha-dependent Endoplasmic reticulum stress and the apoptotic process in medial Frontal Cortex neurons 
BMC Neuroscience  2014;15(1):115.
Background
In our previous researches, we have found that apoptosis was induced in the medial prefrontal cortex (mPFC) of post-traumatic stress disorder (PTSD) rats. Endoplasmic reticulum (ER) stress-induced apoptosis has been implicated in the development of several disorder diseases. The aim of this study was to investigate whether endoplasmic reticulum-related pathway is involved in single-prolonged stress (SPS) induced apoptosis in the mPFC of PTSD rats by examining the expression levels of ATF6 alpha (ATF6α), two important downstream molecular chaperones of ATF6α in the ER stress: Glucose-regulated protein (GRP) 78 and ERP57, and apoptotic factors caspase 12, caspase 9, and caspase 3.
Results
Our results of Morris Water Maze (MWM) test showed that after SPS exposure, a striking increase of the escape latency was observed in SPS rats at day 1 through day 6, and SPS rats had much less time spent in target quadrant compared to control rats ( P < 0.01). And From immunofluorescence assays, we found that there was a gradual increase on the protein expression of ATF6α in response to SPS, which indicated ATF6α was activated by SPS. And additionally, immunohistochemistry assays, western blotting and reverse transcription-polymerase chain reaction (RT-PCR) showed that the immunoreactivity, protein and mRNA expression of GRP78 and ERP57 increased on 1, 4 days, and peaked on 7 days after SPS exposure, which revealed that SPS triggered inductions of GRP78 and ERP57 in the mPFC neurons. Moreover, RT-PCR assays demonstrated that there were up-regulations in the transcripts levels of caspase 12, caspase 9, and caspase 3 in response to SPS, which were according with the proteins changes of these apoptotic factors and indicated that ER stress and the activation of caspases contributed to SPS.
Conclusion
Current data in this study highlight that SPS induced ATF6α-dependent Endoplasmic reticulum stress and ER-related apoptosis in the mPFC neurons, which indicated that the endoplasmic reticulum pathway may be involved in PTSD-induced apoptosis.
doi:10.1186/s12868-014-0115-5
PMCID: PMC4224694  PMID: 25331812
Single-prolonged stress; Post-traumatic stress disorder; Medial prefrontal cortex; Activating transcription factor 6α; Glucose-regulated protein; ERP57; Caspase; Rat
12.  Efficient Open Fermentative Production of Polymer-Grade L-Lactate from Sugarcane Bagasse Hydrolysate by Thermotolerant Bacillus sp. Strain P38 
PLoS ONE  2014;9(9):e107143.
Lactic acid is one of the top 30 potential building-block chemicals from biomass, of which the most extensive use is in the polymerization of lactic acid to poly-lactic-acid (PLA). To reduce the cost of PLA, the search for cheap raw materials and low-cost process for lactic acid production is highly desired. In this study, the final titer of produced L-lactic acid reached a concentration of 185 g·L−1 with a volumetric productivity of 1.93 g·L−1·h−1 by using sugarcane bagasse hydrolysate as the sole carbon source simultaneously with cottonseed meal as cheap nitrogen sources under the open fed-batch fermentation process. Furthermore, a lactic acid yield of 0.99 g per g of total reducing sugars was obtained, which is very close to the theoretical value (1.0 g g−1). No D-isomer of lactic acid was detected in the broth, and thereafter resulted in an optical purity of 100%, which exceeds the requirement of lactate polymerization process. To our knowledge, this is the best performance of fermentation on polymer-grade L-lactic acid production totally using lignocellulosic sources. The high levels of optically pure l-lactic acid produced, combined with the ease of handling and low costs associated with the open fermentation strategy, indicated the thermotolerant Bacillus sp. P38 could be an excellent candidate strain with great industrial potential for polymer-grade L-lactic acid production from various cellulosic biomasses.
doi:10.1371/journal.pone.0107143
PMCID: PMC4156441  PMID: 25192451
13.  MicroRNA Delivery by Cationic Lipoplexes for Lung Cancer Therapy 
Molecular pharmaceutics  2011;8(4):1381-1389.
Lung cancer is the leading cause of cancer deaths in western countries and carries a poor overall five year survival rate. Several studies demonstrate that microRNAs (miRNAs or miRs) are actively involved in tumor development by serving as tumor suppressors, oncogenes or both. In lung cancer, miRNAs may serve as both diagnostic and prognostic biomarkers as well as regulate in vitro and in vivo tumor progression. However, miRNA-based therapy is faced with several challenges including lack of tissue specificity, lack of optimal delivery systems, poor cellular uptake and risk of systemic toxicity. Here, we report a cationic lipid based miRNA delivery system to address some of these challenges. Among many lung cancer related miRNAs, miR-133b, a tumor suppressor, was selected as a therapeutic target because it directly targets the prosurvival gene MCL-1 thus regulating cell survival and sensitivity of lung cancer cells to chemotherapeutic agents. The efficacy of pre-miR-133b containing lipoplexes was evaluated in A549 non-small cell lung cancer (NSCLC) cells. Compared with siPORT NeoFX transfection agent, lipoplexes delivered pre-miR-133b in a more efficient manner with ∼2.3-fold increase in mature miR-133b expression and ∼1.8-fold difference in MCL-1 protein downregulation in vitro. In the in vivo biodistribution study, lipoplexes achieved ∼30% accumulation in lung tissue, which was ∼50-fold higher than siPORT NeoFX transfection agent. Mice treated with pre-miR-133b containing lipoplexes had mature miR-133b expression in lung ∼52-fold higher than untreated mice. Our results demonstrated that cationic lipoplexes are a promising carrier system for the development of miRNA-based therapeutics in lung cancer treatment.
doi:10.1021/mp2002076
PMCID: PMC4136514  PMID: 21648427
microRNA; lipoplexes; lung cancer; cationic lipids
14.  Targeted drug delivery and cross-linking induced apoptosis with anti-CD37 based dual-ligand immunoliposomes in B chronic lymphocytic leukemia cells 
Biomaterials  2013;34(26):6185-6193.
Despite advances in chemo- and immunotherapeutic agents for B chronic lymphocytic leukemia (B-CLL), the undesirable adverse side effects due to non-specific cellular uptake remain to be addressed. We identified anti-CD37 monoclonal antibody immunoliposomes (ILs) as vehicles for targeted delivery to B chronic lymphocytic leukemia cells. To achieve maximal benefits for all patients, a new strategy of dual-ligand immunoliposomes (dILs) was developed. A combinatorial antibody microarray technology was adapted to quickly identify optimal antibody combinations for individual patient cells. For proof-of-concept, a B-cell specific antibody, either anti-CD19 or anti-CD20, was combined with anti-CD37 to construct dILs with enhanced selectivity and efficacy. Consistent with data from the antibody microarray, these dILs provided highly specific targeting to both leukemia cell lines and B-CLL patient cells. Compared with the single antibody ILs, the anti-CD19/CD37 dILs clearly demonstrated superior delivery efficiency and apoptosis induction to B-CLL patient cells, whereas the anti-CD20/anti-CD37 dILs were found to be the most efficient for delivery to leukemia cell lines. In addition, it was observed that anti-CD37 ILs without payload drug mediated effective CD37 cross-linking and induced potent apoptosis induction. The anti-CD19/CD20 dILs showed the improved cell apoptosis induction compared to either anti-CD19 ILs or anti-CD20 ILs. Our findings suggest that the dual-ligand ILs may provide a preferred strategy of personalized nanomedicine for the treatment of B-cell malignancies.
doi:10.1016/j.biomaterials.2013.04.063
PMCID: PMC3756150  PMID: 23726226
15.  Ginsenoside Rb3 Protects Cardiomyocytes against Ischemia-Reperfusion Injury via the Inhibition of JNK-Mediated NF-κB Pathway: A Mouse Cardiomyocyte Model 
PLoS ONE  2014;9(8):e103628.
Ginsenoside Rb3 is extracted from the plant Panax ginseng and plays important roles in cardiovascular diseases, including myocardial ischemia-reperfusion (I/R) injury. NF-κB is an important transcription factor involved in I/R injury. However, the underlying mechanism of ginsenoside Rb3 in myocardial I/R injury remains poorly understood. In the current study, a model of myocardial I/R injury was induced via oxygen and glucose deprivation (OGD) followed by reperfusion (OGD-Rep) in mouse cardiac myoblast H9c2 cells. Our data demonstrate that ginsenoside Rb3 suppresses OGD-Rep-induced cell apoptosis by the suppression of ROS generation. By detecting the NF-κB signaling pathway, we discover that the protective effect of ginsenoside Rb3 on the OGD-Rep injury is closely related to the inhibition of NF-κB activity. Ginsenoside Rb3 inhibits the upregulation of phospho-IκB-α and nuclear translocation of NF-κB subunit p65 which are induced by ORD-Rep injury. In addition, the extract also inhibits the OGD-Rep-induced increase in the expression of inflammation-related factors, such as IL-6, TNF-α, monocyte chemotactic protein-1 (MCP-1), MMP-2 and MMP-9. However, LPS treatment alleviates the protective roles of ginsenoside Rb3 and activates the NF-κB pathway. Finally, the upstream factors of NF-κB were analyzed, including the Akt/Foxo3a and MAPK signaling pathways. We find that ginsenoside Rb3 pretreatment only decreases the phosphorylation of JNK induced by OGD-Rep injury, an indicator of the MAPK pathway. Importantly, an inhibitor of phospho-JNK, SP600125, protects against OGD-Rep induced apoptosis and inhibited NF-κB signaling pathway, similar to the roles of ginsenoside Rb3. Taken together, our results demonstrate that the protective effect of ginsenoside Rb3 on the OGD-Rep injury is attributed to the inhibition of JNK-mediated NF-κB activation, suggesting that ginsenoside Rb3 has the potential to serve as a novel therapeutic agent for myocardial I/R injury.
doi:10.1371/journal.pone.0103628
PMCID: PMC4118887  PMID: 25084093
16.  A Primal Analysis System of Brain Neurons Data 
The Scientific World Journal  2014;2014:348526.
It is a very challenging work to classify the 86 billions of neurons in the human brain. The most important step is to get the features of these neurons. In this paper, we present a primal system to analyze and extract features from brain neurons. First, we make analysis on the original data of neurons in which one neuron contains six parameters: room type, X, Y, Z coordinate range, total number of leaf nodes, and fuzzy volume of neurons. Then, we extract three important geometry features including rooms type, number of leaf nodes, and fuzzy volume. As application, we employ the feature database to fit the basic procedure of neuron growth. The result shows that the proposed system is effective.
doi:10.1155/2014/348526
PMCID: PMC4131436  PMID: 25152908
17.  First- and Second-Order Full-Differential in Edge Analysis of Images 
The Scientific World Journal  2014;2014:121928.
Two concepts of first- and second-order differential of images are presented to deal with the changes of pixels. These are the basic ideas in mathematics. We propose and reformulate them with a uniform definition framework. Based on our observation and analysis with the difference, we propose an algorithm to detect the edge from image. Experiments on Corel5K and PASCAL VOC 2007 are done to show the difference between the first order and the second order. After comparison with Canny operator and the proposed first-order differential, the main result is that the second-order differential has the better performance in analysis of changes of the context of images with good selection of control parameter.
doi:10.1155/2014/121928
PMCID: PMC4099172  PMID: 25054162
18.  Real-Time Hand Gesture Recognition Using Finger Segmentation 
The Scientific World Journal  2014;2014:267872.
Hand gesture recognition is very significant for human-computer interaction. In this work, we present a novel real-time method for hand gesture recognition. In our framework, the hand region is extracted from the background with the background subtraction method. Then, the palm and fingers are segmented so as to detect and recognize the fingers. Finally, a rule classifier is applied to predict the labels of hand gestures. The experiments on the data set of 1300 images show that our method performs well and is highly efficient. Moreover, our method shows better performance than a state-of-art method on another data set of hand gestures.
doi:10.1155/2014/267872
PMCID: PMC4099175  PMID: 25054171
19.  A Novel Support Vector Machine with Globality-Locality Preserving 
The Scientific World Journal  2014;2014:872697.
Support vector machine (SVM) is regarded as a powerful method for pattern classification. However, the solution of the primal optimal model of SVM is susceptible for class distribution and may result in a nonrobust solution. In order to overcome this shortcoming, an improved model, support vector machine with globality-locality preserving (GLPSVM), is proposed. It introduces globality-locality preserving into the standard SVM, which can preserve the manifold structure of the data space. We complete rich experiments on the UCI machine learning data sets. The results validate the effectiveness of the proposed model, especially on the Wine and Iris databases; the recognition rate is above 97% and outperforms all the algorithms that were developed from SVM.
doi:10.1155/2014/872697
PMCID: PMC4086371  PMID: 25045750
20.  Vitamin D Deficiency Causes Defective Resistance to Aspergillus fumigatus in Mice via Aggravated and Sustained Inflammation 
PLoS ONE  2014;9(6):e99805.
Background
Vitamin D plays an important role in pulmonary resistance and immunity, and its deficiency has been linked to various respiratory infections. Little is known about the effect of vitamin D deficiency on host pulmonary defense to Aspergillus fumigatus (A. fumigatus).
Methods
Mice raised on vitamin D sufficient or deficient diets were infected intratracheally with A. fumigatus conidia. Mortality, fungal growth, weight loss and lung histology were monitored. Alveolar macrophages (AMs) were stimulated with A. fumigatus conidia in vitro. The kinetics of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), chemokines (CXCL1, CCL3), and pattern recognition receptors (Toll-like receptor [TLR] 2, TLR 4 and dectin-1) expression in the lungs and AMs were measured.
Results
Upon A. fumigatus infection, vitamin D deficient mice showed higher mortality, greater fungal load, and more weight loss than its sufficient counterparts. Vitamin D deficient mice demonstrated aggravated and prolonged histological evidence of lung inflammation as well as enhanced BAL cell counts, dominated by neutrophils after A. fumigatus inoculation. Increased basal levels of pro-inflammatory cytokines in the lungs and AMs from naïve vitamin D deficient mice were observed. Upon A. fumigatus exposure, vitamin D deficiency led to enhanced and sustained expression of TNF-α, IL-1β, IL-6, CXCL1 and CCL3 both in vivo and in vitro. Up-regulation of TLR2, TLR4 and dectin-1was observed in the lungs and AMs from vitamin D deficient mice both at baseline and after A. fumigatus exposure.
Conclusions
Vitamin D deficiency causes defective pulmonary resistance to A. fumigatus in mice, possibly by the enhanced basal expression of pattern recognition receptors and pro-inflammatory cytokines, which induced excessive inflammatory response in response to A. fumigatus challenge.
doi:10.1371/journal.pone.0099805
PMCID: PMC4057384  PMID: 24926881
21.  A replacement name for Dayus Gerken, 2001 (Crustacea, Peracarida, Cumacea), preoccupied by Dayus Mahmood, 1967 (Insecta, Hemiptera, Cicadellidae) 
ZooKeys  2014;137-138.
A replacement name is proposed for genus Dayus Gerken, 2001 (Crustacea: Peracarida: Cumacea), preoccupied by Dayus Mahmood, 1967 (Insecta: Hemiptera: Cicadellidae). The following changes are proposed: Jennidayus new replacement name = Dayus Gerken, 2001 (nec Mahmood 1967); Jennidayus pharocheradus (Gerken, 2001), comb. n. = Dayus pharocheradus Gerken, 2001; Jennidayus acanthus (Gerken, 2001), comb. n. = Dayus acanthus Gerken, 2001; Jennidayus makrokolosus (Gerken, 2001), comb. n. = Dayus makrokolosus Gerken, 2001.
doi:10.3897/zookeys.414.7673
PMCID: PMC4086053  PMID: 25009419
Crustacea; Peracarida; Cumacea; homonym; replacement name
22.  Resin Composites Reinforced by Nanoscaled Fibers or Tubes for Dental Regeneration 
BioMed Research International  2014;2014:542958.
It has been stated clearly that nanofillers could make an enhancement on the mechanical performances of dental composites. In order to address current shortage of traditional dental composites, fillers in forms of nanofibers or nanotubes are broadly regarded as ideal candidates to greatly increase mechanical performances of dental composites with low content of fillers. In this review, the efforts using nanofibers and nanotubes to reinforce mechanical performances of dental composites, including polymeric nanofibers, metallic nanofibers or nanotubes, and inorganic nanofibers or nanotubes, as well as their researches related, are demonstrated in sequence. The first purpose of current paper was to confirm the enhancement of nanofibers or nanotubes' reinforcement on the mechanical performances of dental restorative composite. The second purpose was to make a general description about the reinforcement mechanism of nanofibers and nanotubes, especially, the impact of formation of interphase boundary interaction and nanofibers themselves on the advanced mechanical behaviors of the dental composites. By means of the formation of interface interaction and poststretching nanofibers, reinforced effect of dental composites by sorts of nanofibers/nanotubes has been successfully obtained.
doi:10.1155/2014/542958
PMCID: PMC4058202  PMID: 24982894
23.  Efficacy of ilaprazole in the treatment of duodenal ulcers: A meta-analysis 
AIM: To compare the efficacy and tolerance of ilaprazole compared with other proton pump inhibitors (PPIs) in the treatment of duodenal ulcer.
METHODS: An electronic database search of Medline, Embase, the Cochrane controlled trials register, Web of Science, PubMed, and the Chinese Biomedical Literature Database (updated to July 2013), and manual searches were conducted. A meta-analysis of randomized controlled trials comparing the efficacy and tolerance of ilaprazole and other PPIs in the treatment of duodenal ulcers was performed.
RESULTS: Five articles involving 1481 patients were included. The meta-analysis showed no difference in the 4-wk healing rate between ilaprazole and other PPIs [89.7% vs 87.0%; relative risk (RR) = 1.02; 95%CI: 0.98-1.06; Z = 1.00; P = 0.32]. The results did not change in the sensitivity analyses. The meta-analysis indicated that the adverse effect rate in the ilaprazole group was lower than that in the control group, but the difference was not significant (9.7% vs 13.0%; RR = 0.81; 95%CI: 0.60-1.07; Z = 1.47; P = 0.14).
CONCLUSION: Ilaprazole is a highly effective and safe PPI in the treatment of duodenal ulcers. Ilaprazole can be recommended as a therapy for acid-related disorders, especially in Asian populations.
doi:10.3748/wjg.v20.i17.5119
PMCID: PMC4009550  PMID: 24803828
Ilaprazole; Proton pump inhibitor; Duodenal ulcer; Meta-analysis
24.  The Immunosuppressant Protosappanin A Diminished Recipient T Cell Migration into Allograft via Inhibition of IP-10 in Rat Heart Transplant 
PLoS ONE  2014;9(5):e96138.
The immunosuppressant Protosappanin A (PrA), isolated from the medicinal herb, promotes cardiac allograft survival, diminishes inflammatory cell infiltration, and inhibits interferon γ-induced protein 10 kDa (IP-10) mRNA expression in rats cardiac grafts. Binding of the chemokine IP-10 to its cognate receptor, CXCR3, plays crucial roles in allograft immunity, especially by mediating the recruitment of effector T cells to allografted tissues. In this study, we attempted to determine whether PrA-mediated inhibition of IP-10 contributes to the effect of reduced T cell infiltration into cardiac allograft within a rat model. Administration of PrA (25 mg/kg daily) via oral gavage following heart transplantation significantly reduced the increase of IP-10 mRNA level in allograft and prevented IP-10 secretion by peripheral blood mononuclear cells (PBMC) isolated from recipient rats seven days posttransplantation. Furthermore, in vitro experiments demonstrated that PrA addition to control PBMC prevented IP-10 secretion. Chemotactic migration assays were utilized to evaluate recipient T cell migration towards PBMC supernatant. PrA administration impaired PBMC supernatant-induced T cell migration. Additional in vitro experiments revealed that PrA slightly reduced naïve T cell migration towards chemokines. The presence of IP-10 in PBMC supernatant prevented PrA from reducing T cell migration in PrA-treated recipients. Neither CXCR3 chemokine ligand Mig nor non-CXCR3 chemokine ligand SDF-1 had any effect on T cell migration in PrA-treated recipients. The addition of anti-CXCR3 antibody restored PrA-mediated inhibition of T cell migration. Immunofluorescence microscopy showed that IP-10 was expressed mainly in CD68 positive infiltrating monocytes. Furthermore, PrA consistently reduced CXCR3+T cell infiltration into cardiac allografts. The reduced intensity of CXCR3 staining in PrA-treated allografts contributed to the previously depressed naïve T cell migrating activity induced by PrA. Collectively, these data indicate that PrA inhibition of IP-10 activity reduced recipient T cell migration and infiltration of cardiac allografts, thus partially explaining the immunosuppressive effect of PrA.
doi:10.1371/journal.pone.0096138
PMCID: PMC4010525  PMID: 24798458
25.  Targeted Delivery of microRNA-29b by Transferrin Conjugated Anionic Lipopolyplex Nanoparticles: A Novel Therapeutic Strategy in Acute Myeloid Leukemia 
Purpose
miR-29b directly or indirectly targets genes involved in acute myeloid leukemia (AML) i.e., DNMTs, CDK6, SP1, KIT and FLT3. Higher miR-29b pretreatment expression is associated with improved response to decitabine and better outcome in AML. Thus designing a strategy to increase miR-29b levels in AML blasts may be of therapeutic value. However, free synthetic miRs are easily degraded in bio-fluids and have limited cellular uptake. To overcome these limitations, we developed a novel transferrin-conjugated nanoparticle delivery system for synthetic miR-29b (Tf-NP-miR-29b).
Experiment Design
Delivery efficiency was investigated by flow-cytometry, confocal microscopy and quantitative-PCR. The expression of miR-29b targets was measured by immunoblotting. The anti-leukemic activity of Tf-NP-miR-29b was evaluated by measuring cell proliferation and colony formation ability and in a leukemia mouse model.
Results
Tf-NP-miR-29b treatment resulted in >200-fold increase of mature miR-29b compared to free miR-29b and was about twice as efficient as treatment with non-Tf-conjugated NP-miR-29b. Tf-NP-miR-29b treatment significantly downregulated DNMTs, CDK6, SP1, KIT and FLT3 and decreased AML cell growth by 30–50% and impaired colony formation by approximately 50%. Mice engrafted with AML cells and then treated with Tf-NP-miR-29b had significantly longer survival compared to Tf-NP-scramble (P=0.015) or free miR-29b (P=0.003). Furthermore, priming AML cell with Tf-NP-miR-29b before decitabine resulted in strong cell viability decrease in vitro and showed improved anti-leukemic activity compared with decitabine alone (P=0.001) in vivo.
Conclusion
Tf-NP effectively delivered functional miR-29b, resulting in target downregulation and anti-leukemic activity, and warrants further investigation as a novel therapeutic approach in AML.
doi:10.1158/1078-0432.CCR-12-3191
PMCID: PMC3644023  PMID: 23493348
lipopolyplex nanoparticles; miR-29b; Acute Myeloid Leukemia

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