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1.  Antifungal Activity of C-27 Steroidal Saponins 
As part of our search for new antifungal agents from natural resources, 22 C-27 steroidal saponins and 6 steroidal sapogenins isolated from several monocotyledonous plants were tested for their antifungal activity against the opportunistic pathogens Candida albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, and Aspergillus fumigatus. The results showed that the antifungal activity of the steroidal saponins was associated with their aglycone moieties and the number and structure of monosaccharide units in their sugar chains. Within the 10 active saponins, four tigogenin saponins (compounds 1 to 4) with a sugar moiety of four or five monosaccharide units exhibited significant activity against C. neoformans and A. fumigatus, comparable to the positive control amphotericin B. The antifungal potency of these compounds was not associated with cytotoxicity to mammalian cells. This suggests that the C-27 steroidal saponins may be considered potential antifungal leads for further preclinical study.
doi:10.1128/AAC.50.5.1710-1714.2006
PMCID: PMC1472193  PMID: 16641439
2.  Effect of reactive and un-reactive substrates on photopolymerization of self-etching adhesives with different aggressiveness 
Dental materials journal  2013;32(3):484-491.
The study investigated the influence of reactive (enamel) and un-reactive (glass) substrates on photo-polymerization of self-etching adhesives. Two commercial adhesives Adper Prompt L-Pop (APLP, pH~0.8) and Adper Easy Bond (AEB, pH~2.5) were applied onto prepared enamel and glass substrates using the same protocol. Micro-Raman spectroscopy was employed to determine the degree of conversion (DC) and the involved mechanism. DC of APLP was dramatically enhanced from ~9.4% to ~82.0% as when changing from glass to enamel, while DC of AEB on both substrates showed no difference. The DC distributions along the adhesive layers of the APLP and AEB on enamel showed descending and constant trends, respectively. Spectral analysis disclosed that the difference in chemical reaction of the two adhesives with enamel might be associated with the results. The chemical reaction of the adhesives with enamel significantly improved the DC of the strong APLP, but not that of the mild AEB.
PMCID: PMC3980577  PMID: 23719012
self-etching; enamel; micro-Raman spectroscopy; photo-polymerization; degree of conversion
3.  The Mechanism of Poly-Galloyl-Glucoses Preventing Influenza A Virus Entry into Host Cells 
PLoS ONE  2014;9(4):e94392.
Hemagglutinin (HA) is essential for Influenza A virus infection, but its diversity of subtypes presents an obstacle to developing broad-spectrum HA inhibitors. In this study, we investigated the molecular mechanisms by which poly-galloyl glucose (pGG) analogs inhibit influenza hemagglutinin (HA) in vitro and in silico. We found that (1) star-shaped pGG analogs exhibit HA-inhibition activity by interacting with the conserved structural elements of the receptor binding domain (RBD); (2) HA inhibition depends on the number of galloyl substituents in a pGG analog; the best number is four; and when PGG binds with two HA trimers at their conserved receptor binding domains (loop 130, loop 220, and 190-α-helix), PGG acts as a molecular glue by aggregating viral particles so as to prevent viral entry into host cells (this was revealed via an in silico simulation on the binding of penta-galloyl-glucose (PGG) with HA). pGGs are also effective on a broad-spectrum influenza A subtypes (including H1, H3, H5, H7); this suggests that pGG analogs can be applied to most influenza A subtypes as a prophylactic against influenza viral infections.
doi:10.1371/journal.pone.0094392
PMCID: PMC3981784  PMID: 24718639
4.  Relationship between Enhanced Intensity of Contrast Enhanced Ultrasound and Microvessel Density of Aortic Atherosclerostic Plaque in Rabbit Model 
PLoS ONE  2014;9(4):e92445.
The aim of this study was to evaluate the relationship between enhanced intensity of contrast enhanced ultrasound and microvessel density of aortic atherosclerotic plaque in rabbit model. The abdominal aortas of thirty-six male New Zealand rabbits were damaged by balloon expansion and the animals were then fed a high fat diet for 12 weeks. Twenty-seven plaques on the near aortic wall were detected using conventional ultrasound examination. The maximum thickness of each plaque was recorded. CEUS was performed on these 27 plaques and the time-intensity curves (TICs) were analyzed offline. Using the quantitative ACQ software, features such as the arrival time (AT), time to peak (TTP), baseline intensity (BI), peak intensity (PI) and enhanced intensity (EI) (EI = PI-BI) were assessed. Inter- and intra-observer agreement of EI were assessed using the Bland-Altman test. After CEUS examination, the rabbits were sacrificed for pathological examination and CD34 monoclonal antibody immunohistochemical detection. Microvessel density (MVD) was counted under the microscope. The relationship between indexes of CEUS and the level of MVD was analyzed. There was a good positive linear correlation between EI and MVD (γ = 0. 854, P<0. 001), the intraclass correlations for inter- and intra-observer agreement for EI were 0.73 and 0.82 respectively, suggesting that EI may be act as a useful index for plaque risk stratification in animal models.
doi:10.1371/journal.pone.0092445
PMCID: PMC3979663  PMID: 24713618
5.  Involvement of the Akt/NF-κB Pathways in the HTNV-Mediated Increase of IL-6, CCL5, ICAM-1, and VCAM-1 in HUVECs 
PLoS ONE  2014;9(4):e93810.
Background
Hantaan virus (HTNV) infection causes a severe form of HFRS(hemorrhagic fever with renal syndrome)in Asia. Although HTNV has been isolated for nearly forty years, the pathogenesis of HFRS is still unknown, and little is known regarding the signaling pathway that is activated by the virus.
Methodology/Principal Findings
Cardamonin was selected as a NF-κB inhibitor, and indirect immunofluorescence assays were used to detect the effect of cardamonin on HTNV-infected HUVECs. The effect of cardamonin on the HTNV-induced phosphorylation of Akt and DNA-binding activity of NF-κB were determined using Western blot analysis and electrophoretic mobility shift assays (EMSAs), respectively. Then, flow cytometric and quantitative real-time PCR analyses were performed to quantify the expression levels of the adhesion molecules ICAM-1 and VCAM-1, and the concentrations of IL-6, IL-8, and CCL5 in HUVEC supernatants were examined using ELISA. The results showed that cardamonin did not effect the proliferation of HUVECs or the replication of HTNV in HUVECs. Instead, cardamonin inhibited the phosphorylation of Akt and nuclear transduction of NF-κB and further reduced the expression of the adhesion molecules ICAM-1 and VCAM-1 in HTNV-infected HUVECs. Cardamonin also inhibited the secretion of IL-6 and CCL5, but not IL-8.
Conclusion/Significance
HTNV replication may not be dependent upon the ability of the virus to activate NF-κB in HUVECs. The Akt/NF-κB pathways may be involved in the pathogenesis of HFRS; therefore, cardamonin may serve as a potential beneficial agent for HFRS therapy.
doi:10.1371/journal.pone.0093810
PMCID: PMC3979720  PMID: 24714064
6.  Oncogenic effects of miR-10b in glioblastoma stem cells 
Journal of neuro-oncology  2013;112(2):153-163.
MicroRNAs and cancer stem cells have emerged as critical players in glioblastoma, one of the deadliest human cancers. In this study, we investigated the expression and function of microRNA-10b in glioblastoma cells and stem cells. An analysis of The Cancer Genome Atlas data revealed a correlation between high miR-10b levels and poor prognosis in glioblastoma patients. We measured the levels of miR-10b and found that it is upregulated in human glioblastoma tissues, glioblastoma cell and stem cell lines as compared to normal human tissues or astrocytes. Inhibition of miR-10b with a specific antagomir inhibited the proliferation of glioblastoma established and stem cell lines. Inhibition of miR-10b strongly reduced cell invasion and migration in glioblastoma cell and stem cell lines while overexpression of miR-10b induced cell migration and invasion. We also investigated several predicted targets of miR-10b but could not verify any of them experimentally. Additionally, miR-10b inhibition significantly decreased the in vivo growth of stem cell-derived orthotopic GBM xenografts. Altogether, our findings confirm the oncogenic effects of miR-10b in GBM cells and show for the first time a role of this microRNA in GBM stem cells. Targeting miR-10b might therefore inhibit glioblastoma stem cells, which are thought to be at the origin of glioblastoma and to contribute its recurrence and resistance to therapy.
doi:10.1007/s11060-013-1047-0
PMCID: PMC3609924  PMID: 23307328
MicroRNA-10b; Glioblastoma; Glioblastoma stem cells; Migration; Invasion
7.  Enhancement in dentin collagen’s biological stability after proanthocyanidins treatment in clinically relevant time periods 
Objective
To investigate whether proanthocyanidins (PA) is capable of improving dentin collagen’s biological stability through cross-linking within time periods that are clinically relevant.
Materials and methods
Demineralized dentin collagen slabs were treated with 3.75 wt% PA solution for 10 s, 1 min, 30 min, 60 min, 120 min, 360 min, and 720 min, respectively. The resultant cross-linked collagen samples were subject to digestion with 0.1% collagenase at 37 °C for 2 h, 6 h, 12 h, 24 h, 36 h, and 48 h. The percentage of weight loss after digestion was calculated to evaluate PA-treated collagen’s resistance toward enzymatic degradation. Fourier-Transformed Infrared (FTIR) spectroscopy was used to probe evidences of PA-collagen interactions after various periods of PA treatment.
Results
The collagenase digestion assay suggests that PA treatment as short as 10 s can enhance collagen’s resistance toward enzymatic challenge. The FTIR spectroscopy further verifies that PA is indeed incorporated into collagen regardless of treatment time, possibly via a mechanism involving the chemical interactions between PA and collagen.
Significance
This study confirmed that PA can effectively cross-link collagen and improve its biological stability in time periods as short as 10 s. The use of PA as a priming agent is therefore clinically feasible and is a promising approach to improving the durability of current dentin bonding systems.
doi:10.1016/j.dental.2013.01.013
PMCID: PMC3640802  PMID: 23434233
Dentin collagen; Cross-linking; Proanthocyanidins; Biodegradation; FTIR
8.  Neuropilin-1 Upholds Dedifferentiation and Propagation Phenotypes of Renal Cell Carcinoma Cells by Activating Akt and Sonic Hedgehog Axes 
Cancer research  2008;68(21):8667-8672.
Expression of neuropilin-1 (NRP-1) has been shown in many cancer cells, but its molecular effect on tumorigenesis is largely unknown. In this report, we show that in aggressive types of renal cell carcinoma (RCC), NRP-1 is expressed at a high level. We show that after knockdown of NRP-1 by short hairpin RNA, RCC cells express significantly lower levels of MDM-2 and p63 proteins but higher levels of p53, and exhibit reduced migration and invasion. When implanted in mice, RCC cells with a reduced NRP-1 level have a statistically significant smaller tumor-forming ability than control cells. Also, NRP-1 knockdown RCC cells exhibit a more differentiated phenotype, as evidenced by the expression of epithelial-specific and kidney-specific cadherins, and the inhibition of sonic hedgehog expression participated in this effect. Inhibition of sonic hedgehog expression can be reversed by ΔNp63α overexpression. Our study reveals that NRP-1 helps maintain an undifferentiated phenotype in cancer cells.
doi:10.1158/0008-5472.CAN-08-2614
PMCID: PMC3964774  PMID: 18974107
9.  Hypertriglyceridemic Waist Phenotype and Chronic Kidney Disease in a Chinese Population Aged 40 Years and Older 
PLoS ONE  2014;9(3):e92322.
Objective
To examine the relationship between the HW phenotype and risk for CKD in a community population aged 40 years and older.
Methods
A cross-sectional study was conducted in Zhuhai from June to October 2012. The participants were divided into three groups: Group 1, Waist circumference >90 cm in men or >85 cm in women and triglycerides ≥2 mmol/l; Group 3, Waist circumference ≤90 cm in men or ≤85 cm in women and triglycerides <2 mmol/l; Group 2, The remaining participants. The prevalence of the three subgroups and CKD were determined. The association between HW phenotype and CKD was then analyzed using SPSS (version 13.0).
Results
After adjusting for age and sex, Group 1 was associated with CKD (OR 3.08, 95% CI 2.01, 4.73, P<0.001), when compared with Group 3. Further adjustment for factors which were potential confounders and unlikely to be in the causal pathway between the HW phenotype and CKD, Group 1 was still significantly associated with CKD. The OR for CKD was 2.65 (95% CI 1.65, 4.26, P<0.001). When adjusted for diabetes and hypertension, the association of Group 1 and CKD was still significant (OR 2.09, 95% CI 1.26, 3.45, P = 0.004). Group 2 was associated with CKD (OR 1.81, 95% CI 1.29, 2.53, P = 0.001), when compared with Group 3. Further adjustment for factors which were potential confounders, Group 2 was still significantly associated with CKD. The OR for CKD was 1.75 (95% CI 1.22, 2.51, P = 0.002). When adjusted for diabetes and hypertension, the association between Group 2 and CKD still existed. The OR for CKD was 1.48 (95% CI 1.01, 2.16, P = 0.046).
Conclusion
Our results showed that HW phenotype was associated with CKD in the population aged 40 years and older.
doi:10.1371/journal.pone.0092322
PMCID: PMC3963886  PMID: 24663403
10.  Brown Fat Determination and Development from Muscle Precursor Cells by Novel Action of Bone Morphogenetic Protein 6 
PLoS ONE  2014;9(3):e92608.
Brown adipose tissue (BAT) plays a pivotal role in promoting energy expenditure by the virtue of uncoupling protein-1 (UCP-1) that differentiates BAT from its energy storing white adipose tissue (WAT) counterpart. The clinical implication of “classical” BAT (originates from Myf5 positive myoblastic lineage) or the “beige” fat (originates through trans-differentiation of WAT) activation in improving metabolic parameters is now becoming apparent. However, the inducers and endogenous molecular determinants that govern the lineage commitment and differentiation of classical BAT remain obscure. We report here that in the absence of any forced gene expression, stimulation with bone morphogenetic protein 6 (BMP6) induces brown fat differentiation from skeletal muscle precursor cells of murine and human origins. Through a comprehensive transcriptional profiling approach, we have discovered that two days of BMP6 stimulation in C2C12 myoblast cells is sufficient to induce genes characteristic of brown preadipocytes. This developmental switch is modulated in part by newly identified regulators, Optineurin (Optn) and Cyclooxygenase-2 (Cox2). Furthermore, pathway analyses using the Causal Reasoning Engine (CRE) identified additional potential causal drivers of this BMP6 induced commitment switch. Subsequent analyses to decipher key pathway that facilitates terminal differentiation of these BMP6 primed cells identified a key role for Insulin Like Growth Factor-1 Receptor (IGF-1R). Collectively these data highlight a therapeutically innovative role for BMP6 by providing a means to enhance the amount of myogenic lineage derived brown fat.
doi:10.1371/journal.pone.0092608
PMCID: PMC3962431  PMID: 24658703
11.  Pan-genome analyses identify lineage- and niche-specific markers of evolution and adaptation in Epsilonproteobacteria 
The rapidly increasing availability of complete bacterial genomes has created new opportunities for reconstructing bacterial evolution, but it has also highlighted the difficulty to fully understand the genomic and functional variations occurring among different lineages. Using the class Epsilonproteobacteria as a case study, we investigated the composition, flexibility, and function of its pan-genomes. Models were constructed to extrapolate the expansion of pan-genomes at three different taxonomic levels. The results show that, for Epsilonproteobacteria the seemingly large genome variations among strains of the same species are less noticeable when compared with groups at higher taxonomic ranks, indicating that genome stability is imposed by the potential existence of taxonomic boundaries. The analyses of pan-genomes has also defined a set of universally conserved core genes, based on which a phylogenetic tree was constructed to confirm that thermophilic species from deep-sea hydrothermal vents represent the most ancient lineages of Epsilonproteobacteria. Moreover, by comparing the flexible genome of a chemoautotrophic deep-sea vent species to (1) genomes of species belonging to the same genus, but inhabiting different environments, and (2) genomes of other vent species, but belonging to different genera, we were able to delineate the relative importance of lineage-specific versus niche-specific genes. This result not only emphasizes the overall importance of phylogenetic proximity in shaping the variable part of the genome, but also highlights the adaptive functions of niche-specific genes. Overall, by modeling the expansion of pan-genomes and analyzing core and flexible genes, this study provides snapshots on how the complex processes of gene acquisition, conservation, and removal affect the evolution of different species, and contribute to the metabolic diversity and versatility of Epsilonproteobacteria.
doi:10.3389/fmicb.2014.00110
PMCID: PMC3958643  PMID: 24678308
pan-genome; core genes; flexible genes; Epsilonproteobacteria; Sulfurimonas; Helicobacter; Campylobacter
12.  Preparation of Primary Amine Derivatives of the Magic-Size Nanocluster (CdSe)13 
Inorganic chemistry  2013;52(6):2933-2938.
Four [(CdSe)13(RNH2)13] derivatives (R = n-propyl, n-pentyl, n-octyl, and oleyl) are prepared by reaction of Cd(OAc)2·2H2O and selenourea in the corresponding primary-amine solvent. The nanoclusters grow in spontaneously formed amine-bilayer templates, and are characterized by elemental analysis, IR spectroscopy, UV-visible spectroscopy, TEM, and low-angle XRD. The derivative [(CdSe)13(n-propylamine)13] is isolated as a yellowish-white solid (MP 98 °C) on the gram scale. These compounds are the first derivatives of magic-size CdSe nanoclusters to be isolated in purity.
doi:10.1021/ic302327p
PMCID: PMC3645328  PMID: 23458416
13.  Antioxidation of Decellularized Stem Cell Matrix Promotes Human Synovium-Derived Stem Cell-Based Chondrogenesis 
Stem Cells and Development  2012;22(6):889-900.
Clinical treatment of cartilage defects is challenging due to concomitant post-traumatic joint inflammation. This study was to demonstrate that the antioxidant ability of human adult synovium-derived stem cells (SDSCs) could be enhanced by ex vivo expansion on a decellularized stem cell matrix (DSCM). Microarray was used to evaluate oxidative, antioxidative, and chondrogenic status in SDSCs after expansion on the DSCM and induction in the chondrogenic medium. Hydrogen peroxide (H2O2) was added to create oxidative stress in either expanded SDSCs or chondrogenically induced premature pellets. The effect of H2O2 on SDSC proliferation was evaluated using flow cytometry. Chondrogenic differentiation of expanded SDSCs was evaluated using histology, immunostaining, biochemical analysis, and real-time polymerase chain reaction. Mitogen-activated protein kinase signaling pathways and p21 were compared in the DSCM and plastic-flask-expanded SDSCs with or without H2O2 treatment. We found that expansion on the DSCM upregulated antioxidative gene levels and chondrogenic potential in human SDSCs (hSDSCs), retarded the decrease in the cell number and the increase in apoptosis, and rendered SDSCs resistant to cell-cycle G1 arrest resulting from H2O2 treatment. Treatment with 0.05 mM H2O2 during cell expansion yielded pellets with increased chondrogenic differentiation; treatment in premature SDSC pellets showed that the DSCM-expanded cells had a robust resistance to H2O2-induced oxidative stress. Extracellular signal-regulated kinases 1 and 2 and p38 were positively involved in antioxidative and chondrogenic potential in SDSCs expanded on the DSCM in which p21 was downregulated. DSCM could be a promising cell expansion system to provide a large number of high-quality hSDSCs for cartilage regeneration in a harsh joint environment.
doi:10.1089/scd.2012.0495
PMCID: PMC3585742  PMID: 23092115
14.  Hepatocyte growth factor sensitizes brain tumors to c-MET kinase inhibition 
Purpose
The receptor tyrosine kinase (RTK) c-MET and its ligand hepatocyte growth factor (HGF) are deregulated and promote malignancy in cancer and brain tumors. Consequently, clinically applicable c-MET inhibitors have been developed. The purpose of this study was to investigate the not well known molecular determinants that predict responsiveness to c-MET inhibitors, and to explore new strategies for improving inhibitor efficacy in brain tumors.
Experimental design
We investigated the molecular factors and pathway activation signatures that determine sensitivity to c-MET inhibitors in a panel of glioblastoma and medulloblastoma cells, glioblastoma stem cells (GSCs), and established cell line-derived xenografts using functional assays, reverse protein microarrays, and in vivo tumor volume measurements, but validation with animal survival analyses remains to be done. We also explored new approaches for improving the efficacy of the inhibitors in vitro and in vivo.
Results
We found that HGF co-expression is a key predictor of response to c-MET inhibition among the examined factors, and identified an ERK/JAK/p53 pathway activation signature that differentiates c-MET inhibition in responsive and non-responsive cells. Surprisingly, we also found that short pre-treatment of cells and tumors with exogenous HGF moderately but statistically significantly enhanced the anti-tumor effects of c-MET inhibition. We observed a similar ligand-induced sensitization effect to an EGFR small molecule kinase inhibitor.
Conclusions
These findings allow the identification of a subset of patients that will be responsive to c-MET inhibition, and propose ligand pre-treatment as a potential new strategy for improving the anti-cancer efficacy of RTK inhibitors.
doi:10.1158/1078-0432.CCR-12-2832
PMCID: PMC3602223  PMID: 23386689
Brain tumors; Receptor tyrosine kinases inhibitors; c-MET; Hepatocyte growth factor; Oncogene addiction
15.  A Stem-Cell Based Bioassay to Critically Assess the Pathology of Dysfunctional Neuromuscular Junctions 
PLoS ONE  2014;9(3):e91643.
Pluripotent stem cells can be directed to differentiate into motor neurons and assessed for functionality in vitro. An emerging application of this technique is to model genetically inherited diseases in differentiated motor neurons and to screen for new therapeutic targets. The neuromuscular junction (NMJ) is essential to the functionality of motor neurons and its dysfunction is a primary hallmark of motor neuron disease. However, mature NMJs that possess the functional and morphological characteristics of those formed in vivo have so far not been obtained in vitro. Here we describe the generation and analysis of mature NMJs formed between embryonic stem cell-derived motor neurons (ESCMNs) and primary myotubes. We compared the formation and maturation of NMJs generated by wild-type (NCAM+/+) ESCMNs to those generated by neural cell adhesion molecule null (NCAM-/-) ESCMNs in order to definitively test the sensitivity of this assay to identify synaptic pathology. We find that co-cultures using NCAM-/- ESCMNs replicate key in vivo NCAM-/- phenotypes and reveal that NCAM influences neuromuscular synaptogenesis by controlling the mode of synaptic vesicle endocytosis. Further, we could improve synapse formation and function in NCAM-/- co-cultures by chronic treatment with nifedipine, which blocks an immature synaptic vesicle recycling pathway. Together, our results demonstrate that this ESCMN/myofiber co-culture system is a highly sensitive bioassay for examining molecules postulated to regulate synaptic function and for screening therapeutics that will improve the function of compromised NMJs.
doi:10.1371/journal.pone.0091643
PMCID: PMC3953473  PMID: 24626225
16.  Clinical study of treatment switching from premixed insulin to basal insulin combined with oral hypoglycemic drugs in patients with type 2 diabetes 
Aim
Premixed insulin regimens are commonly used for the treatment of patients with type-2 diabetes mellitus (T2DM). However, limited data are available regarding next-step therapy options in cases where premixed insulin fails to provide adequate glycemic control. This 20-week observational study of everyday clinical practice evaluated the efficacy, safety and treatment satisfaction of insulin glargine plus oral anti-diabetic drugs (OADs) in T2DM patients previously treated with premixed insulin.
Methods
In this open-label, single-arm, 20-week study, 70 subjects with T2DM inadequately controlled with premixed insulin were switched to insulin glargine plus OADs. Changes in glycaemic control, incidence of hypoglycaemia, treatment satisfaction using the Diabetes Treatment Satisfaction Questionnaire (DTSQ), serum superoxide dismutase (SOD), and serum 8-iso-prostaglandin (8-iso-PG) were evaluated at the start and the end of the study.
Results
Over the 20 week treatment period, mean (±SD) HbA1c levels decreased from 8.28 ± 1.24% to 6.83 ± 1.09%, mean (±SD) FBG levels decreased from 7.64 ± 1.36 mmol/L to 5.57 ± 1.21 mmol/L, and 2 h PBG levels decreased from 12.07 ± 1.17 mmol/L to 8.94 ± 1.56 mmol/L, all P < 0.001. A total of 3 symptomatic hypoglycemic episodes were reported. No significant reductions in body weight were observed. The mean daily dose of insulin decreased by 14 U between week 0 (30.20 ± 9.93 U) and week 20 (16.38 ± 5.15 U). The total treatment satisfaction score showed a significant increase from study baseline to end point. Significant increases in SOD(90.00 ± 16.62 to 108.81 ± 27.02 u/ml, P < 0.01) and reductions in 8-iso-PG(2.15 ± 0.61 to 1.64 ± 0.42 pg/ml, P < 0.05) were observed between the start and end of the observation period. There were significant differences in baseline HbA1c, duration of diabetes, and baseline postprandial C-peptide between the A1c ≤ 6.5% group and the A1c > 7.0% group [HbA1c: 7.25% ± 1.02% vs. 9.32% ± 1.23%; duration: 7.84 ± 1.02 vs. 13.96 ± 1.35 years; postprandial C-peptide: 4.83 ± 2.11 vs 2.54 ± 0.87 nmol/L, all P < 0.05].
Conclusions
The observational study shows that, in T2DM patients inadequately controlled with premixed insulin, switching therapy to glargine plus OADs is associated with significant improvements in glycaemic control and treatment satisfaction, and is with low incidence of hypoglycemia. Baseline postprandial C-peptide, HbA1c, and duration of diabetes are the key factors closely related to efficacy of this treatment regimen.
doi:10.1186/1758-5996-6-37
PMCID: PMC3984683  PMID: 24620742
Type 2 diabetes mellitus; Glargine; Premixed insulin; Oxidative stress
17.  DLK1 Promotes Lung Cancer Cell Invasion through Upregulation of MMP9 Expression Depending on Notch Signaling 
PLoS ONE  2014;9(3):e91509.
The transmembrane and secreted protein delta-like 1 homolog (DLK1) belongs to the EGF-like family. It is widely accepted that DLK1 plays important roles in regulating cell differentiation, such as adipogenesis and osteogenesis. Aberrant expression of DLK1 has been found in various types of human cancers, including lung cancer. A previous study in this lab has revealed that DLK1 is associated with tumor invasion, although the mechanism is still unknown. To explore the potential effects that DLK1 might have on invasion, DLK1 was overexpressed or knocked down in the human lung cancer cell lines. The protein's influences on cell invasion were subsequently evaluated. A transwell assay showed that DLK1 overexpression significantly promoted cancer cell invasion. Western blotting and gelatin zymography analysis indicated that DLK1 could affect both matrix metalloproteinase-9 (MMP9) expression and its extracellular activity. An analysis of NOTCH1 and HES1 gene expression and Notch intracellular domain (NICD) nuclear translocation during DLK1 stimulation or depletion demonstrated that DLK1 could activate Notch signaling in lung cancer cells. Additionally, the elevated expression of MMP9 induced by DLK1 stimulation could be significantly decreased by inhibiting Notch signaling using γ-secretase inhibitor (GSI). The data presented in this study suggest that DLK1 can promote the invasion of lung cancer cells by upregulating MMP9 expression, which depends on Notch signaling.
doi:10.1371/journal.pone.0091509
PMCID: PMC3951400  PMID: 24621612
18.  Transcriptome Profiling of a Multiple Recurrent Muscle-Invasive Urothelial Carcinoma of the Bladder by Deep Sequencing 
PLoS ONE  2014;9(3):e91466.
Urothelial carcinoma of the bladder (UCB) is one of the commonly diagnosed cancers in the world. The UCB has the highest rate of recurrence of any malignancy. A genome-wide screening of transcriptome dysregulation between cancer and normal tissue would provide insight into the molecular basis of UCB recurrence and is a key step to discovering biomarkers for diagnosis and therapeutic targets. Compared with microarray technology, which is commonly used to identify expression level changes, the recently developed RNA-seq technique has the ability to detect other abnormal regulations in the cancer transcriptome, such as alternative splicing. In this study, we performed high-throughput transcriptome sequencing at ∼50× coverage on a recurrent muscle-invasive cisplatin-resistance UCB tissue and the adjacent non-tumor tissue. The results revealed cancer-specific differentially expressed genes between the tumor and non-tumor tissue enriched in the cell adhesion molecules, focal adhesion and ECM-receptor interaction pathway. Five dysregulated genes, including CDH1, VEGFA, PTPRF, CLDN7, and MMP2 were confirmed by Real time qPCR in the sequencing samples and the additional eleven samples. Our data revealed that more than three hundred genes showed differential splicing patterns between tumor tissue and non-tumor tissue. Among these genes, we filtered 24 cancer-associated alternative splicing genes with differential exon usage. The findings from RNA-Seq were validated by Real time qPCR for CD44, PDGFA, NUMB, and LPHN2. This study provides a comprehensive survey of the UCB transcriptome, which provides better insight into the complexity of regulatory changes during recurrence and metastasis.
doi:10.1371/journal.pone.0091466
PMCID: PMC3951401  PMID: 24622401
19.  MicroRNA-608 and MicroRNA-34a Regulate Chordoma Malignancy by Targeting EGFR, Bcl-xL and MET 
PLoS ONE  2014;9(3):e91546.
Chordomas are rare malignant tumors that originate from the notochord remnants and occur in the skull base, spine and sacrum. Due to a very limited understanding of the molecular pathogenesis of chordoma, there are no adjuvant and molecular therapies besides surgical resection and radiation therapy. microRNAs (miRNAs) are small noncoding regulatory RNA molecules with critical roles in cancer. The role of miRNAs in chordomas is mostly unknown. We uncover microRNA-608 (miR-608) and microRNA-34a (miR-34a) as novel tumor suppressive microRNAs that regulate malignancy in chordoma. We find that miR-608 and miR-34a expressions are downregulated in human chordoma cell lines and primary cells at least partially via alteration of their genes’ copy numbers. We identify the commonly deregulated oncogenes EGFR and Bcl-xL as direct targets of miR-608 and the receptor tyrosine kinase MET as direct target of miR-34a. We show that EGFR and MET activations promote chordoma cell proliferation and invasion and that pharmacological inhibition of EGFR and MET inhibits chordoma cell proliferation and survival. We demonstrate that restoration of miR-608 and miR-34a inhibits cell proliferation and invasion and induces apoptosis in chordoma cells. We find that miR-34a inversely correlates with MET expression and miR-608 inversely correlates with EGFR expression in chordoma cells. These findings demonstrate for the first time that miR-608 and miR-34a regulate chordoma malignancy by regulating EGFR, MET and Bcl-xL.
doi:10.1371/journal.pone.0091546
PMCID: PMC3951453  PMID: 24621885
20.  Patients with Old Age or Proximal Tumors Benefit from Metabolic Syndrome in Early Stage Gastric Cancer 
PLoS ONE  2014;9(3):e89965.
Background
Metabolic syndrome and/or its components have been demonstrated to be risk factors for several cancers. They are also found to influence survival in breast, colon and prostate cancer, but the prognostic value of metabolic syndrome in gastric cancer has not been investigated.
Methods
Clinical data and pre-treatment information of metabolic syndrome of 587 patients diagnosed with early stage gastric cancer were retrospectively collected. The associations of metabolic syndrome and/or its components with clinical characteristics and overall survival in early stage gastric cancer were analyzed.
Results
Metabolic syndrome was identified to be associated with a higher tumor cell differentiation (P = 0.036). Metabolic syndrome was also demonstrated to be a significant and independent predictor for better survival in patients aged >50 years old (P = 0.009 in multivariate analysis) or patients with proximal gastric cancer (P = 0.047 in multivariate analysis). No association was found between single metabolic syndrome component and overall survival in early stage gastric cancer. In addition, patients with hypertension might have a trend of better survival through a good control of blood pressure (P = 0.052 in univariate analysis).
Conclusions
Metabolic syndrome was associated with a better tumor cell differentiation in patients with early stage gastric cancer. Moreover, metabolic syndrome was a significant and independent predictor for better survival in patients with old age or proximal tumors.
doi:10.1371/journal.pone.0089965
PMCID: PMC3943843  PMID: 24599168
21.  Tea polyphenols alleviate high fat and high glucose-induced endothelial hyperpermeability by attenuating ROS production via NADPH oxidase pathway 
BMC Research Notes  2014;7:120.
Background
Hyperglycemia-induced endothelial hyperpermeability is crucial to cardiovascular disorders and macro-vascular complications in diabetes mellitus. The objective of this study is to investigate the effects of green tea polyphenols (GTPs) on endothelial hyperpermeability and the role of nicotinamide adenine dinucleotide phosphate (NADPH) pathway.
Methods
Male Wistar rats fed on a high fat diet (HF) were treated with GTPs (0, 0.8, 1.6, 3.2 g/L in drinking water) for 26 weeks. Bovine aortic endothelial cells (BAECs) were treated with high glucose (HG, 33 mmol/L) and GTPs (0.0, 0.4, or 4 μg/mL) for 24 hours in vitro. The endothelial permeabilities in rat aorta and monolayer BAECs were measured by Evans blue injection method and efflux of fluorescein isothiocyanate (FITC)-dextran, respectively. The reactive oxygen species (ROS) levels in rat aorta and monolayer BAECs were measured by dihydroethidium (DHE) and 2′, 7′-dichloro-fluorescein diacetate (DCFH-DA) fluorescent probe, respectively. Protein levels of NADPH oxidase subunits were determined by Western-blot.
Results
HF diet-fed increased the endothelial permeability and ROS levels in rat aorta while HG treatments increased the endothelial permeability and ROS levels in cultured BAECs. Co-treatment with GTPs alleviated those changes both in vivo and in vitro. In in vitro studies, GTPs treatments protected against the HG-induced over-expressions of p22phox and p67phox. Diphenylene iodonium chloride (DPI), an inhibitor of NADPH oxidase, alleviated the hyperpermeability induced by HG.
Conclusions
GTPs could alleviate endothelial hyperpermeabilities in HF diet-fed rat aorta and in HG treated BAECs. The decrease of ROS production resulting from down-regulation of NADPH oxidase contributed to the alleviation of endothelial hyperpermeability.
doi:10.1186/1756-0500-7-120
PMCID: PMC3944679  PMID: 24580748
Green tea polyphenols; High fat; High glucose; Hyperpermeability; NADPH oxidase
22.  Effect of application mode on interfacial morphology and chemistry between dentin and self-etch adhesives 
Journal of dentistry  2012;41(3):231-240.
Objective
To investigate the influence of application mode on the interfacial morphology and chemistry between dentin and self-etch adhesives with different aggressiveness.
Methods
The occlusal one-third of the crown was removed from un-erupted human third molars, followed by abrading with 600 grit SiC under water. Rectangular dentin slabs were prepared by sectioning the tooth specimens perpendicular to the abraded surfaces. The obtained dentin slabs were treated with one of the two one-step self-etch adhesives: Adper Easy Bond (AEB, PH~2.5) and Adper Prompt L-Pop (APLP, PH~0.8) with (15s, active application) or without (15s, inactive application) agitation. The dentin slabs were fractured and the exposed adhesive/dentin (A/D) interfaces were examined with micro-Raman spectroscopy and scanning electron microscopy (SEM).
Results
The interfacial morphology, degree of dentin demineralization (DD) and degree of conversion (DC) of the strong self-etch adhesive APLP showed more significant dependence on the application mode than the mild AEB. APLP exhibited inferior bonding at the A/D interface if applied without agitation, evidenced by debonding from the dentin substrate. The DDs and DCs of the APLP with agitation were higher than those of without agitation in the interface, in contrast to the comparable DD and DC values of two AEB specimen groups with different application modes. Raman spectral analysis revealed the important role of chemical interaction between acid monomers of self-etch adhesives and dentin in the above observations.
Conclusion
The chemical interaction with dentin is especially important for improving the DC of the strong self-etching adhesive at the A/D interface. Agitation could benefit polymerization efficacy of the strong self-etch adhesive through enhancing the chemical interaction with tooth substrate.
doi:10.1016/j.jdent.2012.11.006
PMCID: PMC3593798  PMID: 23153573
self-etch adhesives; degree of conversion; micro-Raman; agitation; adhesive/dentin interface
23.  A Spodoptera exigua Cadherin Serves as a Putative Receptor for Bacillus thuringiensis Cry1Ca Toxin and Shows Differential Enhancement of Cry1Ca and Cry1Ac Toxicity 
Applied and Environmental Microbiology  2013;79(18):5576-5583.
Crystal toxin Cry1Ca from Bacillus thuringiensis has an insecticidal spectrum encompassing lepidopteran insects that are tolerant to current commercially used B. thuringiensis crops (Bt crops) expressing Cry1A toxins and may be useful as a potential bioinsecticide. The mode of action of Cry1A is fairly well understood. However, whether Cry1Ca interacts with the same receptor proteins as Cry1A remains unproven. In the present paper, we first cloned a cadherin-like gene, SeCad1b, from Spodoptera exigua (relatively susceptible to Cry1Ca). SeCad1b was highly expressed in the larval gut but scarcely detected in fat body, Malpighian tubules, and remaining carcass. Second, we bacterially expressed truncated cadherin rSeCad1bp and its interspecific homologue rHaBtRp from Helicoverpa armigera (more sensitive to Cry1Ac) containing the putative toxin-binding regions. Competitive binding assays showed that both Cry1Ca and Cry1Ac could bind to rSeCad1bp and rHaBtRp, and they did not compete with each other. Third, Cry1Ca ingestion killed larvae and decreased the weight of surviving larvae. Dietary introduction of SeCad1b double-stranded RNA (dsRNA) reduced approximately 80% of the target mRNA and partially alleviated the negative effect of Cry1Ca on larval survival and growth. Lastly, rSeCad1bp and rHaBtRp differentially enhanced the negative effects of Cry1Ca and Cry1Ac on the larval mortalities and growth of S. exigua and H. armigera. Thus, we provide the first lines of evidence to suggest that SeCad1b from S. exigua is a functional receptor of Cry1Ca.
doi:10.1128/AEM.01519-13
PMCID: PMC3754171  PMID: 23835184
24.  Mitochondrial genome of Babesia orientalis, apicomplexan parasite of water buffalo (Bubalus babalis, Linnaeus, 1758) endemic in China 
Parasites & Vectors  2014;7:82.
Background
Apicomplexan parasites of the genus Babesia, Theileria and Plasmodium are very closely related organisms. Interestingly, their mitochondrial (mt) genomes are highly divergent. Among Babesia, Babesia orientalis is a new species recently identified and specifically epidemic to the southern part of China, causing severe disease to water buffalo. However, no information on the mt genome of B. orientalis was available.
Methods
Four pairs of primers were designed based on the full genome sequence of B. orientalis (unpublished data) and by aligning reported mt genomes of B. bovis, B. bigemina, and T. parva. The entire mt genome was amplified by four sets of PCR. The obtained mt genome was annotated by aligning with published apicomplexan mt genomes and Artemis software v11. Phylogenetic analysis was performed by using cox1 and cob amino acid sequences.
Results
The complete mt genome of B. orientalis (Wuhan strain) was sequenced and characterized. The entire mt genome is 5996 bp in length with a linear form, containing three protein-coding genes including cytochrome c oxidase I (cox1), cytochrome b (cob) and cytochrome c oxidase III (cox3) and six rRNA large subunit gene fragments. The gene arrangement in B. orientalis mt genome is similar to those of B. bovis, B. gibsoni and Theileria parva, but different from those of T. orientalis, T. equi and Plasmodium falciparum. Comparative analysis indicated that cox1 and cob genes were more conserved than cox3. Phylogenetic analysis based on amino acid sequences of cox1, cob and cox1 + cob, respectively, revealed that B. orientalis fell into Babesia clade with the closest relationship to B. bovis.
Conclusions
The availability of the entire mt genome sequences of B. orientalis provides valuable information for future phylogenetic, population genetics and molecular epidemiological studies of apicomplexan parasites.
doi:10.1186/1756-3305-7-82
PMCID: PMC3941609  PMID: 24580772
Babesia orientalis; Mitochondrion; Mitochondrial genome; Phylogeny
25.  Photoresponsive Supramolecular Complexes as Efficient DNA Regulator 
Scientific Reports  2014;4:4210.
Two supramolecular complexes of trans-1⊂CB[8] and trans-2⊂CB[8] were successfully achieved by the controlled selective complexation process of cucurbit[8]uril (CB[8]) with hetero-guest pair containing azobenzene and bispyridinium moieties in aqueous solution, exhibiting the reversibly light-driven movements of CB[8] upon the photocontrollable isomerization of azophenyl axle components. Significantly, the obtained bistable supramolecular complexes and their corresponding [2]pseudorotaxanes could act as a promising concentrator and cleavage agent to regulate the binding behaviors with DNA molecules.
doi:10.1038/srep04210
PMCID: PMC3936212  PMID: 24572680

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