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1.  Antiviral Activity of (+)-Rutamarin against Kaposi's Sarcoma-Associated Herpesvirus by Inhibition of the Catalytic Activity of Human Topoisomerase II 
Kaposi's sarcoma-associated herpesvirus (KSHV) is an etiological agent of several AIDS-associated malignancies, including Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). Its lytic replication cycle has been proven to be critical for the pathogenesis of KSHV-associated diseases. In KS lesions, lytic viral replication, production of virion particles, and reinfection of endothelial cells are essential to sustain the population of infected cells that otherwise would be quickly lost as spindle cells divide. Thus, antivirals that block KSHV replication could be a strategy in the treatment of KSHV-associated diseases. However, there is no effective anti-KSHV drug currently available. Our previous work showed that human topoisomerase II (Topo II) is indispensable for KSHV lytic replication and is suggested to be an effective target for antiviral drugs. Here, we report the discovery and characterization of a novel catalytic inhibitor of human Topo IIα, namely, (+)-rutamarin. The binding mode of (+)-rutamarin to the ATPase domain of human Topo IIα was established by docking and validated by molecular dynamics (MD) simulations. More importantly, (+)-rutamarin efficiently inhibits KSHV lytic DNA replication in BCBL-1 cells with a half-maximal inhibitory concentration (IC50) of 1.12 μM and blocks virion production with a half-maximal antiviral effective concentration (EC50) of 1.62 μM. It possesses low cytotoxicity, as indicated by the selectivity index (SI) of 84.14. This study demonstrated great potential for (+)-rutamarin to become an effective drug for treatment of human diseases associated with KSHV infection.
doi:10.1128/AAC.01259-13
PMCID: PMC3910736  PMID: 24295975
2.  SPF Rabbits Infected with Rabbit Hepatitis E Virus Isolate Experimentally Showing the Chronicity of Hepatitis 
PLoS ONE  2014;9(6):e99861.
This study focused on investigating the pathogenesis seen in specific-pathogen-free (SPF) rabbits following infection with a homologous rabbit HEV isolate (CHN-BJ-rb14) and comparing it to that seen following infection with a heterologous swine genotype 4 HEV isolate (CHN-XJ-SW13). Three of the four animals inoculated with the homologous rabbit HEV became infected, exhibiting an intermittent viremia, obvious fluctuations of liver function biomarkers alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and persistent fecal virus shedding throughout the nine month study. In addition, liver histopathology showed both chronic inflammation and some degree of fibrosis. Both positive and negative-stranded HEV RNA and HEV antigen expression were detected in liver, brain, stomach, duodenum and kidney from the necropsied rabbits. Inflammation of extrahepatic tissue (duodenum and kidney) was also observed. Three of the four rabbits inoculated with the heterologous genotype 4 swine HEV also became infected, showing similar levels of anti-HEV antibody to that generated following infection with the homologous virus isolate. The duration of both viremia and fecal shedding of virus was however shorter following infection with the heterologous virus and there was no significant elevation of liver function biomarkers. These results suggest that rabbit HEV infection may cause more severe hepatitis and prolong the course of the disease, with a possible chronic trend of hepatitis in SPF rabbits.
doi:10.1371/journal.pone.0099861
PMCID: PMC4061063  PMID: 24937350
3.  Function and Interaction of the Coupled Genes Responsible for Pik-h Encoded Rice Blast Resistance 
PLoS ONE  2014;9(6):e98067.
Pik-h, an allele of Pik, confers resistance against the rice blast pathogen Magnaporthe oryzae. Its positional cloning has shown that it comprises a pair of NBS-LRR genes, Pikh-1 and Pikh-2. While Pikh-1 appears to be constitutively transcribed, the transcript abundance of Pikh-2 responds to pathogen challenge. The Pikh-1 CC (coiled coil) domain interacts directly with both AvrPik-h and Pikh-2. Transient expression assays demonstrated that Pikh-2 mediates the initiation of the host defence response. Nucleocytoplasmic partitioning of both Pikh-1 and Pikh-2 is required for their functionalities. In a proposed mechanistic model of Pik-h resistance, it is suggested that Pikh-1 acts as an adaptor between AvrPik-h and Pikh-2, while Pikh-2 transduces the signal to trigger Pik-h-specific resistance.
doi:10.1371/journal.pone.0098067
PMCID: PMC4045721  PMID: 24896089
4.  Immunogenicity, Safety, and Lot Consistency of a Novel Inactivated Enterovirus 71 Vaccine in Chinese Children Aged 6 to 59 Months 
Clinical and Vaccine Immunology : CVI  2013;20(12):1805-1811.
The determination of lot-to-lot consistency in the manufacturing process is a mandatory step in the clinical development of the novel enterovirus 71 (EV71) vaccine. A phase III, randomized, placebo-controlled, double-blind trial assessed the lot consistency, immunogenicity, and safety of the EV71 vaccine in children aged 6 to 59 months. Healthy children (n = 1,400) received one of three lots of the EV71 vaccine containing 400 U of EV71 antigen or a placebo at days 0 and 28. Blood samples were collected before dose 1 and at 28 days after dose 2 (day 56) for an anti-EV71 neutralizing antibody (NTAb) assay. The geometric mean titer (GMT) and the seropositivity rates (with titers of ≥1:8) were compared at day 56. After each dose, the solicited injection site and general adverse events (AEs) were recorded for 7 days, and unsolicited AEs were recorded for 28 days. At day 56, the seropositivity rates ranged from 99.7% to 100% for the vaccine groups. The NTAb GMTs for the vaccine were 140.3 (95% confidence interval [CI], 117.8 to 167.1), 141.5 (95% CI, 118.0 to 169.6), and 146.6 (95% CI, 122.5 to 175.3). The two-sided 95% CI of the log difference in GMTs between the pairs of lots were between −0.176 and 0.176, therefore meeting the predefined equivalence criteria. The percentages of subjects reporting any injection site AEs, general AEs, or serious AEs were similar across the four vaccination groups. In conclusion, the demonstration of consistency between the manufacturing lots confirms for the purposes of clinical development the reliability of the EV71 vaccine production process. (This study has been registered at ClinicalTrials.gov under registration no. NCT01636245.)
doi:10.1128/CVI.00491-13
PMCID: PMC3889509  PMID: 24108780
5.  The Continual Reassessment Method for Multiple Toxicity Grades: A Bayesian Model Selection Approach 
PLoS ONE  2014;9(5):e98147.
Grade information has been considered in Yuan et al. (2007) wherein they proposed a Quasi-CRM method to incorporate the grade toxicity information in phase I trials. A potential problem with the Quasi-CRM model is that the choice of skeleton may dramatically vary the performance of the CRM model, which results in similar consequences for the Quasi-CRM model. In this paper, we propose a new model by utilizing bayesian model selection approach – Robust Quasi-CRM model – to tackle the above-mentioned pitfall with the Quasi-CRM model. The Robust Quasi-CRM model literally inherits the BMA-CRM model proposed by Yin and Yuan (2009) to consider a parallel of skeletons for Quasi-CRM. The superior performance of Robust Quasi-CRM model was demonstrated by extensive simulation studies. We conclude that the proposed method can be freely used in real practice.
doi:10.1371/journal.pone.0098147
PMCID: PMC4038518  PMID: 24875783
6.  EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation 
Cancer cell  2013;23(5):677-692.
The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B-cells and targeted by somatic mutations in B-cell lymphomas. Here we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions in mice. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B-cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets in B-cells, and in human B-cell lymphomas. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GCB-type DLBCLs are mostly addicted to EZH2, regardless of mutation status, but not the more differentiated ABC-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting.
doi:10.1016/j.ccr.2013.04.011
PMCID: PMC3681809  PMID: 23680150
7.  Predicting mTOR Inhibitors with a Classifier Using Recursive Partitioning and Naïve Bayesian Approaches 
PLoS ONE  2014;9(5):e95221.
Background
Mammalian target of rapamycin (mTOR) is a central controller of cell growth, proliferation, metabolism, and angiogenesis. Thus, there is a great deal of interest in developing clinical drugs based on mTOR. In this paper, in silico models based on multi-scaffolds were developed to predict mTOR inhibitors or non-inhibitors.
Methods
First 1,264 diverse compounds were collected and categorized as mTOR inhibitors and non-inhibitors. Two methods, recursive partitioning (RP) and naïve Bayesian (NB), were used to build combinatorial classification models of mTOR inhibitors versus non-inhibitors using physicochemical descriptors, fingerprints, and atom center fragments (ACFs).
Results
A total of 253 models were constructed and the overall predictive accuracies of the best models were more than 90% for both the training set of 964 and the external test set of 300 diverse compounds. The scaffold hopping abilities of the best models were successfully evaluated through predicting 37 new recently published mTOR inhibitors. Compared with the best RP and Bayesian models, the classifier based on ACFs and Bayesian shows comparable or slightly better in performance and scaffold hopping abilities. A web server was developed based on the ACFs and Bayesian method (http://rcdd.sysu.edu.cn/mtor/). This web server can be used to predict whether a compound is an mTOR inhibitor or non-inhibitor online.
Conclusion
In silico models were constructed to predict mTOR inhibitors using recursive partitioning and naïve Bayesian methods, and a web server (mTOR Predictor) was also developed based on the best model results. Compound prediction or virtual screening can be carried out through our web server. Moreover, the favorable and unfavorable fragments for mTOR inhibitors obtained from Bayesian classifiers will be helpful for lead optimization or the design of new mTOR inhibitors.
doi:10.1371/journal.pone.0095221
PMCID: PMC4018356  PMID: 24819222
8.  Formulation and In Vivo Evaluation of Orally Disintegrating Tablets of Clozapine/Hydroxypropyl-β-cyclodextrin Inclusion Complexes 
AAPS PharmSciTech  2013;14(2):854-860.
The aim of this study was to improve the solubility and oral bioavailability of clozapine (CLZ), a poorly water-soluble drug subjected to substantial first-pass metabolism, employing cyclodextrin complexation technique. The inclusion complexes were prepared by an evaporation method. Phase solubility studies, differential scanning calorimetry, X-ray powder diffraction, and Fourier transform infrared spectroscopy were used to evaluate the complexation of CLZ with hydroxypropyl-β-cyclodextrin (HP-β-CD) and the formation of true inclusion complexes. Characterization and dissolution studies were carried out to evaluate the orally disintegrating tablets (ODTs) containing CLZ/HP-β-CD complexes prepared by direct compression. Finally, the bioavailability studies of the prepared ODTs were performed by oral administration to rabbits. The ODTs showed a higher in vitro dissolution rate and bioavailability compared with the commercial tablets. It is evident from the results herein that the developed ODTs provide a promising drug delivery system in drug development, owing to their excellent performance of a rapid onset of action, improved bioavailability, and good patient compliance.
doi:10.1208/s12249-013-9973-x
PMCID: PMC3666014  PMID: 23649995
bioavailability; clozapine; hydroxypropyl-β-cyclodextrin; inclusion complexes; orally disintegrating tablets
9.  A Walk-In Screening of Dementia in the General Population in Taiwan 
The Scientific World Journal  2014;2014:243738.
Alzheimer's disease (AD) has increased in its prevalence due to the increasing aged population. Currently there is no updated data on the prevalence of dementia including its very mild stage in Taiwan. Under the extensive coverage of Mentality Protection Center (MPC), Fo Guang Shan, Taiwan, the volunteers of MPC have conducted the medicine-related services and the screening of dementia by AD8 (ascertainment of dementia 8) that can screen the dementia even at its very mild stage in general population in all Taiwan. From 2011 to 2013, in total, 2,171 participants, 368 in the northern, 549 in the central, 877 in the southern, and 377 in the eastern part, were recruited with the mean age being 66.9 ± 10.2 years old. The ratio of suspected dementia patients, AD8 score greater than or equal to 2, was 13.6% of all recruited participants with their mean AD8 score being 2.9 ± 1.3, mean age being 69.4 ± 10.8 years old, and female predominance being 73.0%. Although this is a screening study, it has extensive coverage of all Taiwan and the use of AD8 is capable of screening very mild dementia. A further study with a randomized sampling to examine the prevalence and incidence of dementia including its very mild stage is encouraged.
doi:10.1155/2014/243738
PMCID: PMC4032722  PMID: 24883363
10.  Effects of Nutrition and Exercise Health Behaviors on Predicted Risk of Cardiovascular Disease among Workers with Different Body Mass Index Levels 
Workplace health promotion programs should be tailored according to individual needs and efficient intervention. This study aimed to determine the effects of nutrition and exercise health behaviors on predicted risk for cardiovascular disease (CVD) when body mass index (BMI) is considered. In total, 3350 Taiwanese workers were included in this cross-sectional study. A self-reported questionnaire was used to measure their nutrition and exercise behaviors. Data on anthropometric values, biochemical blood determinations, and predicted CVD risk (using the Framingham risk score) were collected. In multiple regression analyses, the nutrition behavior score was independently and negatively associated with CVD risk. Exercise was not significantly associated with the risk. However, the interactive effect of exercise and BMI on CVD risk was evident. When stratified by BMI levels, associations between exercise and CVD risk were statistically significant for ideal weight and overweight subgroups. In conclusion, nutrition behavior plays an important role in predicting the CVD risk. Exercise behavior is also a significant predictor for ideal weight and overweight workers. Notably, for underweight or obese workers, maintaining health-promoting exercise seems insufficient to prevent the CVD. In order to improve workers’ cardiovascular health, more specific health-promoting strategies should be developed to suit the different BMI levels.
doi:10.3390/ijerph110504664
PMCID: PMC4053920  PMID: 24785541
nutrition; exercise; body mass index; CVD; Framingham risk score; health promotion; worker
11.  Specific Changes of Serum Proteins in Parkinson's Disease Patients 
PLoS ONE  2014;9(4):e95684.
The aim of this study is to identify and validate protein change in the serum from PD patients. We used serum samples from 21 PD patients and 20 age-matched normal people as control to conduct a comparative proteomic study. We performed 2-DE and analyzed the differentially expressed protein spots by LC-MS/MS. In PD group 13 spots were shown to be differentially expressed compared to control group. They were identified as 6 proteins. Among these, 3 proteins were confirmed by Western blot analysis. It showed that the frequency of fibrinogen γ-chain (FGG) appeared 70% in PD, which could not be detected in control group. The protein of inter-alpha-trypsin inhibitor heavy chain H4 (ITI-H4) was found to exist two forms in serum. The full size (120 kDa) of the protein was increased and the fragmented ITI-H4 (35 kDa) was decreased in PD group. The ratio of full size ITI-H4 to fragmented ITI-H4 in PD patients was 3.85±0.29-fold higher than in control group. Furthermore, fragmented Apo A-IV (∼26 kDa) was mainly detected in control group, while it was rare to be found in PD group. Above findings might be useful for diagnosis of PD. When the expressions of FGG and 120 kDa ITI-H4 are increase, as well as ∼26 kDa Apo A-IV disappear would provide strong evidence for PD.
doi:10.1371/journal.pone.0095684
PMCID: PMC4000217  PMID: 24769800
12.  Comparative proteomic analysis of plasma proteins in patients with age-related macular degeneration 
AIM
To find the significant altered proteins in age-related macular degeneration (AMD) patients as potential biomarkers of AMD.
METHODS
A comparative analysis of the protein pattern of AMD patients versus healthy controls was performed by means of proteomic analysis using two-dimensional gel electrophoresis followed by protein identification with MALDI TOF/TOF mass spectrometry.
RESULTS
We identified 28 proteins that were significantly altered with clinical relevance in AMD patients. These proteins were involved in a wide range of biological functions including immune responses, growth cytokines, cell fate determination, wound healing, metabolism, and anti-oxidance.
CONCLUSION
These results demonstrate the capacity of proteomic analysis of AMD patient plasma. In addition to the utility of this approach for biomarker discovery, identification of alterations in endogenous proteins in the plasma of AMD patient could improve our understanding of the disease pathogenesis.
doi:10.3980/j.issn.2222-3959.2014.02.12
PMCID: PMC4003079  PMID: 24790867
age-related macular degeneration; clinical patients; comparative proteomics; plasma proteins; two-dimensional electrophoresis
13.  Malignant myoepithelioma of the breast: a case report and review of literature 
In this article, we described a malignant myoepithelioma of the breast (MMB) in a 69-year-old woman. Breast cancer derived from myoepithelial cells is very rare, usually benign. The diagnosis of MMB based on histological and immunohistochemical finding. In this case, the author diagnosed the tumor as MMB, because tumor tissues were immunopositive for 34βE12, P63, SMA, S-100, CD10, E-Cad and Ki-67, and immunnegative for CK5/6, desmin, ER, PR and C-erbB-2, because tumor tissue showed invasive growth and local hemorrhage or necrosis, suggesting malignant, and also because there was a transition between the tumor cells and hyperplastic myoepithelium of non-tumorous ducts. The patient’s postoperative recovery is smooth and regular following of patient is essential.
PMCID: PMC4069952  PMID: 24966981
Malignant myoepithelioma; breast; immunohistochemistry
14.  From Commodity Polymers to Functional Polymers 
Scientific Reports  2014;4:4604.
Functional polymers bear specified chemical groups, and have specified physical, chemical, biological, pharmacological, or other uses. To adjust the properties while keeping material usage low, a method for direct synthesis of functional polymers is indispensable. Here we show that various functional polymers can be synthesized by in situ cross-linked polymerization/copolymerization. We demonstrate that the polymers synthesized by the facile method using different functional monomers own outstanding pH-sensitivity and pH-reversibility, antifouling property, antibacterial, and anticoagulant property. Our study opens a route for the functionalization of commodity polymers, which lead to important advances in polymeric materials applications.
doi:10.1038/srep04604
PMCID: PMC3978497  PMID: 24710333
15.  PFOS induced lipid metabolism disturbances in BALB/c mice through inhibition of low density lipoproteins excretion 
Scientific Reports  2014;4:4582.
Male BALB/c mice fed with either a regular or high fat diet were exposed to 0, 5 or 20 mg/kg perfluorooctane sulfonate (PFOS) for 14 days. Increased body weight, serum glucose, cholesterol and lipoprotein levels were observed in mice given a high fat diet. However, all PFOS-treated mice got reduced levels of serum lipid and lipoprotein. Decreasing liver glycogen content was also observed, accompanied by reduced serum glucose levels. Histological and ultrastructural examination detected more lipid droplets accumulated in hepatocytes after PFOS exposure. Moreover, transcripitonal activity of lipid metabolism related genes suggests that PFOS toxicity is probably unrelevant to PPARα's transcription. The present study demonstrates a lipid disturbance caused by PFOS and thus point to its role in inhibiting the secretion and normal function of low density lipoproteins.
doi:10.1038/srep04582
PMCID: PMC3974142  PMID: 24694979
16.  Interaction between Two Timing MicroRNAs Controls Trichome Distribution in Arabidopsis 
PLoS Genetics  2014;10(4):e1004266.
The miR156-targeted SQUAMOSA PROMOTER BINDING PROTEIN LIKE (SPL) transcription factors function as an endogenous age cue in regulating plant phase transition and phase-dependent morphogenesis, but the control of SPL output remains poorly understood. In Arabidopsis thaliana the spatial pattern of trichome is a hallmark of phase transition and governed by SPLs. Here, by dissecting the regulatory network controlling trichome formation on stem, we show that the miR171-targeted LOST MERISTEMS 1 (LOM1), LOM2 and LOM3, encoding GRAS family members previously known to maintain meristem cell polarity, are involved in regulating the SPL activity. Reduced LOM abundance by overexpression of miR171 led to decreased trichome density on stems and floral organs, and conversely, constitutive expression of the miR171-resistant LOM (rLOM) genes promoted trichome production, indicating that LOMs enhance trichome initiation at reproductive stage. Genetic analysis demonstrated LOMs shaping trichome distribution is dependent on SPLs, which positively regulate trichome repressor genes TRICHOMELESS 1 (TCL1) and TRIPTYCHON (TRY). Physical interaction between the N-terminus of LOMs and SPLs underpins the repression of SPL activity. Importantly, other growth and developmental events, such as flowering, are also modulated by LOM-SPL interaction, indicating a broad effect of the LOM-SPL interplay. Furthermore, we provide evidence that MIR171 gene expression is regulated by its targeted LOMs, forming a homeostatic feedback loop. Our data uncover an antagonistic interplay between the two timing miRNAs in controlling plant growth, phase transition and morphogenesis through direct interaction of their targets.
Author Summary
MicroRNAs are important aging regulators in many organisms. In Arabidopsis the miR156-targeted SQUAMOSA PROMOTER BINDING PROTEIN LIKE (SPL) transcription factors play important roles as an endogenous age cue in programming phase transition and phase-dependent morphogenesis, including trichome patterning. However, how the timely increasing SPL output is modulated remains elusive. By dissecting the regulatory network controlling trichome formation on stem, we show that a group of GRAS family members, LOST MERISTEMS 1 (LOM1), LOM2 and LOM3, targeted by timing miR171, function in modulating the SPL activity through direct protein-protein interaction. LOMs promote trichome formation through attenuating the SPL (such as SPL9) activity of trichome repression. The LOM-SPL interaction affects many aspects of plant growth and development, including flowering, aging and chlorophyll biosynthesis. Interestingly, MIR171A gene expression is regulated by its own targets (LOMs), forming a feedback loop to program plant life. Our study establishes an age-dependent regulatory network composed of two timing miRNAs which act oppositely through direct interaction of their target proteins.
doi:10.1371/journal.pgen.1004266
PMCID: PMC3974651  PMID: 24699192
17.  mTOR inhibitors block Kaposi sarcoma growth by inhibiting essential autocrine growth factors and tumor angiogenesis 
Cancer research  2013;73(7):2235-2246.
Kaposi’s Sarcoma (KS) originates from endothelial cells and it is one of the most overt angiogenic tumors. In Sub-Saharan Africa, where HIV and the Kaposi Sarcoma-associated Herpes Virus (KSHV) are endemic, KS is the most common cancer overall, but model systems for disease study are insufficient. Here we report the development of a novel mouse model of KS where KSHV is retained stably and tumors are elicited rapidly. Tumor growth was sensitive to specific allosteric inhibitors (rapamycin, CCI-779, RAD001) of the pivotal cell growth regulator mTOR. Inhibition of tumor growth was durable up to 130 days and reversible. mTOR blockade reduced VEGF secretion and formation of tumor vasculature. Together, the results demonstrated that mTOR inhibitors exert a direct anti-KS effect by inhibiting angiogenesis and paracrine effectors, suggesting their application as a new treatment modality for KS and other cancers of endothelial origin.
doi:10.1158/0008-5472.CAN-12-1851
PMCID: PMC3618543  PMID: 23382046
Kaposi’s Sarcoma (KS); Kaposi’s Sarcoma-associated Herpes Virus (KSHV); Human Herpes Virus-8 (HHV8); Rapamycin; mTOR; Angiogenesis; Vascular Endothelial Growth Factor (VEGF); CCI-779; RAD001
18.  Early BDNF Treatment Ameliorates Cell Loss in the Entorhinal Cortex of APP Transgenic Mice 
The Journal of Neuroscience  2013;33(39):15596-15602.
Brain-derived neurotrophic factor (BDNF) improves molecular, cellular, and behavioral measures of neural dysfunction in genetic models of Alzheimer's disease (Blurton-Jones et al., 2009; Nagahara et al., 2009). However, BDNF treatment after disease onset has not been reported to improve neuronal survival in these models. We now report prevention of neuronal loss with early life BDNF treatment in mutant mice expressing two amyloid precursor protein (APP) mutations associated with early-onset familial Alzheimer's disease. APP transgenic mice underwent lentiviral BDNF gene delivery into the entorhinal cortices at age 2 months and were examined 5 months later. BDNF-treated mice exhibited significant improvements in hippocampal-dependent contextual fear conditioning compared with control-treated APP mice (p < 0.05). Stereological analysis of entorhinal cortical cell number demonstrated ∼20% reductions in neuronal number in layers II-VI of the entorhinal cortex in untreated APP mutant mice compared with wild-type mice (p < 0.0001), and significant amelioration of cell loss by BDNF (p < 0.001). Moreover, BDNF gene delivery improved synaptophysin immunoreactivity in the entorhinal cortex and, through anterograde BDNF transport, in the hippocampus (p < 0.01). Notably, BDNF did not affect amyloid plaque numbers, indicating that direct amyloid reduction is not necessary to achieve significant neuroprotective benefits in mutant amyloid models of Alzheimer's disease.
doi:10.1523/JNEUROSCI.5195-12.2013
PMCID: PMC3782628  PMID: 24068826
19.  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
20.  A Novel Functional TagSNP Rs7560488 in the DNMT3A1 Promoter Is Associated with Susceptibility to Gastric Cancer by Modulating Promoter Activity 
PLoS ONE  2014;9(3):e92911.
DNA-methyltransferase (DNMT)-3A which contains DNMT3A1 and DNMT3A2 isoforms have been suggested to play a crucial role in carcinogenesis and showed aberrant expression in most cancers. Accumulated evidences also indicated that single nucleotide polymorphisms (SNP) in DNMT genes were associated with susceptibility to different tumors. We hypothesized that genetic variants in DNMT3A1 promoter region are associated with gastric cancer risk. We selected the tagSNPs from the HapMap database for the Chinese and genotyped in a case-control study to evaluate the association with gastric cancer (GC) in a Chinese population. We identified that the functional tagSNP rs7560488 T>C associated with a significantly increased risk of GC. In vitro functional analysis by luciferase reporter assay and EMSA indicated that the tagSNP rs7560488 T>C substantially altered transcriptional activity of DNMT3A1 gene via influencing the binding of some transcriptional factors, although a definite transcriptional factor remains to be established. Compared with TT homozygotes, subjects who were TC heterozygotes and CC homozygotes exhibited a reduced expression of DNMT3A1. Furthermore, stratified analysis showed that individuals who harbor TC or CC genotypes less than 60 years old were more susceptible to GC. Our results suggest that the genetic variations in the DNMT3A1 promoter contribute to the susceptibility to GC and also provide an insight that tagSNP rs7560488 T>C may be a promising biomarker for predicting GC genetic susceptibility and a valuable information in GC pathogenesis.
doi:10.1371/journal.pone.0092911
PMCID: PMC3965498  PMID: 24667323
21.  TiO2 Nanoparticles Induced Hippocampal Neuroinflammation in Mice 
PLoS ONE  2014;9(3):e92230.
Titanium dioxide nanoparticles (TiO2 NPs) have been used in various medical and industrial areas. However, the impacts of these nanoparticles on neuroinflammation in the brain are poorly understood. In this study, mice were exposed to 2.5, 5, or 10 mg/kg body weight TiO2 NPs for 90 consecutive days, and the TLRs/TNF-α/NF-κB signaling pathway associated with the hippocampal neuroinflammation was investigated. Our findings showed titanium accumulation in the hippocampus, neuroinflammation and impairment of spatial memory in mice following exposure to TiO2 NPs. Furthermore, TiO2 NPs significantly activated the expression of Toll-like receptors (TLR2, TLR4), tumor necrosis factor-α, nucleic IκB kinase, NF-κB-inducible kinase, nucleic factor–κB, NF-κB2(p52), RelA(p65), and significantly suppressed the expression of IκB and interleukin-2. These findings suggest that neuroinflammation may be involved in TiO2 NP-induced alterations of cytokine expression in mouse hippocampus. Therefore, more attention should be focused on the application of TiO2 NPs in the food industry and their long-term exposure effects, especially in the human central nervous system.
doi:10.1371/journal.pone.0092230
PMCID: PMC3962383  PMID: 24658543
22.  Detection and Analysis of Human Papillomavirus (HPV) DNA in Breast Cancer Patients by an Effective Method of HPV Capture 
PLoS ONE  2014;9(3):e90343.
Despite an increase in the number of molecular epidemiological studies conducted in recent years to evaluate the association between human papillomavirus (HPV) and the risk of breast carcinoma, these studies remain inconclusive. Here we aim to detect HPV DNA in various tissues from patients with breast carcinoma using the method of HPV capture combined with massive paralleled sequencing (MPS). To validate the confidence of our methods, 15 cervical cancer samples were tested by PCR and the new method. Results showed that there was 100% consistence between the two methods.DNA from peripheral blood, tumor tissue, adjacent lymph nodes and adjacent normal tissue were collected from seven malignant breast cancer patients, and HPV type 16(HPV16) was detected in 1/7, 1/7, 1/7and 1/7 of patients respectively. Peripheral blood, tumor tissue and adjacent normal tissue were also collected from two patients with benign breast tumor, and 1/2, 2/2 and 2/2 was detected to have HPV16 DNA respectively. MPS metrics including mapping ratio, coverage, depth and SNVs were provided to characterize HPV in samples. The average coverage was 69% and 61.2% for malignant and benign samples respectively. 126 SNVs were identified in all 9 samples. The maximum number of SNVs was located in the gene of E2 and E4 among all samples. Our study not only provided an efficient method to capture HPV DNA, but detected the SNVS, coverage, SNV type and depth. The finding has provided further clue of association between HPV16 and breast cancer.
doi:10.1371/journal.pone.0090343
PMCID: PMC3948675  PMID: 24614680
23.  Clinical and Epidemiological Study on Severe Fever with Thrombocytopenia Syndrome in Yiyuan County, Shandong Province, China 
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease in China. Polymerase chain reaction and enzyme-linked immunosorbent assay were used to detect SFTS virus (SFTSV) and Anaplasma phagocytophilum in previous clinically diagnosed human anaplasmosis patients and SFTS patients. A serosurvey for SFTSV infection was also conducted on healthy persons and animals in Yiyuan County in Shandong Province of China. Among 21 patients SFTSV was detected in 17 (81%) however A. phagocytophilum was not detected in any of the patients. The seroprevalence rate of IgG antibody to SFTSV antigens was 1.3% (1 of 78) in healthy persons, 95% (19 of 20) in goats, 50% (1 of 2) in dogs, 0% in cattle (0 of 21), and rats (Rattus norvegicus) (0 of 35). The conclusion of this study was that co-infection of SFTSV and A. phagocytophilum are rare in SFTS patients and goats might play an important role in transmission of SFTSV.
doi:10.4269/ajtmh.11-0760
PMCID: PMC3592533  PMID: 23339197
24.  Therapeutic strategy for hair regeneration: Hair cycle activation, niche environment modulation, wound-induced follicle neogenesis and stem cell engineering 
Introduction
There are major new advancements in the fields of stem cell biology, developmental biology, regenerative hair cycling, and tissue engineering. The time is ripe to integrate, translate and apply these findings to tissue engineering and regenerative medicine. Readers will learn about new progress in cellular and molecular aspects of hair follicle development, regeneration and potential therapeutic opportunities these advances may offer.
Areas covered
Here we use hair follicle formation to illustrate this progress and to identify targets for potential strategies in therapeutics. Hair regeneration is discussed in four different categories. (1) Intra-follicle regeneration (or renewal) is the basic production of hair fibers from hair stem cells and dermal papillae in existing follicles. (2) Chimeric follicles via epithelial-mesenchymal recombination to identify stem cells and signaling centers. (3) Extra-follicular factors including local dermal and systemic factors can modulate the regenerative behavior of hair follicles, and may be relatively easy therapeutic targets. (4) Follicular neogenesis means the de novo formation of new follicles. In addition, scientists are working to engineer hair follicles, which require hair forming competent epidermal cells and hair inducing dermal cells.
Expert opinion
Ideally self-organizing processes similar to those occurring during embryonic development should be elicited with some help from biomaterials.
doi:10.1517/14712598.2013.739601
PMCID: PMC3706200  PMID: 23289545
regenerative medicine; tissue engineering; alopecia; wound healing; dermal papilla; stem cells; wound; biomaterials
25.  Interferon Regulatory Factor 4 Is Activated through c-Src-Mediated Tyrosine Phosphorylation in Virus-Transformed Cells 
Journal of Virology  2013;87(17):9672-9679.
The importance of the oncogenic transcription factor interferon regulatory factor 4 (IRF4) in hematological malignancies has been increasingly recognized. We have previously identified the B cell integration cluster (BIC), the gene encoding miR-155, as the first microRNA (miRNA)-encoding gene transcriptionally targeted by IRF4 in virus-transformed cancer cells. Activation of IRFs is prerequisite for their functions. However, how IRF4 is activated in cancer is an open question. Our phosphoproteome profiling has identified several tyrosine phosphorylation sites on IRF4 in Epstein-Barr virus (EBV)-transformed cells. Further, we show here that c-Src dramatically stimulates IRF4 phosphorylation and activity and that Y61 and Y124 are two key sites responding to c-Src-mediated activation. Consistently, c-Src is constitutively expressed and active in EBV-transformed cells. However, c-Src is unlikely to be a direct kinase for IRF4. Furthermore, we have a polyclonal antibody specific to phospho-IRF4(Y121/124) developed in rabbit. We have further shown that inhibition of c-Src activity reduces p-IRF4(Y121/124) and significantly represses transcription of the IRF4 target BIC in EBV-transformed cells. Our results therefore, for the first time, demonstrate that IRF4 is phosphorylated and activated through a c-Src-mediated pathway in virus-transformed cells. These findings will improve our understanding of IRF4 in neoplasia and will provide profound insights into the interaction of oncogenic viruses with IRF4 in the development of hematological malignancies.
doi:10.1128/JVI.01435-13
PMCID: PMC3754115  PMID: 23804646

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