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1.  Histone deacetylase 3 modulates Tbx5 activity to regulate early cardiogenesis 
Human Molecular Genetics  2014;23(14):3801-3809.
Congenital heart defects often result from improper differentiation of cardiac progenitor cells. Although transcription factors involved in cardiac progenitor cell differentiation have been described, the associated chromatin modifiers in this process remain largely unknown. Here we show that mouse embryos lacking the chromatin-modifying enzyme histone deacetylase 3 (Hdac3) in cardiac progenitor cells exhibit precocious cardiomyocyte differentiation, severe cardiac developmental defects, upregulation of Tbx5 target genes and embryonic lethality. Hdac3 physically interacts with Tbx5 and modulates its acetylation to repress Tbx5-dependent activation of cardiomyocyte lineage-specific genes. These findings reveal that Hdac3 plays a critical role in cardiac progenitor cells to regulate early cardiogenesis.
doi:10.1093/hmg/ddu093
PMCID: PMC4065153  PMID: 24565863
2.  MITOSCISSOR: A Useful Tool for Auto-Assembly of Mitogenomic Datasets in the Evolutionary Analysis of Fishes 
As a result of the development of rapid and efficient sequencing technologies, complete sequences of numerous mitochondrial genomes are now available. Mitochondrial genomes have been widely used to evaluate relationships between species in several fields, including evolutionary and population genetics, as well as in forensic identification and in the study of mitochondrial diseases in humans. However, the creation of mitochondrial genomes is extremely time consuming. In this paper, we present a new tool, MITOSCISSOR, which is a rapid method for parsing and formatting dozens of complete mitochondrial genome sequences. With the aid of MITOSCISSOR, complete mitochondrial genome sequences of 103 species from Tetraodontiformes (a difficult-to-classify order of fish) were easily parsed and formatted. It typically takes several days to produce similar results when relying upon manual editing. This tool could open the .gb file of Genbank directly and help us to use existing mitogenomic data. In the present study, we established the first clear and robust molecular phylogeny of 103 tetraodontiform fishes, a goal that has long eluded ichthyologists. MITOSCISSOR greatly increases the efficiency with which DNA data files can be parsed and annotated, and thus has the potential to greatly facilitate evolutionary analysis using mitogenomic data. This software is freely available for noncommercial users at http://www.filedropper.com/mitoscissor.
doi:10.4137/EBO.S22340
PMCID: PMC4467657  PMID: 26106259
mitochondrial genome; evolution; Perl script; phylogeny
3.  Quantitative Risk Stratification of Oral Leukoplakia with Exfoliative Cytology 
PLoS ONE  2015;10(5):e0126760.
Exfoliative cytology has been widely used for early diagnosis of oral squamous cell carcinoma (OSCC). Test outcome is reported as “negative”, “atypical” (defined as abnormal epithelial changes of uncertain diagnostic significance), and “positive” (defined as definitive cellular evidence of epithelial dysplasia or carcinoma). The major challenge is how to properly manage the “atypical” patients in order to diagnose OSCC early and prevent OSCC. In this study, we collected exfoliative cytology data, histopathology data, and clinical data of normal subjects (n=102), oral leukoplakia (OLK) patients (n=82), and OSCC patients (n=93), and developed a data analysis procedure for quantitative risk stratification of OLK patients. This procedure involving a step called expert-guided data transformation and reconstruction (EdTAR) which allows automatic data processing and reconstruction and reveals informative signals for subsequent risk stratification. Modern machine learning techniques were utilized to build statistical prediction models on the reconstructed data. Among the several models tested using resampling methods for parameter pruning and performance evaluation, Support Vector Machine (SVM) was found to be optimal with a high sensitivity (median>0.98) and specificity (median>0.99). With the SVM model, we constructed an oral cancer risk index (OCRI) which may potentially guide clinical follow-up of OLK patients. One OLK patient with an initial OCRI of 0.88 developed OSCC after 40 months of follow-up. In conclusion, we have developed a statistical method for qualitative risk stratification of OLK patients. This method may potentially improve cost-effectiveness of clinical follow-up of OLK patients, and help design clinical chemoprevention trial for high-risk populations.
doi:10.1371/journal.pone.0126760
PMCID: PMC4433206  PMID: 25978541
4.  Multilayer thin films with compositional PbZr0.52Ti0.48O3/Bi1.5Zn1.0Nb1.5O7 layers for tunable applications 
Scientific Reports  2015;5:10173.
The dielectric properties and tunability of multilayer thin films with compositional PbZr0.52Ti0.48O3/Bi1.5Zn1.0Nb1.5O7 (PZT/BZN) layers (PPBLs) fabricated by pulsed laser deposition on Pt/TiO2/SiO2/Si substrate have been investigated. Dielectric measurements indicate that the PZT/BZN bilayer thin films exhibit medium dielectric constant of about 490, low loss tangent of 0.017, and superior tunable dielectric properties (tunability = 49.7% at 500 kV/cm) at a PZT/BZN thickness ratio of 3, while the largest figure of merit is obtained as 51.8. The thickness effect is discussed with a series connection model of bilayer capacitors, and the calculated dielectric constant and loss tangent are obtained. Furthermore, five kinds of thin–film samples comprising single bilayers, two, three, four and five PPBLs were also elaborated with the final same thickness. The four PPBLs show the largest dielectric constant of ~538 and tunability of 53.3% at a maximum applied bias field of 500 kV/cm and the lowest loss tangent of ~0.015, while the largest figure of merit is 65.6. The results indicate that four PPBLs are excellent candidates for applications of tunable devices.
doi:10.1038/srep10173
PMCID: PMC4426694  PMID: 25960043
5.  Mutation Breeding of Extracellular Polysaccharide-Producing Microalga Crypthecodinium cohnii by a Novel Mutagenesis with Atmospheric and Room Temperature Plasma 
Extracellular polysaccharides (EPS) produced by marine microalgae have the potential to be used as antioxidants, antiviral agents, immunomodulators, and anti-inflammatory agents. Although the marine microalga Crypthecodinium cohnii releases EPS during the process of docosahexaenoic acid (DHA) production, the yield of EPS remains relatively low. To improve the EPS production, a novel mutagenesis of C. cohnii was conducted by atmospheric and room temperature plasma (ARTP). Of the 12 mutants obtained, 10 mutants exhibited significantly enhanced EPS yield on biomass as compared with the wild type strain. Among them, mutant M7 was the best as it could produce an EPS volumetric yield of 1.02 g/L, EPS yield on biomass of 0.39 g/g and EPS yield on glucose of 94 mg/g, which were 33.85%, 85.35% and 57.17% higher than that of the wild type strain, respectively. Results of the present study indicated that mutagenesis of the marine microalga C. cohnii by ARTP was highly effective leading to the high-yield production of EPS.
doi:10.3390/ijms16048201
PMCID: PMC4425076  PMID: 25872142
extracellular polysaccharides; atmospheric and room temperature plasma (ARTP); mutation; microalgae; Crypthecodinium cohnii
6.  Electrical stimulation of the vagus nerve protects against cerebral ischemic injury through an anti-infammatory mechanism 
Neural Regeneration Research  2015;10(4):576-582.
Vagus nerve stimulation exerts protective effects against ischemic brain injury; however, the underlying mechanisms remain unclear. In this study, a rat model of focal cerebral ischemia was established using the occlusion method, and the right vagus nerve was given electrical stimulation (constant current of 0.5 mA; pulse width, 0.5 ms; frequency, 20 Hz; duration, 30 seconds; every 5 minutes for a total of 60 minutes) 30 minutes, 12 hours, and 1, 2, 3, 7 and 14 days after surgery. Electrical stimulation of the vagus nerve substantially reduced infarct volume, improved neurological function, and decreased the expression levels of tumor necrosis factor-α and interleukin-6 in rats with focal cerebral ischemia. The experimental findings indicate that the neuroprotective effect of vagus nerve stimulation following cerebral ischemia may be associated with the inhibition of tumor necrosis factor-α and interleukin-6 expression.
doi:10.4103/1673-5374.155430
PMCID: PMC4424749  PMID: 26170817
nerve regeneration; vagus nerve stimulation; cerebral ischemia; inflammatory cytokines; infarct volume; neurological function; NSFC grants; neural regeneration
7.  P16 Methylation as an Early Predictor for Cancer Development From Oral Epithelial Dysplasia: A Double-blind Multicentre Prospective Study 
EBioMedicine  2015;2(5):432-437.
Background
Silencing of P16 through methylation and locus deletion is the most frequent early events in carcinogenesis. The aim of this study is to prospectively determine if early P16 methylation is a predictor for oral cancer development.
Methods
Patients (n = 181) with mild or moderate oral epithelial dysplasia (OED) were recruited into the double blind multicentre cohort. P16 methylation was analyzed using the MethyLight assay. Progression of OEDs was monitored for a minimum 3 year follow-up period.
Findings
P16 methylation-informative cases (n = 152) were enrolled in the prospective multicenter cohorts with an ultimate compliance of 96.7%. OED-derived squamous cell carcinomas were observed in 21 patients (14.3%) during the follow-up (median, 41.0 months). The cancer progression rate from the P16 methylation-positive patients was significantly increased when compared to P16 methylation-negative patients [27.1% vs 8.1%; adjusted odds ratio = 4.6; P = 0.006]. When the P16 methylation-positive criteria were used as a biomarker for early prediction of cancer development from OEDs, sensitivity and specificity of 62% and 76% were obtained, respectively.
Interpretation
P16 methylation is unequivocally a marker for determining the malignant potential of OED and there is no need for further research regarding this aspect.
Funding
National Basic Research Programs of China (2011CB504201 and 2015CB553902), Beijing Science and Technology Commission (Z090507017709016), and Beijing Municipal Administration of Hospital (XM201303) to Dajun Deng. The funding agencies have no role in the actual experimental design, patient recruitment, data collection, analysis, interpretation, or writing of this manuscript.
Highlight
•P16 is most frequently inactivated through methylation and deletion in many cancers.•A multicentral prospective study was carried out to test association between P16 methylation and oral cancer development.•P16 methylation significantly increased risk of malignant transformation of oral epithelial dysplasia in Chinese patients.
doi:10.1016/j.ebiom.2015.03.015
PMCID: PMC4485905  PMID: 26137587
P16; Methylation; Oral dysplasia; Transformation; Prospective cohort
8.  CRABP-II- and FABP5-independent responsiveness of human glioblastoma cells to all-trans retinoic acid 
Oncotarget  2015;6(8):5889-5902.
Glioblastomas respond differently to all-trans retinoic acid (RA) for unknown reasons. Because CRABP-II and FABP5 mediate RA intracellular signaling respectively and lead to distinct biological consequences, their expression patterns in different grades of astrocytomas and the glioblastoma cells lines LN18, LN428 and U251 were examined to identify potential correlations with RA sensitivities. The response of glioblastoma cells to RA, decitabine or the FABP5 competitive inhibitor, BMS309403, was analyzed. CRABP-II and FABP5 were expressed to varying degrees by the 84-astrocytoma cases examined. Treatment of LN428, U251 and LN18 cells with RA failed to suppress their growth; however, U251 proliferation was inhibited by decitabine. The combination of decitabine and RA suppressed the growth of all three cell lines and induced significant apoptosis of LN428 and U251 cells. Both CRABP-II and FABP5 were transcribed in the three cell lines but FABP5 proteins were undetectable in U251 cells. The ratio of CRABP-II to FABP5 was not altered after RA, decitabine or RA and decitabine treatment and the resistance of cells to RA was not reversed by BMS309403 treatment. In conclusion, CRABP-II and FABP5 expression patterns are neither related to the tumor grades nor correlated with RA sensitivity. Additional molecular factors may be present that determines the sensitivity of glioblastoma cells to RA. Dicitabine may improve the sensitivity of glioblastoma cells to RA, however, its underlying mechanism and its in vivo feasibility need to be investigated.
PMCID: PMC4467409  PMID: 25797252
Glioblastoma; All-trans retinoic acid; Chemosensitivity; CRABP-II; FABP5
9.  Role and mechanism of Sophoridine on proliferation inhibition in human glioma U87MG cell line 
Sophoridine, a natural product obtained from medicinal plants, which has a variety of pharmacological effects, including anti-cancer effects, and selectively induces apoptotic cell death in a variety of human cancer cells in vitro and in vivo; however, its mechanism of action needs to be further elaborated. In this study, we investigated the effects of Sophoridine on the induction of apoptosis in human Glioma U87MG cells. Here, we found that Sophoridine can significantly inhibited cell proliferation, G2/M phase arrest, induced cell apoptosis and caused reactive oxygen species (ROS) generation and GSH content reduction. Sophoridine also triggered significant down-regulated the expression of p27, CDK2, Survivin, Livin, Bcl-2, E2F1 and the transcriptional activity of FoxM1, NF-κb and AP-1, meanwhile, up-regulated the expression of caspase-3/8, p53, Smac, c-JNK and p38-MAPK. Moreover, we found that Sophoridine significantly inhibited ubiquitin-proteasome in tumor cells. In conclusion, Sophoridine shows obvious anti-cancer activity on glioma cells by inducing cell apoptosis, inducing ROS accumulation, and activating mitochondrial signal pathways. Eventually, we believe Sophoridine could be used as a new drug for the treatment of glioma.
PMCID: PMC4358473  PMID: 25785018
Glioma; U87MG; cell apoptosis; Sophoridine
10.  Deacetylase-Independent Function of HDAC3 in Transcription and Metabolism Requires Nuclear Receptor Corepressor 
Molecular cell  2013;52(6):10.1016/j.molcel.2013.10.022.
Histone deacetylases (HDACs) are believed to regulate gene transcription by catalyzing deacetylation reactions. HDAC3 depletion in mouse liver upregulates lipogenic genes and results in severe hepatosteatosis. Here we show that pharmacologic HDAC inhibition in primary hepatocytes causes histone hyperacetylation but does not upregulate expression of HDAC3 target genes. Meanwhile, deacetylase-dead HDAC3 mutants can rescue hepatosteatosis and repress lipogenic genes expression in HDAC3-depleted mouse liver, demonstrating that histone acetylation is insufficient to activate gene transcription. Mutations abolishing interactions with the nuclear receptor corepressor (NCOR or SMRT) render HDAC3 nonfunctional in vivo. Additionally, liver-specific knockout of NCOR, but not SMRT, causes metabolic and transcriptomal alterations resembling those of mice without hepatic HDAC3, demonstrating that interaction with NCOR is essential for deacetylase-independent function of HDAC3. These findings highlight non-enzymatic roles of a major HDAC in transcriptional regulation in vivo and warrant reconsideration of the mechanism of action of HDAC inhibitors.
doi:10.1016/j.molcel.2013.10.022
PMCID: PMC3877208  PMID: 24268577
11.  Clinical Significance of IL-23 Regulating IL-17A and/or IL-17F Positive Th17 Cells in Chronic Periodontitis 
Mediators of Inflammation  2014;2014:627959.
Objective. To investigate the expression level and clinical significance of (IL-17A+ and/or IL-17F+) Th17 cells under IL-23 regulation in patients of chronic periodontitis (CP) and healthy controls (HC). Materials and Methods. The whole peripheral blood samples were collected from 30 CP patients and 25 healthy controls. Flow cytometry was used to test the (IL-17A+ and/or IL-17F+) Th17 expression level. Recombinant human IL-23 (rhIL-23) was used to detect Th17 differentiation and expansion. Correlation coefficient analysis between Th17 expression level and clinical parameters was analyzed by SPSS software. Results. Flow cytometry results showed that IL-17A+IL-17F− and IL-17A−IL-17F+ Th17 were both increased in CP group than in HC group (P < 0.01), while, under recombinant human IL-23 (rhIL-23) stimulation, the number of IL-17A+IL-17F− Th17 cells was significantly increased in both CP and HC groups (P < 0.01). Interestingly, IL-17A−IL-17F+ Th17 cells were only increased in CP group after rhIL-23 stimulation. Additionally, correlation coefficient analysis showed significant correlation between IL-17A+IL-17F− Th17 cell and attachment loss or probing depth (P < 0.05). Conclusions. This study indicates that both the IL-17A+IL-17F− and IL-17A−IL-17F+ Th17 cells may be involved in pathogenesis of periodontitis. The role of these Th17 cells in the disease pathogenesis needs to be further investigated.
doi:10.1155/2014/627959
PMCID: PMC4265697  PMID: 25525302
12.  Fermentative Polyhydroxybutyrate Production from a Novel Feedstock Derived from Bakery Waste 
BioMed Research International  2014;2014:819474.
In this study, Halomonas boliviensis was cultivated on bakery waste hydrolysate and seawater in batch and fed-batch cultures for polyhydroxybutyrate (PHB) production. Results demonstrated that bakery waste hydrolysate and seawater could be efficiently utilized by Halomonas boliviensis while PHB contents between 10 and 30% (w/w) were obtained. Furthermore, three methods for bakery waste hydrolysis were investigated for feedstock preparation. These include: (1) use of crude enzyme extracts from Aspergillus awamori, (2) Aspergillus awamori solid mashes, and (3) commercial glucoamylase. In the first method, the resultant free amino nitrogen (FAN) concentration in hydrolysates was 150 and 250 mg L−1 after 20 hours at enzyme-to-solid ratios of 6.9 and 13.1 U g−1, respectively. In both cases, the final glucose concentration was around 130–150 g L−1. In the second method, the resultant FAN and glucose concentrations were 250 mg L−1 and 150 g L−1, respectively. In the third method, highest glucose and lowest FAN concentrations of 170–200 g L−1 and 100 mg L−1, respectively, were obtained in hydrolysates after only 5 hours. The present work has generated promising information contributing to the sustainable production of bioplastic using bakery waste hydrolysate.
doi:10.1155/2014/819474
PMCID: PMC4127261  PMID: 25136626
13.  USP15 negatively regulates Nrf2 through deubiquitination of Keap1 
Molecular cell  2013;51(1):68-79.
Summary
Nrf2 is a master regulator of the antioxidant response. Under basal conditions Nrf2 is polyubiquitinated by the Keap1-Cul3-E3 ligase and degraded by the 26S-proteasome. In response to Nrf2 inducers there is a switch in polyubiquitination from Nrf2 to Keap1. Currently, regulation of the Nrf2-Keap1 pathway by ubiquitination is largely understood. However, the mechanism responsible for removal of ubiquitin conjugated to Nrf2 or Keap1 remains unknown. Here we report that the deubiquitinating enzyme, USP15, specifically deubiquitinates Keap1, which suppresses the Nrf2 pathway. We demonstrated that deubiquitinated-Keap1 incorporates into the Keap1-Cul3-E3 ligase complex more efficiently, enhancing the complex stability and enzymatic activity. Consequently, there is an increase in Nrf2 protein degradation and a reduction in Nrf2 target gene expression. Furthermore, USP15-siRNA enhances chemoresistance of cells through upregulation of Nrf2. These findings further our understanding of how the Nrf2-Keap1 pathway is regulated, which is imperative in targeting this pathway for chemoprevention or chemotherapy.
doi:10.1016/j.molcel.2013.04.022
PMCID: PMC3732832  PMID: 23727018
Nrf2; Keap1; USP15; Cul3; ubiquitination; deubiquitination; antioxidant response; chemoresistance
14.  Chlorella zofingiensis as an Alternative Microalgal Producer of Astaxanthin: Biology and Industrial Potential 
Marine Drugs  2014;12(6):3487-3515.
Astaxanthin (3,3′-dihydroxy-β,β-carotene-4,4′-dione), a high-value ketocarotenoid with a broad range of applications in food, feed, nutraceutical, and pharmaceutical industries, has been gaining great attention from science and the public in recent years. The green microalgae Haematococcus pluvialis and Chlorella zofingiensis represent the most promising producers of natural astaxanthin. Although H. pluvialis possesses the highest intracellular astaxanthin content and is now believed to be a good producer of astaxanthin, it has intrinsic shortcomings such as slow growth rate, low biomass yield, and a high light requirement. In contrast, C. zofingiensis grows fast phototrophically, heterotrophically and mixtrophically, is easy to be cultured and scaled up both indoors and outdoors, and can achieve ultrahigh cell densities. These robust biotechnological traits provide C. zofingiensis with high potential to be a better organism than H. pluvialis for mass astaxanthin production. This review aims to provide an overview of the biology and industrial potential of C. zofingiensis as an alternative astaxanthin producer. The path forward for further expansion of the astaxanthin production from C. zofingiensis with respect to both challenges and opportunities is also discussed.
doi:10.3390/md12063487
PMCID: PMC4071588  PMID: 24918452
astaxanthin; Chlorella zofingiensis; fed-batch; genetic engineering; mass cultivation; microalgae; stress
15.  Bioinformatic Prediction of WSSV-Host Protein-Protein Interaction 
BioMed Research International  2014;2014:416543.
WSSV is one of the most dangerous pathogens in shrimp aquaculture. However, the molecular mechanism of how WSSV interacts with shrimp is still not very clear. In the present study, bioinformatic approaches were used to predict interactions between proteins from WSSV and shrimp. The genome data of WSSV (NC_003225.1) and the constructed transcriptome data of F. chinensis were used to screen potentially interacting proteins by searching in protein interaction databases, including STRING, Reactome, and DIP. Forty-four pairs of proteins were suggested to have interactions between WSSV and the shrimp. Gene ontology analysis revealed that 6 pairs of these interacting proteins were classified into “extracellular region” or “receptor complex” GO-terms. KEGG pathway analysis showed that they were involved in the “ECM-receptor interaction pathway.” In the 6 pairs of interacting proteins, an envelope protein called “collagen-like protein” (WSSV-CLP) encoded by an early virus gene “wsv001” in WSSV interacted with 6 deduced proteins from the shrimp, including three integrin alpha (ITGA), two integrin beta (ITGB), and one syndecan (SDC). Sequence analysis on WSSV-CLP, ITGA, ITGB, and SDC revealed that they possessed the sequence features for protein-protein interactions. This study might provide new insights into the interaction mechanisms between WSSV and shrimp.
doi:10.1155/2014/416543
PMCID: PMC4055298  PMID: 24982879
16.  Transcriptome Analysis of the Initial Stage of Acute WSSV Infection Caused by Temperature Change 
PLoS ONE  2014;9(3):e90732.
White spot syndrome virus (WSSV) is the most devastating virosis threatening the shrimp culture industry worldwide. Variations of environmental factors in shrimp culture ponds usually lead to the outbreak of white spot syndrome (WSS). In order to know the molecular mechanisms of WSS outbreak induced by temperature variation and the biological changes of the host at the initial stage of WSSV acute infection, RNA-Seq technology was used to analyze the differentially expressed genes (DEGs) in shrimp with a certain amount of WSSV cultured at 18°C and shrimp whose culture temperature were raised to 25°C. To analyze whether the expression changes of the DEGs were due to temperature rising or WSSV proliferation, the expression of selected DEGs was analyzed by real-time PCR with another shrimp group, namely Group T, as control. Group T didn’t suffer WSSV infection but was subjected to temperature rising in parallel. At the initial stage of WSSV acute infection, DEGs related to energy production were up-regulated, whereas most DEGs related to cell cycle and positive regulation of cell death and were down-regulated. Triose phosphate isomerase, enolase and alcohol dehydrogenase involved in glycosis were up-regulated, while pyruvate dehydrogenase, citrate synthase and isocitrate dehydrogenase with NAD as the coenzyme involved in TCA pathway were down-regulated. Also genes involved in host DNA replication, including DNA primase, DNA topoisomerase and DNA polymerase showed down-regulated expression. Several interesting genes including crustin genes, acting binding or inhibiting protein genes, a disintegrin and metalloproteinase domain-containing protein 9 (ADAM9) gene and a GRP 78 gene were also analyzed. Understanding the interactions between hosts and WSSV at the initial stage of acute infection will not only help to get a deep insight into the pathogenesis of WSSV but also provide clues for therapies.
doi:10.1371/journal.pone.0090732
PMCID: PMC3942461  PMID: 24595043
17.  Stochastic modeling of stem-cell dynamics with control 
Mathematical biosciences  2012;240(2):231-240.
Tissue development and homeostasis are thought to be regulated endogenously by control loops that ensure that the numbers of stem cells and daughter cells are maintained at desired levels, and that the cell dynamics are robust to perturbations. In this paper we consider several classes of stochastic models that describe stem/daughter cell dynamics in a population of constant size, which are generalizations of the Moran process that include negative control loops that affect differentiation probabilities for stem cells. We present analytical solutions for the steady-state expectations and variances of the numbers of stem and daughter cells; these results remain valid for non-constant cell populations. We show that in the absence of differentiation/proliferation control, the number of stem cells is subject to extinction or overflow. In the presence of linear control, a steady state may be maintained but no tunable parameters are available to control the mean and the spread of the cell population sizes. Two types of nonlinear control considered here incorporate tunable parameters that allow specification of the expected number of stem cells and also provide control over the size of the standard deviation. We show that under a hyperbolic control law, there is a trade-off between minimizing standard deviations and maintaining the system robustness against external perturbations. For the Hill-type control, the standard deviation is inversely proportional to the Hill coefficient of the control loop. Biologically this means that ultrasensitive response that is observed in a number of regulatory loops may have evolved in order to reduce fluctuations while maintaining the desired population levels.
doi:10.1016/j.mbs.2012.08.004
PMCID: PMC3921979  PMID: 22960597
18.  Dissociating Fatty Liver and Diabetes 
Fatty liver disease is epidemiologically associated with type 2 diabetes (T2D), leading to a speculation of a reciprocal cause-effect relationship and a vicious cycle of pathology. Here, we summarize recent literature reporting dissociation of hepatosteatosis from insulin resistance, in genetic mouse models and clinical studies. We highlight rhythmic flows of metabolic intermediates between hepatic lipid synthesis and glucose production in normal circadian physiology. Blocking triglyceride (TG) secretion, subcellular lipid sequestration, lipolysis deficiency, enhanced lipogenesis, gluconeogenesis defects, or inhibition of fatty acid oxidation, all result in hepatosteatosis without causing hyperglycemia or insulin resistance, suggesting that the cause-effect relationship between hepatosteatosis and diabetes does not exist in all situations.
doi:10.1016/j.tem.2012.09.005
PMCID: PMC3532558  PMID: 23043895
19.  Enzyme-processed Korean Red Ginseng extracts protects against skin damage induced by UVB irradiation in hairless mice 
Journal of Ginseng Research  2013;37(4):425-434.
UV irradiation is the main factor contributing to skin damages that are associated with an excessive production of matrix-degrading metalloproteinase (MMP)-1 and a deficient expression of collagens. To date, red ginseng has been revealed to possess many biomedical effects, such as anti-aging, anti-oxidation, and anti-inflammatory. In this study, we prepared the Korean Red Ginseng extracts treated with enzyme (KRGE) and investigated the effects of dietary KRGE on the formation of wrinkles generated by UVB irradiation in hairless mice. It was found that KRGE inhibited the UVB-induced formation of wrinkles, epidermal thickness, and skin dryness in hairless mice. Further results also showed that KRGE attenuated UVB-induced MMP-1 level, while accelerated procollagen type I, transforming growth factor-β1 secretion. Interestingly, the expression of profilaggrin and filaggrin in both the epidermis and dermis were decreased due to UVB exposure and reversed by KRGE. The KRGE 0.06% was prior to KRGE 0.24%. In view of these results, which indicated that KRGE protected skin from UVB-induced photodamages, which may not only mediated by regulating of MMP-1 and procollagen type I, but also by increasing the production of profilaggrin and filaggrin. In conclusion, our results suggest that KRGE may be a promising agent for the treatment of skin photodamages. The challenge of KRGE will be expected as cosmeceuticals and nutraceuticals in order to intervene in aging-related degenerative skin changes.
doi:10.5142/jgr.2013.37.425
PMCID: PMC3825857  PMID: 24233239
Panax ginseng; Red ginseng; Enzyme; Photoaging; Skin hydration
20.  Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced Hamster Cheek Pouch Carcinogenesis by a 5-Lipoxygenase Inhibitor, Garcinol 
Nutrition and cancer  2012;64(8):1211-1218.
Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis, and can be targeted for cancer prevention. In order to develop potent topical agents for oral cancer chemoprevention, five known 5-Lox inhibitors from dietary and synthetic sources, Zileuton, ABT-761, Licofelone, Curcumin and Garcinol, were evaluated in silico for their potential efficacy. Garcinol, a polyisoprenylated benzophenone from the fruit rind of Garcinia spp., was found to be a promising agent based on the calculation of a theoretical activity index. Computer modeling showed that garcinol well fit the active site of 5-Lox, and potentially inhibited enzyme activity through interactions between the phenolic hydroxyl groups and the non-heme catalytic iron. In a short-term study on 7,12-dimethylbenz[a]anthracene (DMBA)-treated hamster cheek pouch, topical garcinol suppressed leukotriene B4 (LTB4) biosynthesis and inhibited inflammation and cell proliferation in the oral epithelium. In a long-term carcinogenesis study, topical garcinol significantly reduced the size of visible tumors, the number of cancer lesions, cell proliferation, and LTB4 biosynthesis. These results demonstrated that topical application of a 5-Lox inhibitor, garcinol, had chemopreventive effect on DMBA-induced hamster cheek pouch carcinogenesis.
doi:10.1080/01635581.2012.718032
PMCID: PMC3780792  PMID: 23137051
Oral cancer; Chemoprevention; Garcinol; 5-Lipoxygenase; Topical
21.  Circadian Epigenomic Remodeling and Hepatic Lipogenesis: Lessons from HDAC3 
Circadian rhythms have evolved to anticipate metabolic needs across the 24-hour light/dark cycle. This is accomplished by circadian expression of metabolic genes orchestrated by transcription factors through chromatin remodeling and histone modifications. Our recent genome-wide study on histone deacetylase 3 (HDAC3) in mouse liver provides novel insights into the molecular link between circadian rhythm and hepatic de novo lipogenesis. We found that liver-specific knockout of HDAC3 in adult mouse display severe hepatic steatosis associated with enhanced de novo lipogenesis and increased expression of lipogenic genes. Genome-wide analysis (ChIP-seq) revealed a pronounced circadian pattern of HDAC3 occupancy on genes involved in lipid metabolism, which is inversely related to histone acetylation and RNA polymerase II recruitment at these sites. The cistromes of HDAC3 and its binding partner, nuclear receptor co-repressor (NCoR), significantly overlap with that of Rev-erbα, a nuclear receptor directly involved in the core circadian machinery. Knockout of Rev-erbα in mouse also leads to hepatic steatosis and enhanced de novo lipogenesis. Collectively, these data suggest that the circadian epigenomic remodeling controlled by HDAC3, and largely directed by Rev-erbα, is essential for homeostasis of the lipogenic process in liver.
doi:10.1101/sqb.2011.76.011494
PMCID: PMC3755609  PMID: 21900149
22.  Nuclear Receptor Corepressors are Required for the Histone Deacetylase Activity of HDAC3 In Vivo 
Histone deacetylase 3 (HDAC3) is an epigenome-modifying enzyme that is required for normal mouse development and tissue-specific functions. In vitro, HDAC3 protein itself has minimal enzyme activity, but gains its histone deacetylation function from stable association with the conserved deacetylase activation domain (DAD) contained in nuclear receptor corepressors NCOR1 and SMRT. Here we show that HDAC3 enzyme activity is undetectable in mice bearing point mutations in the DAD of both NCOR1 and SMRT (NS-DADm), despite normal levels of HDAC3 protein. Local histone acetylation is increased, and genomic HDAC3 recruitment is reduced though not abrogated. Remarkably, the NS-DADm mice are born and live to adulthood, whereas genetic deletion of HDAC3 is embryonic lethal. These findings demonstrate that nuclear receptor corepressors are required for HDAC3 enzyme activity in vivo, and suggest that a deacetylase-independent function of HDAC3 may be required for life.
doi:10.1038/nsmb.2476
PMCID: PMC3565028  PMID: 23292142
23.  Cinnamoyl-based Nrf2-Activators Targeting Human Skin Cell Photo-oxidative Stress 
Free radical biology & medicine  2008;45(4):385-395.
Strong experimental evidence suggests the involvement of photo-oxidative stress mediated by reactive oxygen species as a crucial mechanism of solar damage relevant to human skin photoaging and photocarcinogenesis. Based on the established role of antioxidant response element (ARE)-mediated gene expression in cancer chemoprevention, we tested the hypothesis that small molecule Nrf2-activators may serve a photo-chemopreventive role by targeting skin cell photo-oxidative stress. A luciferase-based reporter gene assay was used as a primary screen for the identification of novel agents that modulate the Nrf2-Keap1 signaling pathway. A series of cinnamoyl-based electrophilic Michael acceptors including cinnamic aldehyde and methyl-1-cinnamoyl-5-oxo-2-pyrrolidine-carboxylate was identified as potent Nrf2-activators. Hit confirmation was performed in a secondary screen, based on immunodetection of Nrf2 protein upregulation in human Hs27 skin fibroblasts, HaCaT keratinocytes, and primary skin keratinocytes. Bioefficacy profiling of positive test compounds in skin cells demonstrated compound-induced upregulation of hemeoxygenase I and NAD(P)H-quinone oxidoreductase, two Nrf2 target genes involved in the cellular antioxidant response. Pretreatment with cinnamoyl-based Nrf2-activators suppressed intracellular oxidative stress and protected against photo-oxidative induction of apoptosis in skin cells exposed to high doses of singlet oxygen. Our pilot studies suggest feasibility of developing cinnamoyl-based Nrf2-activators as novel photo-chemopreventive agents targeting skin cell photo-oxidative stress.
doi:10.1016/j.freeradbiomed.2008.04.023
PMCID: PMC3710742  PMID: 18482591
Nrf2; skin cancer; photo-oxidative stress; photo-chemoprevention; Michael acceptor; cinnamic aldehyde; singlet oxygen
24.  Association among Polymorphisms in EGFR Gene Exons, Lifestyle and Risk of Gastric Cancer with Gender Differences in Chinese Han Subjects 
PLoS ONE  2013;8(3):e59254.
Background
The epidermal growth factor receptor (EGFR) gene plays a key role in tumor survival, invasion, angiogenesis, and metastatic spread. Recent studies showed that gastric cancer (GC) was associated with polymorphisms of the EGFR gene and environmental influences, such as lifestyle factors. In this study, seven known SNPs in EGFR exons were investigated in a high-risk Chinese population in Jiangsu province to test whether genetic variants of EGFR exons and lifestyle are associated with an increased risk of GC.
Methodology/Principal Findings
A hospital-based case-control study was performed in Jiangsu province. The results showed that smoking, drinking and preference for salty food were significantly associated with the risk of GC. The differences of lifestyle between males and females might be as the reason of higher incidence rates in males than those in females. Seven exon SNPs were genotyped rs2227983,rs2072454,rs17337023,rs1050171,rs1140475, rs2293347, and rs28384375. It was noted that the variant rs2072454 T allele and TT genotype were significantly associated with an increased risk of GC. Interestingly, our result suggested the ACAGCA haplotype might be associated with decreased risk of GC. However, no significant association was examined between the other six SNPs and the risk of GC both in the total population and the age-matching population even with gender differences.
Conclusions
Smoking, drinking and preference for salty food were significantly associated with the risk of GC in Jiangsu province with gender differences. Although only one SNP (rs2072454) was significantly associated with an increased risk of GC, combined the six EGFR exon SNPs together may be useful for predicting the risk of GC.
doi:10.1371/journal.pone.0059254
PMCID: PMC3612075  PMID: 23555641
25.  Transcriptome Analysis on Chinese Shrimp Fenneropenaeus chinensis during WSSV Acute Infection 
PLoS ONE  2013;8(3):e58627.
Previous studies have discovered a lot of immune-related genes responding to white spot syndrome virus (WSSV) infection in crustacean. However, little information is available in relation to underlying mechanisms of host responses during the WSSV acute infection stage in naturally infected shrimp. In this study, we employed next-generation sequencing and bioinformatic techniques to observe the transcriptome differences of the shrimp between latent infection stage and acute infection stage. A total of 64,188,426 Illumina reads, including 31,685,758 reads from the latent infection group and 32,502,668 reads from the acute infection group, were generated and assembled into 46,676 unigenes (mean length: 676 bp; range: 200–15,094 bp). Approximately 24,000 peptides were predicted and classified based on homology searches, gene ontology, clusters of orthologous groups of proteins, and biological pathway mapping. Among which, 805 differentially expressed genes were identified and categorized into 11 groups based on their possible function. Genes in the Toll and IMD pathways, the Ras-activated endocytosis process, the RNA interference pathway, anti-lipopolysaccharide factors and many other genes, were found to be activated in shrimp from latent infection stage to acute infection stage. The anti-bacterially proPO-activating cascade was firstly uncovered to be probably participated in antiviral process. These genes contain not only members playing function in host defense against WSSV, but also genes utilized by WSSV for its rapid proliferation. In addition, the transcriptome data provides detail information for identifying novel genes in absence of the genome database of shrimp.
doi:10.1371/journal.pone.0058627
PMCID: PMC3602427  PMID: 23527000

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