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1.  Biological Properties of Acidic Cosmetic Water from Seawater 
This current work was to investigate the biological effects of acidic cosmetic water (ACW) on various biological assays. ACW was isolated from seawater and demonstrated several bio-functions at various concentration ranges. ACW showed a satisfactory effect against Staphylococcus aureus, which reduced 90% of bacterial growth after a 5-second exposure. We used cultured human peripheral blood mononuclear cells (PBMCs) to test the properties of ACW in inflammatory cytokine release, and it did not induce inflammatory cytokine release from un-stimulated, normal PBMCs. However, ACW was able to inhibit bacterial lipopolysaccharide (LPS)-induced inflammatory cytokine TNF-α released from PBMCs, showing an anti-inflammation potential. Furthermore, ACW did not stimulate the rat basophilic leukemia cell (RBL-2H3) related allergy response on de-granulation. Our data presented ACW with a strong anti-oxidative ability in a superoxide anion radical scavenging assay. In mass spectrometry information, magnesium and zinc ions demonstrated bio-functional detections for anti-inflammation as well as other metal ions such as potassium and calcium were observed. ACW also had minor tyrosinase and melanin decreasing activities in human epidermal melanocytes (HEMn-MP) without apparent cytotoxicity. In addition, the cell proliferation assay illustrated anti-growth and anti-migration effects of ACW on human skin melanoma cells (A375.S2) indicating that it exerted the anti-cancer potential against skin cancer. The results obtained from biological assays showed that ACW possessed multiple bioactivities, including anti-microorganism, anti-inflammation, allergy-free, antioxidant, anti-melanin and anticancer properties. To our knowledge, this was the first report presenting these bioactivities on ACW.
doi:10.3390/ijms13055952
PMCID: PMC3382787  PMID: 22754342
acidic cosmetic water (ACW); antioxidant activity; anti-microorganism; anti-inflammation; allergy-free; skin-whitening; anti-melanoma
2.  Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice 
Hepatology (Baltimore, Md.)  2013;58(1):108-119.
The intestinal mucus layer protects the epithelium from noxious agents, viruses, and pathogenic bacteria present in the gastrointestinal tract. It is composed of mucins, predominantly mucin-2 (Muc2), secreted by goblet cells of the intestine. Experimental alcoholic liver disease requires translocation of bacterial products across the intestinal barrier into the systemic circulation, which induces an inflammatory response in the liver and contributes to steatohepatitis. We investigated the roles of the intestinal mucus layer, and in particular Muc2, in development of experimental alcohol-associated liver disease in mice. We studied experimental alcohol-induced liver disease, induced by the Tsukamoto-French method (which involves continuous intragastric feeding of an isocaloric diet or alcohol) in wild-type and Muc2−/− mice. Muc2−/− mice showed less alcohol-induced liver injury and steatosis that developed in wild-type mice. Most notably, Muc2−/− mice had significantly lower plasma levels of lipopolysaccharide than wild-type mice after alcohol feeding. In contrast to wild-type mice, Muc2−/− mice were protected from alcohol-associated microbiome changes that are dependent on intestinal mucins. The anti-microbial proteins Reg3b and Reg3g were expressed at significantly higher levels in the jejunum of Muc2−/− mice fed the isocaloric diet or alcohol, compared with wild-type mice. Consequently, Muc2−/− mice showed increased killing of commensal bacteria and prevented intestinal bacterial overgrowth. Conclusion: Muc2−/− mice are protected from intestinal bacterial overgrowth and dysbiosis in response to alcohol feeding. Subsequently, lower amounts of bacterial products such as endotoxin translocate into the systemic circulation, decreasing liver disease.
doi:10.1002/hep.26321
PMCID: PMC3695050  PMID: 23408358
microbiome; intestinal bacterial overgrowth; bacterial translocation; endotoxin; Reg3
3.  Identification of CD24 as a Cancer Stem Cell Marker in Human Nasopharyngeal Carcinoma 
PLoS ONE  2014;9(6):e99412.
Cancer stem cells (CSCs) represent a unique sub-population of tumor cells with the ability to initiate tumor growth and sustain self-renewal. Although CSC biomarkers have been described for various tumors, only a few markers have been identified for nasopharyngeal carcinoma (NPC). In this study, we show that CD24+ cells isolated from human NPC cell lines express stem cell genes (Sox2, Oct4, Nanog, Bmi-1, and Rex-1), and show activation of the Wnt/β-catenin signaling pathway. CD24+ cells possess typical CSC characteristics that include enhanced cell proliferation, increased colony and sphere formation, maintenance of cell differentiation potential in prolonged culture, and enhanced resistance to chemotherapeutic drugs. Notably, CD24+ cells produce tumors following inoculation of as few as 500 cells in immunodeficient NOD/SCID mice. CD24+ cells further show increased invasion ability in vitro, which correlates with enhanced expression of matrix metalloproteinase 2 and 9. In summary, our results suggest that CD24 represents a novel CSC biomarker in NPC.
doi:10.1371/journal.pone.0099412
PMCID: PMC4067285  PMID: 24955581
4.  Comparison of 18F-AIF-NOTA-PRGD2 and 18F-FDG Uptake in Lymph Node Metastasis of Differentiated Thyroid Cancer 
PLoS ONE  2014;9(6):e100521.
A widespread application of integrin αvβ3 imaging has been emerging in both pre-clinical and clinical studies. But few studies reported its value as compared with 18F-FDG PET, especially for differentiated thyroid cancer (DTC). In this study, we compared the tracer uptake of 18F-AIF-NOTA-PRGD2 and 18F-FDG in lymph node metastasis of DTC to evaluate 18F-AIF-NOTA-PRGD2 as compared with 18F-FDG.
Methods
20 DTC patients with presumptive lymph node metastasis were examined with 18F-AIF-NOTA-PRGD2 and 18F-FDG PET/CT. 16 patients undergoing fine needle aspiration biopsy (FNAB) were evaluated by cytology results. For lesions without FNAB, the findings of clinical staging procedures served as the standard of reference (including neck ultrasound and serum thyroglobulin).
Results
A total of 39 presumptive lymph node metastases were visualized on PET/CT images. 35 lesions were confirmed as malignant by FNAB and other clinical findings. The mean 18F-AIF-NOTA-PRGD2 in radioactive iodine-refractory (RAIR) lesions and benign lesions were 2.5±0.9 and 2.8±0.9 respectively. The mean SUV for 18F-FDG in all malignant lesions was 4.5±1.6 while in benign lesions it was 3.3±1.2. For all malignant lesions, the mean SUV for 18F-FDG was significantly higher than that for 18F-AIF-NOTA-PRGD2 (P<0.05). No significant correlation was found between the SUVs of 18F-AIF-NOTA-PRGD2 and 18F-FDG for 35 lesions (r = 0.114, P = 0.515). Moreover, 15 lesions of which the diameter larger than 1.5cm had higher 18F-AIF-NOTA-PRGD2 uptake as compared with the lesions smaller than 1.5cm.
Conclusion
Although most lymph node metastases of DTC showed abnormal uptake of 18F-AIF-NOTA-PRGD2, its diagnostic value was inferior to 18F-FDG. No correlation was found between the uptake of 18F-AIF-NOTA-PRGD2 and 18F-FDG, which may suggest the two tracers provide complementary information in DTC lesions.
doi:10.1371/journal.pone.0100521
PMCID: PMC4067334  PMID: 24956393
5.  Synergistic Inhibitory Effect of Hyperbaric Oxygen Combined with Sorafenib on Hepatoma Cells 
PLoS ONE  2014;9(6):e100814.
Objectives
Hypoxia is a common phenomenon in solid tumors, associated with chemotherapy and radiotherapy resistance, recurrence and metastasis. Hyperbaric oxygen (HBO) therapy can increase tissue oxygen pressure and content to prevent the resistance, recurrence and metastasis of cancer. Presently, Sorafenib is a first-line drug, targeted for hepatocellular carcinoma (HCC) but effective in only a small portion of patients and can induce hypoxia. The purpose of this study is to investigate the effect of HBO in combination with sorafenib on hepatoma cells.
Methods
Hepatoma cell lines (BEL-7402 and SK-Hep1) were treated with HBO at 2 atmosphere absolute pressure for 80 min per day or combined with sorafenib or cisplatin. At different time points, cells were tested for cell growth, colony formation, apoptosis, cell cycle and migration. Finally, miRNA from the hepatoma cells was detected by microRNA array and validated by qRT-PCR.
Results
Although HBO, sorafenib or cisplatin alone could inhibit growth of hepatoma cells, HBO combined with sorafenib or cisplatin resulted in much greater synergistic growth inhibition (cell proliferation and colony formation) in hepatoma cells. Similarly, the synergistic effect of HBO and sorafenib on induction of apoptosis was also observed in hepatoma cells. HBO induced G1 arrest in SK-Hep1 not in BEL-7402 cells, but enhanced cell cycle arrest induced by sorafenib in BEL-7402 treated cells. However, HBO had no obvious effect on the migration of hepatoma cells, and microRNA array analysis showed that hepatoma cells with HBO treatment had significantly different microRNA expression profiles from those with blank control.
Conclusions
We show for the first time that HBO combined with sorafenib results in synergistic growth inhibition and apoptosis in hepatoma cells, suggesting a potential application of HBO combined with sorafenib in HCC patients. Additionally, we also show that HBO significantly altered microRNA expression in hepatoma cells.
doi:10.1371/journal.pone.0100814
PMCID: PMC4067386  PMID: 24956259
6.  ROP18 Is a Key Factor Responsible for Virulence Difference between Toxoplasma gondii and Neospora caninum 
PLoS ONE  2014;9(6):e99744.
Toxoplasma gondii (T. gondii) and Neospora caninum (N. caninum) are both obligate intracellular protozoan parasites and share many common morphological and biological features. Despite these similarities the two parasites differ dramatically in virulence in mice, but the factors involved in virulence differences between the two parasites remain unknown. A secreted serine-threonine kinase called rhoptry protein 18 (ROP18) was identified to play a crucial role on virulence differences among different T. gondii clonal lineages. Intriguingly, we found that ROP18 in Nc1 strain of N. caninum (NcROP18) is a pseudogene due to several interrupting stop codons in the sequence in our previous studies. We assume that the difference of ROP18 leads to virulence difference between T. gondii and N. caninum. We constructed a transgenic N. caninum Nc1 stain by transfecting the TgROP18 from the T. gondii RH strain. Phenotype and virulence assays showed that the expression of TgROP18 in N. caninum did not affect the motility and cell invasion, but resulted in a significant increase in intracellular parasite proliferation and virulence in mice. Immunity-Related GTPase (IRG) phosphorylation assay showed that the transgenic parasite Nc1-TgROP18 was able to phosphorylate IRGs as T. gondii did. The present study indicated that the ROP18 plays a crucial role in virulence of the closely related parasites T. gondii and N. caninum and it is indeed a key factor responsible for the virulence difference between T. gondii and N. caninum.
doi:10.1371/journal.pone.0099744
PMCID: PMC4057265  PMID: 24927100
7.  Aberrant PTPRO methylation in tumor tissues as a potential biomarker that predicts clinical outcomes in breast cancer patients 
BMC Genetics  2014;15:67.
Background
Aberrant hypermethylation of gene promoter regions is a primary mechanism by which tumor suppressor genes become inactivated in breast cancer. Epigenetic inactivation of the protein tyrosine phosphatase receptor-type O gene (PTPRO) has been described in several types of cancer.
Results
We screened primary breast cancer tissues for PTPRO promoter hypermethylation and assessed potential associations with pathological features and patient outcome. We also evaluated its potential as a breast cancer biomarker. PTPRO methylation was observed in 53 of 98 (54%) breast cancer tissues but not in adjacent normal tissue. Among matched peripheral blood samples from breast cancer patients, 33 of 98 (34%) exhibited methylated PTPRO in plasma. In contrast, no methylated PTPRO was observed in normal peripheral blood from 30 healthy individuals. PTPRO methylation was positively associated with lymph node involvement (P = 0.014), poorly differentiated histology (P = 0.037), depth of invasion (P = 0.004), and HER2 amplification (P = 0.001). Multivariate analysis indicated that aberrant PTPRO methylation could serve as an independent predictor for overall survival hazard ratio (HR): 2.7; 95% CI: 1.1-6.2; P = 0.023), especially for patients with HER2-positive (hazard ratio (HR): 7.5; 95% CI: 1.8-31.3; P = 0.006), but not in ER + and PR + subpopulation. In addition, demethylation induced by 5-azacytidine led to gene reactivation in PTPRO-methylated and -silenced breast cancer cell lines.
Conclusions
Here, we report that tumor PTPRO methylation is a strong prognostic factor in breast cancer. Methylation of PTPRO silences its expression and plays an important role in breast carcinogenesis. The data we present here may provide insight into the development of novel therapies for breast cancer treatment. Additionally, detection of PTPRO methylation in peripheral blood of breast cancer patients may provide a noninvasive means to diagnose and monitor the disease.
doi:10.1186/1471-2156-15-67
PMCID: PMC4062905  PMID: 24919593
Protein tyrosine phosphatase receptor-type O (PTPRO); Methylation; Breast cancer; Clinical outcome; Biomarker
9.  A General Method to Determine Ionization Constants of Responsive Polymer Thin Films 
A general method has been developed to determine the ionization constants of polymer thin films based on the stimuli-responsiveness of the polymer. Robust polymer films were fabricated on silicon wafers and gold slides using perfluorophenyl azide (PFPA) as the coupling agent. The ionization constants were measured by a number of techniques including ellipsometry, dynamic contact angle goniometry, and surface plasmon resonance imaging (SPRi). Using poly(4-vinylpyridine) (P4VP) as the model system, P4VP thin films were fabricated and the ionization constants of the films were measured taking advantage of the pH responsive property of the polymer. The pKa determined by ellipsometry, ~4.0, reflects the swelling of the polymer film in response to pH. The pKa value calculated from the dynamic contact angle measurements, ~5.0, relies on the change in hydrophilicity/hydrophobicity of the films as the polymer undergoes protonation/deprotonation. The pKa value measured by SPRi, ~4.9, monitors in situ the change of refractive index of the polymer thin film as it swells upon protonation. This was the first example where SPRi was used to measure the ionization constant of polymers.
doi:10.1016/j.jcis.2011.08.081
PMCID: PMC4034268  PMID: 21962542
Polymer thin films; covalent immobilization; ionization constant; poly(4-vinylpyridine); contact angle titration; surface plasmon resonance imaging
10.  Peripheral blood miRNAs as a biomarker for chronic cardiovascular diseases 
Scientific Reports  2014;4:5026.
Vascular diseases are the most prevalent diseases worldwide. This study intended to analyze peripheral blood miRNA levels and their correlation with NT-pro-BNP and cTN-I in patients with atherosclerosis or pre-atherosclerotic conditions to build a dynamic correlation between vascular diseases and their biomarkers. Serum NT-pro-BNP and cTN-I levels were measured by their respective ELISA kits. The miRNA levels were assayed by quantitative PCR. Unique miRNA signatures were identified for both atherosclerosis and pre-atherosclerosis. The levels of miR-92a, 126, 130a, 222, and 370 levels were decreased in the peripheral blood of pre-atherosclerotic subjects. In atherosclerosis, miR-21, 122, 130a, and 211 were significantly increased whereas miR-92a, 126, and 222 were markedly decreased. Serum levels of NT-pro-BNP and cTN-I correlated with each other and increased with the progression of atherosclerosis. Moreover, the levels of cTN-I and NT-pro-BNP were positively correlated with miR-21 and negatively correlated with miR-126. Integrating specific pattern of miRNA levels with NT-pro-BNP and/or cardiac troponin may improve the diagnosis of cardiovascular diseases.
doi:10.1038/srep05026
PMCID: PMC4052773  PMID: 24848278
11.  Transgenic Tobacco Overexpressing Brassica juncea HMG-CoA Synthase 1 Shows Increased Plant Growth, Pod Size and Seed Yield 
PLoS ONE  2014;9(5):e98264.
Seeds are very important not only in the life cycle of the plant but they represent food sources for man and animals. We report herein a mutant of 3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMGS), the second enzyme in the mevalonate (MVA) pathway that can improve seed yield when overexpressed in a phylogenetically distant species. In Brassica juncea, the characterisation of four isogenes encoding HMGS has been previously reported. Enzyme kinetics on recombinant wild-type (wt) and mutant BjHMGS1 had revealed that S359A displayed a 10-fold higher enzyme activity. The overexpression of wt and mutant (S359A) BjHMGS1 in Arabidopsis had up-regulated several genes in sterol biosynthesis, increasing sterol content. To quickly assess the effects of BjHMGS1 overexpression in a phylogenetically more distant species beyond the Brassicaceae, wt and mutant (S359A) BjHMGS1 were expressed in tobacco (Nicotiana tabacum L. cv. Xanthi) of the family Solanaceae. New observations on tobacco OEs not previously reported for Arabidopsis OEs included: (i) phenotypic changes in enhanced plant growth, pod size and seed yield (more significant in OE-S359A than OE-wtBjHMGS1) in comparison to vector-transformed tobacco, (ii) higher NtSQS expression and sterol content in OE-S359A than OE-wtBjHMGS1 corresponding to greater increase in growth and seed yield, and (iii) induction of NtIPPI2 and NtGGPPS2 and downregulation of NtIPPI1, NtGGPPS1, NtGGPPS3 and NtGGPPS4. Resembling Arabidopsis HMGS-OEs, tobacco HMGS-OEs displayed an enhanced expression of NtHMGR1, NtSMT1-2, NtSMT2-1, NtSMT2-2 and NtCYP85A1. Overall, increased growth, pod size and seed yield in tobacco HMGS-OEs were attributed to the up-regulation of native NtHMGR1, NtIPPI2, NtSQS, NtSMT1-2, NtSMT2-1, NtSMT2-2 and NtCYP85A1. Hence, S359A has potential in agriculture not only in improving phytosterol content but also seed yield, which may be desirable in food crops. This work further demonstrates HMGS function in plant reproduction that is reminiscent to reduced fertility of hmgs RNAi lines in let-7 mutants of Caenorhabditis elegans.
doi:10.1371/journal.pone.0098264
PMCID: PMC4029903  PMID: 24847714
12.  Efficient 18F labeling of cysteine containing peptides and proteins using the tetrazine-trans-cyclooctene ligation 
Molecular imaging  2013;12(2):121-128.
18F PET has a number of attributes that make it clinically attractive, including nearly 100% positron efficiency, very high specific radioactivity, and short half-life of ~110 min. However, the short half-life of 18F and the poor nucleophilicity of fluoride introduce challenges for the incorporation of 18F into complex molecules. Recently, the tetrazine-trans-cyclooctene ligation has been introduced as a novel 18F labeling method that proceeds with fast reaction rates without catalysis. Herein, we report an efficient method for 18F-labeling of free cysteines of peptides and proteins based on sequential ligation with a bifunctional tetrazinyl-maleimide and an 18F-labeled trans-cyclooctene. The newly developed method was tested for site specific labeling of both c(RGDyC) peptide and VEGF-SH protein. Starting with 4 mCi of 18F-trans-cyclooctene and only 10 μg of tetrazine-RGD (80–100 μM) or 15 μg of tetrazine-VEGF (6.0 μM), 18F labeled RGD peptide and VEGF protein could be obtained within five minutes in 95% yield and 75% yield, respectively. The obtained tracers were then evaluated in mice. In conclusion, a highly efficient method has been developed for site-specific 18F labeling of cysteine containing peptides and proteins. The special characteristics of the tetrazine-trans-cyclooctene ligation provide unprecedented opportunities to synthesize 18F-labeled probes with high specific activity for PET applications.
PMCID: PMC4027965  PMID: 23415400
18F; tetrazine-trans-cyclooctene; PET; Protein labeling; Maleimide
13.  A Novel Method for Identification and Quantification of Consistently Differentially Methylated Regions 
PLoS ONE  2014;9(5):e97513.
Advances in biotechnology have resulted in large-scale studies of DNA methylation. A differentially methylated region (DMR) is a genomic region with multiple adjacent CpG sites that exhibit different methylation statuses among multiple samples. Many so-called “supervised” methods have been established to identify DMRs between two or more comparison groups. Methods for the identification of DMRs without reference to phenotypic information are, however, less well studied. An alternative “unsupervised” approach was proposed, in which DMRs in studied samples were identified with consideration of nature dependence structure of methylation measurements between neighboring probes from tiling arrays. Through simulation study, we investigated effects of dependencies between neighboring probes on determining DMRs where a lot of spurious signals would be produced if the methylation data were analyzed independently of the probe. In contrast, our newly proposed method could successfully correct for this effect with a well-controlled false positive rate and a comparable sensitivity. By applying to two real datasets, we demonstrated that our method could provide a global picture of methylation variation in studied samples. R source codes to implement the proposed method were freely available at http://www.csjfann.ibms.sinica.edu.tw/eag/programlist/ICDMR/ICDMR.html.
doi:10.1371/journal.pone.0097513
PMCID: PMC4018258  PMID: 24818602
14.  Inhibition of Tumor Vasculogenic Mimicry and Prolongation of Host Survival in Highly Aggressive Gallbladder Cancers by Norcantharidin via Blocking the Ephrin Type a Receptor 2/Focal Adhesion Kinase/Paxillin Signaling Pathway 
PLoS ONE  2014;9(5):e96982.
Vasculogenic mimicry (VM) is a newly-defined tumor microcirculation pattern in highly aggressive malignant tumors. We recently reported tumor growth and VM formation of gallbladder cancers through the contribution of the ephrin type a receptor 2 (EphA2)/focal adhesion kinase (FAK)/Paxillin signaling pathways. In this study, we further investigated the anti-VM activity of norcantharidin (NCTD) as a VM inhibitor for gallbladder cancers and the underlying mechanisms. In vivo and in vitro experiments to determine the effects of NCTD on tumor growth, host survival, VM formation of GBC-SD nude mouse xenografts, and vasculogenic-like networks, malignant phenotypes i.e., proliferation, apoptosis, invasion and migration of GBC-SD cells. Expression of VM signaling-related markers EphA2, FAK and Paxillin in vivo and in vitro were examined by immunofluorescence, western blotting and real-time polymerase chain reaction (RT-PCR), respectively. The results showed that after treatment with NCTD, GBC-SD cells were unable to form VM structures when injecting into nude mouse, growth of the xenograft was inhibited and these observations were confirmed by facts that VM formation by three-dimensional (3-D) matrix, proliferation, apoptosis, invasion, migration of GBC-SD cells were affected; and survival time of the xenograft mice was prolonged. Furthermore, expression of EphA2, FAK and Paxillin proteins/mRNAs of the xenografts was downregulated. Thus, we concluded that NCTD has potential anti-VM activity against human gallbladder cancers; one of the underlying mechanisms may be via blocking the EphA2/FAK/Paxillin signaling pathway.
doi:10.1371/journal.pone.0096982
PMCID: PMC4014585  PMID: 24811250
15.  Structural basis for action by diverse antidepressants on biogenic amine transporters 
Nature  2013;503(7474):141-145.
Summary
The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents that include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)1, 2. Because eukaryotic BATs are recalcitrant to crystallographic analysis, our understanding of the mechanism of these inhibitors and antidepressants is limited. LeuT is a bacterial homolog of BATs and has proven a valuable paradigm for understanding relationships between structure and function in BATs3. However, because LeuT has only ~20% amino acid sequence identity to BATs and is a promiscuous amino acid transporter4, it does not recapitulate the pharmacological properties of BATs. Indeed, SSRIs and TCAs bind in the extracellular vestibule of LeuT5-7 and act as non-competitive inhibitors of transport5. In contrast, multiple studies demonstrate that both TCAs and SSRIs are competitive inhibitors for eukaryotic BATs and bind to the primary binding pocket8-16. Here, we engineered LeuT to harbor human BAT-like pharmacology by mutating key residues around the primary binding pocket. The final LeuBAT mutant binds the SSRI sertraline with a binding constant of 18 nM and displays high affinity binding to a range of SSRIs, SNRIs and a TCA. We determined 12 crystal structures of LeuBAT in complex with four classes of antidepressants. The chemically diverse inhibitors have a remarkably similar mode of binding in which they straddle TM3, wedge between TM3/TM8 and TM1/TM6, and lock the transporter in a sodium and chloride-bound outward facing open conformation. Together, these studies define common and simple principles for the action of SSRIs, SNRIs and TCAs on BATs.
doi:10.1038/nature12648
PMCID: PMC3904662  PMID: 24121440
16.  Toll-like receptor alterations in myelodysplastic syndrome 
Leukemia  2013;27(9):1832-1840.
Recent studies have implicated the innate immunity system in the pathogenesis of myelodysplastic syndromes (MDS). Toll-like receptor (TLR) genes encode key innate immunity signal initiators. We recently identified multiple genes, known to be regulated by TLRs, to be overexpressed in MDS bone marrow (BM) CD34+ cells, and hypothesized that TLR signaling is abnormally activated in MDS. We analyzed a large cohort of MDS cases and identified that TLR1, 2 and 6 to be significantly overexpressed in MDS BM CD34+ cells. Deep-sequencing followed by Sanger-resequencing of TLR1, 2, 4 and 6 genes uncovered a recurrent genetic variant, TLR2-F217S, in 11% of 149 patients. Functionally, TLR2-F217S results in enhanced activation of downstream signaling including NF-kB activity after TLR2 agonist treatment. In cultured primary BM CD34+ cells of normal donors, TLR2 agonists induced histone demethylase JMJD3 and interleukin-8 gene expression. Inhibition of TLR2 in BM CD34+ cells from patients with lower-risk MDS using shRNA resulted in increased erythroid colony formation. Finally, RNA expression levels of TLR2 and 6 as well as presence of TLR2-F217S are associated with distinct prognosis and clinical characteristics. These findings indicate that TLR2-centered signaling is deregulated in MDS and that its targeting may have potential therapeutic benefit in MDS.
doi:10.1038/leu.2013.180
PMCID: PMC4011663  PMID: 23765228
myelodysplastic syndromes; innate immunity; Toll like receptor; IL-8; JMJD3
17.  Targeted Knockdown of IQGAP1 Inhibits the Progression of Esophageal Squamous Cell Carcinoma In Vitro and In Vivo 
PLoS ONE  2014;9(5):e96501.
IQGAP1 is a scaffolding protein that can regulate several distinct signaling pathways. The accumulating evidence has demonstrated that IQGAP1 plays an important role in tumorigenesis and tumor progression. However, the function of IQGAP1 in esophageal squamous cell carcinoma (ESCC) has not been thoroughly investigated. In the present study, we showed that IQGAP1 was overexpressed in ESCC tumor tissues, and its overexpression was correlated with the invasion depth of ESCC. Importantly, by using RNA interference (RNAi) technology we successfully silenced IQGAP1 gene in two ESCC cell lines, EC9706 and KYSE150, and for the first time found that suppressing IQGAP1 expression not only obviously reduced the tumor cell growth, migration and invasion in vitro but also markedly inhibited the tumor growth, invasion, lymph node and lung metastasis in xenograft mice. Furthermore, Knockdown of IQGAP1 expression in ESCC cell lines led to a reversion of epithelial to mesenchymal transition (EMT) progress. These results suggest that IQGAP1 plays crucial roles in regulating ESCC occurrence and progression. IQGAP1 silencing may therefore develop into a promising novel anticancer therapy.
doi:10.1371/journal.pone.0096501
PMCID: PMC4011758  PMID: 24800852
18.  Nrf2 Deficiency Exaggerates Doxorubicin-Induced Cardiotoxicity and Cardiac Dysfunction 
The anticancer therapy of doxorubicin (Dox) has been limited by its acute and chronic cardiotoxicity. In addition to a causative role of oxidative stress, autophagy appears to play an important role in the regulation of Dox-induced cardiotoxicity. However, the underlying mechanisms remain unclear. Accordingly, we explored a role of nuclear factor erythroid-2 related factor 2 (Nrf2) in Dox-induced cardiomyopathy with a focus on myocardial oxidative stress and autophagic activity. In wild type (WT) mice, a single intraperitoneal injection of 25 mg/kg Dox rapidly induced cardiomyocyte necrosis and cardiac dysfunction, which were associated with oxidative stress, impaired autophagy, and accumulated polyubiquitinated protein aggregates. However, these Dox-induced adverse effects were exaggerated in Nrf2 knockout (Nrf2−/−) mice. In cultured cardiomyocytes, overexpression of Nrf2 increased the steady levels of LC3-II, ameliorated Dox-induced impairment of autophagic flux and accumulation of ubiquitinated protein aggregates, and suppressed Dox-induced cytotoxicity, whereas knockdown of Nrf2 exerted opposite effects. Moreover, the exaggerated adverse effects in Dox-intoxicated Nrf2 depleted cardiomyocytes were dramatically attenuated by forced activation of autophagy via overexpression of autophagy related gene 5 (Atg5). Thus, these results suggest that Nrf2 is likely an endogenous suppressor of Dox-induced cardiotoxicity by controlling both oxidative stress and autophagy in the heart.
doi:10.1155/2014/748524
PMCID: PMC4033424  PMID: 24895528
19.  Peripheral Surgical Wounding and Age-Dependent Neuroinflammation in Mice 
PLoS ONE  2014;9(5):e96752.
Post-operative cognitive dysfunction is associated with morbidity and mortality. However, its neuropathogenesis remains largely to be determined. Neuroinflammation and accumulation of β-amyloid (Aβ) have been reported to contribute to cognitive dysfunction in humans and cognitive impairment in animals. Our recent studies have established a pre-clinical model in mice, and have found that the peripheral surgical wounding without the influence of general anesthesia induces an age-dependent Aβ accumulation and cognitive impairment in mice. We therefore set out to assess the effects of peripheral surgical wounding, in the absence of general anesthesia, on neuroinflammation in mice with different ages. Abdominal surgery under local anesthesia was established in 9 and 18 month-old mice. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), Iba1 positive cells (the marker of microglia activation), CD33, and cognitive function in mice were determined. The peripheral surgical wounding increased the levels of TNF-α, IL-6, and Iba1 positive cells in the hippocampus of both 9 and 18 month-old mice, and age potentiated these effects. The peripheral surgical wounding increased the levels of CD33 in the hippocampus of 18, but not 9, month-old mice. Finally, anti-inflammatory drug ibuprofen ameliorated the peripheral surgical wounding-induced cognitive impairment in 18 month-old mice. These data suggested that the peripheral surgical wounding could induce an age-dependent neuroinflammation and elevation of CD33 levels in the hippocampus of mice, which could lead to cognitive impairment in aged mice. Pending further studies, anti-inflammatory therapies may reduce the risk of postoperative cognitive dysfunction in elderly patients.
doi:10.1371/journal.pone.0096752
PMCID: PMC4010504  PMID: 24796537
20.  Involvement of c-KIT mutation in the development of gastrointestinal stromal tumors through proliferation promotion and apoptosis inhibition 
OncoTargets and therapy  2014;7:637-643.
The aim of this study was to discuss the role of c-KIT mutation in the pathogenesis of gastrointestinal stromal tumors (GISTs) and analyze its correlation with proliferation and apoptosis. c-KIT and PDGFRA genotypes were examined by deoxyribonucleic acid sequencing. Immunohistochemistry was performed to determine the expression levels of Kit, Ki-67 (proliferation marker), and apoptotic protease-activating factor (APAF)-1 (apoptosis marker) and the relationship between their three genes. In the 68 cases examined, 44 cases (64.7%) showed mutations in one of the four exons of c-KIT. The mutations were most frequently found in exon 11 (30 cases [44.1%]), followed by exon 9 (ten cases [14.7%]) and exon 13 (four cases [5.9%]). c-KIT mutation showed no association with prognostic factors using the classification of risk of aggressive behavior in GIST proposed by Fletcher et al. No cases had mutated exon 17 of c-KIT, and neither did exon 12, 14, or 18 of PDGFRA in our present study. There was a positive correlation between the expression level of Kit and Ki-67 (R=0.282, P=0.020). Conversely, a negative correlation was found between the expression levels of Kit and APAF1 (R=−0.243, P=0.046). In conclusion, most GISTs with Kit expression showed c-KIT mutation. Kit expression has a positive correlation with Ki-67 and a negative correlation with APAF1, showing that c-KIT is involved in GIST occurrence and development through proliferation promotion and apoptosis inhibition.
doi:10.2147/OTT.S60458
PMCID: PMC4014364  PMID: 24833907
gastrointestinal stromal tumors; c-KIT; mutation; proliferation; apoptosis
21.  Interplay of pro- and anti-inflammatory cytokines to determine lipid accretion in adipocytes 
International journal of obesity (2005)  2013;37(11):10.1038/ijo.2013.9.
Objective
Obesity is associated with an increase in various pro-inflammatory and anti-inflammatory cytokines, but the interplay of these cytokines is incompletely understood. We conducted experiments to test a broader hypothesis that a dynamic interplay of pro-inflammatory and anti-inflammatory cytokines controls lipid storage in adipocytes.
Design
Three experiments were designed to test the overall hypothesis that pro-inflammatory cytokine (e.g. TNF-α) inhibits anti-inflammatory cytokine (e.g. adiponectin) activity in an attempt to limit excess lipid accumulation in adipocytes.
Results
Experiment 1 showed that in pro-inflammatory animal models (ap2-P65, ob/ob and high fat diet-induced obese mice), the increase in TNF-α expression was associated with a decrease in adiponectin expression. Experiment 2 showed that in 3T3-L1 adipocytes, TNF-α significantly reduced lipid accumulation and glucose uptake induced by adiponectin, and increased lipolysis. Experiment 3 showed that in 3T3-L1 adipocytes, TNF-α reduced mRNA and protein expression of adiponectin. Adiponectin gene transcription and mRNA stability were both reduced by TNF-α. The expression of PPAR-γ, an activator of adiponectin gene promoter, was reduced by TNF-α. The inhibitory activity of TNF-α was blocked by chemical inhibitors of NF-κB and super suppressor IκBα (ssIκBα).
Conclusion
TNF-α opposes the action of adiponectin in the regulation of lipid metabolism, and inhibits adiponectin expression at transcriptional and post-transcriptional levels. The results suggest that pro-inflammatory cytokine inhibit anti-inflammatory cytokine in adipocytes to reduce lipid storage. This suggests a potential role of anti-inflammatory cytokines in the control of adipose tissue expansion.
doi:10.1038/ijo.2013.9
PMCID: PMC3657600  PMID: 23381555
Adiponectin; mRNA stability; transcription; TNF-α; NF-κB; PPARγ
22.  Hemoglobin in normal range, the lower the better?—Evidence from a study from Chinese community-dwelling participants 
Journal of Thoracic Disease  2014;6(5):477-482.
Objective
To examine the association between hemoglobin (Hb) levels and cardiovascular risk factors in a large community-dwelling cohort.
Methods
A total of 4,186 women and 4,851 men were enrolled in the study. Data on personal history, physical examination and biochemical parameters were collected. Subjects were categorized by gender and divided into different group according to the level of Hb or blood pressure, and the association between Hb levels and cardiovascular risk factors was examined using Pearson’s correlation analysis.
Results
In both men and women even with normal Hb level, tertiles of Hb levels were positively associated with body mass index (BMI), total-cholesterol (TC), triglyceride (TG), uric acid (UA), diastolic blood pressures (DBP) and fasting plasma glucose (FPG) (all P=0.000 in men and women). Furthermore, significantly increased incidence of hyperuricemia (P=0.000 both in men and women) and obesity (P=0.000 both in men and women) were observed with the gradually increased Hb level. In addition, Pearson’s correlation analysis revealed obvious correlation between Hb level and various cardiovascular risk factors including blood pressure and UA. Binary logistic regression analysis further demonstrated that the level of Hb was an important risk factor for elevated blood pressure (OR =1.216; 95% CI: 1.138-1.293, P=0.000 in men; OR =1.287; 95% CI: 1.229-1.363, P=0.000 in women).
Conclusions
Increasing Hb levels, even in subjects with normal level were associated with increasing prevalence of cardiovascular risk factors, suggesting that a slightly low Hb level might be beneficial to Chinese community-dwelling individuals.
doi:10.3978/j.issn.2072-1439.2014.02.12
PMCID: PMC4014990  PMID: 24822106
Hemoglobin; cardiovascular risk; blood pressure
23.  Biological Evaluation and 3D-QSAR Studies of Curcumin Analogues as Aldehyde Dehydrogenase 1 Inhibitors 
Aldehyde dehydrogenase 1 (ALDH1) is reported as a biomarker for identifying some cancer stem cells, and down-regulation or inhibition of the enzyme can be effective in anti-drug resistance and a potent therapeutic for some tumours. In this paper, the inhibitory activity, mechanism mode, molecular docking and 3D-QSAR (three-dimensional quantitative structure activity relationship) of curcumin analogues (CAs) against ALDH1 were studied. Results demonstrated that curcumin and CAs possessed potent inhibitory activity against ALDH1, and the CAs compound with ortho di-hydroxyl groups showed the most potent inhibitory activity. This study indicates that CAs may represent a new class of ALDH1 inhibitor.
doi:10.3390/ijms15058795
PMCID: PMC4057759  PMID: 24840575
curcumin; curcumin analogues; ALDH1; inhibitor; 3D-QSAR
24.  Single-Molecule Spectroscopic Study of Dynamic Nanoscale DNA Bending Behavior of HIV-1 Nucleocapsid Protein† 
The journal of physical chemistry. B  2012;117(16):4183-4196.
We have studied the conformational dynamics associated with the nanoscale DNA bending induced by human immunodeficiency virus type 1 (HIV-1) nucleocapsid (NC) protein using single-molecule Förster Resonance Energy Transfer (SM-FRET). To gain molecular-level insights into how HIV-1 NC locally distorts the structures of duplexed DNA segments, the dynamics, reversibility, and sequence specificity of NC’s DNA bending behavior have been systematically studied. We have performed SM-FRET measurements on a series of duplexed DNA segments with varying sequences, lengths, and local structures in the presence of the wide-type HIV-1 NC and NC mutants lacking either the basic N-terminal domain or the zinc fingers. Based on the SM-FRET results, we have proposed a possible mechanism for the NC-induced DNA bending in which both NC’s zinc fingers and N-terminal domain are found to play crucial roles. The SM-FRET results reported here add new mechanistic insights to the biological behaviors and functions of HIV-1 NC as a retroviral DNA-architectural protein which may play critical roles in the compaction, nuclear import, and integration of the proviral DNA during the retroviral life-cycle.
doi:10.1021/jp3018259
PMCID: PMC3491087  PMID: 22591315
single-molecule spectroscopy; FRET; HIV-1; nucleocapsid; DNA bending; nucleic acid chaperone
25.  Risk of Budd-Chiari Syndrome Associated with Factor V Leiden and G20210A Prothrombin Mutation: A Meta-Analysis 
PLoS ONE  2014;9(4):e95719.
Background
Various studies have demonstrated that factor V Leiden (FVL) and G20210A prothrombin mutation contribute to the risk of Budd-Chiari syndrome (BCS), while other studies provided conflicting findings. In order to derive more precise estimations of the relationships, a meta-analysis was performed.
Methods
Eligible articles were identified through search of databases including Pubmed, Chinese Biomedical Database (CBM, Chinese), and Chinese National Knowledge Infrastructure (CNKI, Chinese). Odd ratios (ORs) with 95% confidence intervals (CIs) were calculated using random- or fixed- model.
Results
Finally, twelve studies were included for FVL and nine studies were included for G20210A prothrombin mutation. With respect to FVL, significantly increased BCS risk was found in the overall population (OR = 6.29, 95%CI = 4.23–9.36). Subgroup analyses suggested that FVL was associated with an increased risk of BCS in the population with high background mutation prevalence (>1% in the normal population). No significant association was found between BCS and G20210A prothrombin mutation (OR = 1.78, 95%CI = 0.77–4.11).
Conclusion
The presence of FVL should be evaluated in patients with BCS. Conversely, G20210A prothrombin mutation is not significantly associated with risk of BCS. Large-scale well designed studies are necessary to be conducted to further confirm or refute the observed association.
doi:10.1371/journal.pone.0095719
PMCID: PMC3995749  PMID: 24755609

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