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1.  The GLRA1 Missense Mutation W170S Associates Lack of Zn2+ Potentiation with Human Hyperekplexia 
The Journal of Neuroscience  2013;33(45):17675-17681.
Hyperekplexia is a neurological disorder associated primarily with mutations in the α1 subunit of glycine receptors (GlyRs) that lead to dysfunction of glycinergic inhibitory transmission. To date, most of the identified mutations result in disruption of surface expression or altered channel properties of α1-containing GlyRs. Little evidence has emerged to support an involvement of allosteric GlyR modulation in human hyperekplexia. Here, we report that recombinant human GlyRs containing α1 or α1β subunits with a missense mutation in the α1 subunit (W170S), previously identified from familial hyperekplexia, caused remarkably reduced potentiation and enhanced inhibition by Zn2+. Interestingly, mutant α1W170Sβ GlyRs displayed no significant changes in potency or maximum response to glycine, taurine, or β-alanine. By temporally separating the potentiating and the inhibitory effects of Zn2+, we found that the enhancement of Zn2+ inhibition resulted from a loss of Zn2+-mediated potentiation. The W170S mutation on the background of H107N, which was previously reported to selectively disrupt Zn2+ inhibition, showed remarkable attenuation of Zn2+-mediated potentiation and thus indicated that W170 is an important residue for the Zn2+-mediated GlyR potentiation. Moreover, overexpressing the α1W170S subunit in cultured rat neurons confirmed the results from heterologous expression. Together, our results reveal a new zinc potentiation site on α1 GlyRs and a strong link between Zn2+ modulation and human disease.
doi:10.1523/JNEUROSCI.3240-13.2013
PMCID: PMC3873627  PMID: 24198360
2.  Protective Effects of the Polyphenol Sesamin on Allergen-Induced TH2 Responses and Airway Inflammation in Mice 
PLoS ONE  2014;9(4):e96091.
Allergic asthma is a lifelong airway condition that affects people of all ages. In recent decades, asthma prevalence continues to increase globally, with an estimated number of 250,000 annual deaths attributed to the disease. Although inhaled corticosteroids and β-adrenergic receptor agonists are the primary therapeutic avenues that effectively reduce asthma symptoms, profound side effects may occur in patients with long-term treatments. Therefore, development of new therapeutic strategies is needed as alternative or supplement to current asthma treatments. Sesamin is a natural polyphenolic compound with strong anti-oxidative effects. Several studies have reported that sesamin is effective in preventing hypertension, thrombotic tendency, and neuroinflammation. However, it is still unknown whether sesamin can reduce asthma-induced allergic inflammation and airway hyperresponsiveness (AHR). Our study has revealed that sesamin exhibited significant anti-inflammatory effects in ovalbumin (OVA)-induced murine asthma model. We found that treatments with sesamin after OVA sensitization and challenge significantly decreased expression levels of interleukin-4 (IL-4), IL-5, IL-13, and serum IgE. The numbers of total inflammatory cells and eosinophils in BALF were also reduced in the sesamin-treated animals. Histological results demonstrated that sesamin attenuated OVA-induced eosinophil infiltration, airway goblet cell hyperplasia, mucus occlusion, and MUC5AC expression in the lung tissue. Mice administered with sesamin showed limited increases in AHR compared with mice receiving vehicle after OVA challenge. OVA increased phosphorylation levels of IκB-α and nuclear expression levels of NF-κB, both of which were reversed by sesamin treatments. These data indicate that sesamin is effective in treating allergic asthma responses induced by OVA in mice.
doi:10.1371/journal.pone.0096091
PMCID: PMC3996011  PMID: 24755955
3.  Decitabine of Reduced Dosage in Chinese Patients with Myelodysplastic Syndrome: A Retrospective Analysis 
PLoS ONE  2014;9(4):e95473.
Decitabine has been approved for the treatment of all subtypes of myelodysplastic syndrome (MDS). However, the optimal regimen for decitabine treatment is not well established. In this study, an observational, retrospective and multi-center analysis was performed to explore the decitabine schedule for the treatment of MDS. A total of 79 patients received reduced dosage decitabine treatment (15 mg/M2/day intravenously for five consecutive days every four weeks). Fifty-three out of the 79 patients were defined as intermediate-2/high risk by international prognostic scoring system (IPSS) risk category. 67.1% of MDS patients achieved treatment response including complete response (CR) (n = 23), Partial response (n = 1), marrow CR (mCR) with hematological improvement (HI) (n = 11), mCR without HI (n = 11) and HI alone (n = 7) with a median of 4 courses (range 1–11). The median overall survival (OS) was 18.0 months. The median OS was 22.0, 17.0 and 12.0 months in the patients with CR, those with other response, and those without response, respectively. In addition, this regimen contributed to zero therapy-related death and punctual course delivery, although III or IV grade of cytopenia was frequently observed. In conclusion, the 15 mg/M2/d×5 day decitabine regimen was effective and safe for Chinese MDS patients with IPSS score of 0.5 or higher.
doi:10.1371/journal.pone.0095473
PMCID: PMC3991661  PMID: 24748149
4.  DNA methylation study of fetus genome through a genome-wide analysis 
BMC Medical Genomics  2014;7:18.
Background
DNA methylation is a crucial epigenetic modification of the genome which is involved in embryonic development, transcription, chromatin structure, X chromosome inactivation, genomic imprinting and chromosome stability. Consistent with these important roles, DNA methylation has been demonstrated to be required for vertebrate early embryogenesis and essential for regulating temporal and spatial expression of genes controlling cell fate and differentiation. Further studies have shown that abnormal DNA methylation is associated with human diseases including the embryonic development diseases. We attempt to study the DNA methylation status of CpG islands in fetus related to fetus growth and development.
Methods
GeneChip® Human Tiling 2.0R Array set is used for analysis of methylated DNA in a whole-genome wide in 8 pairs amniotic fluid and maternal blood DNA samples.
Results
We found 1 fetus hypermethylation DNA markers and 4 fetus hypomethylation DNA markers though a Genome-wide analysis. These DNA markers all found to be associated with the critical genes for fetus growth and development (SH2D3C gene, EML3 gene, TRIM71 gene, HOXA3 gene and HOXA5 gene).
Conclusions
These genes can be used as a biomarker for association studying of embryonic development, pathological pregnancy and so on. The present study has provided new and fundamental insights into the roles that DNA methylation has in embryonic development and in the pathological pregnancy.
doi:10.1186/1755-8794-7-18
PMCID: PMC3996908  PMID: 24731722
DNA methylation; Fetus; GeneChip® human tiling 2.0R array set; Clone sequencing; Embryonic development
5.  Gene silencing of β-galactosamide α-2,6-sialyltransferase 1 inhibits human influenza virus infection of airway epithelial cells 
BMC Microbiology  2014;14:78.
Background
Human influenza virus hemagglutinin prefers to use sialic acid (SA) receptors via α-2,6 linkages. The β-galactoside α-2,6-sialyltransferase I (ST6Gal I) protein is encoded by the ST6GAL1 gene and is responsible for the addition of α-2,6 linked SA to the Galβ1-4GlcNAc disaccharide of glycans and glycoproteins found on the cellular surface. Therefore, ST6GAL1 could be a potential target for anti-influenza therapeutics. We used specific small interfering RNAs (siRNAs) to block expression of ST6GAL1 and limit distribution of SA receptors on the surface of airway epithelial cells.
Results
The siRNA duplexes we used inhibited ST6GAL1 mRNA expression and subsequent expression of the encoding protein. As a result, synthesis of α-2,6 SA galactose was inhibited. Adsorption of influenza virus particles to the surface of cells transfected with appropriate specific siRNAs was significantly reduced. Intracellular viral genome copy number and virus titer within the supernatant of cells transfected with siRNAs was significantly reduced in a dose-dependent manner compared with those for untransfected cells and cells transfected with non-specific siRNAs.
Conclusions
We used siRNAs targeting ST6GAL1 to inhibit the expression of certain cell surface receptors, thereby preventing virus adsorption. This resulted in the inhibition of human influenza virus infection. Our findings are a significant development in the identification of potential new anti-influenza drug targets.
doi:10.1186/1471-2180-14-78
PMCID: PMC3986885  PMID: 24670114
Influenza virus; Receptors; Sialyltransferase; RNAi
6.  Hepatitis B Virus Polymerase Suppresses NF-κB Signaling by Inhibiting the Activity of IKKs via Interaction with Hsp90β 
PLoS ONE  2014;9(3):e91658.
Nuclear factor-κB (NF-κB) plays a central role in the regulation of diverse biological processes, including immune responses, development, cell growth, and cell survival. To establish persistent infection, many viruses have evolved strategies to evade the host’s antiviral immune defenses. In the case of hepatitis B virus (HBV), which can cause chronic infection in the liver, immune evasion strategies used by the virus are not fully understood. It has recently been reported that the polymerase of HBV (Pol) inhibits interferon-β (IFN-β) activity by disrupting the interaction between IKKε and the DDX3. In the current study, we found that HBV Pol suppressed NF-κB signaling, which can also contribute to IFN-β production. HBV Pol did not alter the level of NF-κB expression, but it prevented NF-κB subunits involved in both the canonical and non-canonical NF-κB pathways from entering the nucleus. Further experiments demonstrated that HBV Pol preferentially suppressed the activity of the IκB kinase (IKK) complex by disrupting the association of IKK/NEMO with Cdc37/Hsp90, which is critical for the assembly of the IKK complex and recruitment of the IKK complex to the tumor necrosis factor type 1 receptor (TNF-R1). Furthermore, we found that HBV Pol inhibited the NF-κB-mediated transcription of target genes. Taken together, it is suggested that HBV Pol could counteract host innate immune responses by interfering with two distinct signaling pathways required for IFN-β activation. Our studies therefore shed light on a potential therapeutic target for persistent infection with HBV.
doi:10.1371/journal.pone.0091658
PMCID: PMC3950214  PMID: 24618592
7.  Phosphodiesterase 3A rs7134375 single nucleotide polymorphism and serum lipid levels 
Molecular Medicine Reports  2014;9(5):1618-1628.
The association between the phosphodiesterase 3A (PDE3A) rs7134375 single nucleotide polymorphism (SNP) and serum lipid levels are not well understood in the general population. The present study was performed in order to detect the association between the rs7134375 SNP and serum lipid levels in the Guangxi Mulao and Han populations. The genotypes of the PDE3A rs7134375 SNP in 761 subjects of the Mulao population and 774 subjects of the Han Chinese population were determined by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. It was observed that serum low-density lipoprotein cholesterol and apolipoprotein B levels were higher in the Mulao population than in the Han population (P<0.05 for each). The frequencies of the C and A alleles were 72.14 and 27.86% in the Mulao population, and 78.55 and 21.45% in the Han population (P<0.01), respectively. The frequencies of the CC, CA and AA genotypes were 52.04, 40.21 and 7.75% in the Mulao population, and 61.50, 34.11 and 4.39% in the Han population (P<0.01), respectively. The frequencies of the C and A alleles were 74.89 and 25.11% in Mulao females, and 68.08 and 31.92% in Mulao males (P<0.01), respectively. The serum triglyceride (TG) levels were different among the genotypes in the Mulao population; however, not in the Han population (P<0.01), and the A allele carriers exhibited lower TG levels than the A allele noncarriers. The serum lipid parameters were also correlated with several environmental factors in the two ethnic groups (P<0.05-0.001). It was concluded that the genotypic and allelic frequencies of the rs7134375 SNP are different between the Mulao and Han populations. In addition, the PDE3A rs7134375 SNP is associated with serum TG levels in the Mulao population, however, not in the Han population.
doi:10.3892/mmr.2014.2007
PMCID: PMC4020489  PMID: 24604378
phosphodiesterase 3A gene; single nucleotide polymorphism; lipids; apolipoproteins
8.  Association between Single Nucleotide Polymorphism rs1044925 and the Risk of Coronary Artery Disease and Ischemic Stroke 
The present study was performed to clarify the association between the acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) single nucleotide polymorphism (SNP) rs1044925 and the risk of coronary artery disease (CAD) and ischemic stroke (IS) in the Guangxi Han population. Polymerase chain reaction and restriction fragment length polymorphism was performed to determine the genotypes of the ACAT-1 SNP rs1044925 in 1730 unrelated subjects (CAD, 587; IS, 555; and healthy controls; 588). The genotypic and allelic frequencies of rs1044925 were significantly different between the CAD patients and controls (p = 0.015) and borderline different between the IS patients and controls (p = 0.05). The AC/CC genotypes and C allele were associated with a decreased risk of CAD and IS (CAD: p = 0.014 for AC/CC vs. AA, p = 0.022 for C vs. A; IS: p = 0.014 for AC/CC vs. AA; p = 0.017 for C vs. A). The AC/CC genotypes in the healthy controls, but not in CAD or IS patients, were associated with an increased serum high-density lipoprotein cholesterol (HDL-C) concentration. The present study shows that the C allele carriers of ACAT-1 rs1044925 were associated with an increased serum HDL-C level in the healthy controls and decreased risk in CAD and IS patients.
doi:10.3390/ijms15033546
PMCID: PMC3975353  PMID: 24577316
acyl-CoA:cholesterol acyltransferase gene; single nucleotide polymorphism; coronary artery disease; ischemic stroke; lipids
9.  Luteoloside Suppresses Proliferation and Metastasis of Hepatocellular Carcinoma Cells by Inhibition of NLRP3 Inflammasome 
PLoS ONE  2014;9(2):e89961.
The inflammasome is a multi-protein complex which when activated regulates caspase-1 activation and IL-1β secretion. Inflammasome activation is mediated by NLR proteins that respond to stimuli. Among NLRs, NLRP3 senses the widest array of stimuli. NLRP3 inflammasome plays an important role in the development of many cancer types. However, Whether NLRP3 inflammasome plays an important role in the process of hepatocellular carcinoma (HCC) is still unknown. Here, the anticancer effect of luteoloside, a naturally occurring flavonoid isolated from the medicinal plant Gentiana macrophylla, against HCC cells and the underlying mechanisms were investigated. Luteoloside significantly inhibited the proliferation of HCC cells in vitro and in vivo. Live-cell imaging and transwell assays showed that the migration and invasive capacities of HCC cells, which were treated with luteoloside, were significantly inhibited compared with the control cells. The inhibitory effect of luteoloside on metastasis was also observed in vivo in male BALB/c-nu/nu mouse lung metastasis model. Further studies showed that luteoloside could significantly reduce the intracellular reactive oxygen species (ROS) accumulation. The decreased levels of ROS induced by luteoloside was accompanied by decrease in expression of NLRP3 inflammasome resulting in decrease in proteolytic cleavage of caspase-1. Inactivation of caspase-1 by luteoloside resulted in inhibition of IL-1β. Thus, luteoloside exerts its inhibitory effect on proliferation, invasion and metastasis of HCC cells through inhibition of NLRP3 inflammasome. Our results indicate that luteoloside can be a potential therapeutic agent not only as an adjuvant therapy for HCC, but also, in the control and prevention of metastatic HCC.
doi:10.1371/journal.pone.0089961
PMCID: PMC3935965  PMID: 24587153
10.  Establishment and Validation of an Updated Diagnostic FCM Scoring System Based on Pooled Immunophenotyping in CD34+ Blasts and Its Clinical Significance for Myelodysplastic Syndromes 
PLoS ONE  2014;9(2):e88706.
Abnormal immunophenotypes of hematopoietic cells can be detected by flow cytometry (FCM) to assist the diagnosis of myelodysplastic syndromes (MDS). We previously established a FCM scoring system for the diagnosis of low-grade MDS. In this study, additional valuable antigens were involved in an updated FCM scoring system (u-FCMSS) for all MDS subtypes. The u-FCMSS showed better sensitivity and specificity (89.4% and 96.5%) in distinguishing MDS from non-clonal cytopenia diseases. Validation analysis of u-FCMSS exhibited comparable sensitivity and specificity (86.7% and 93.3%) and high agreement rate (88.9%) of FCM diagnosis with morphological diagnosis at optimal cut-off (score 3). The distribution of FCM scores in different disease stages was also analyzed. The results suggested that early scoring from abnormal expression of mature myeloid/lymphoid antigens and advanced scoring from abnormal expression of stem/progenitor antigens expression constituted the majority of FCM scores of low-grade and high-grade MDS, respectively. High early scoring was generally accompanied by low IPSS-R score and superior survival, whereas high advanced scoring was accompanied by high IPSS-R score and inferior survival. In addition, the low-risk MDS patients with high early scoring and low advanced scoring were revealed as candidates for immunosuppressive therapy, whereas those with high advanced scoring and low early scoring may be more suitable for decitabine treatment. In conclusion, the u-FCMSS is a useful tool for diagnosis, prognosis and treatment selection in MDS. Differences in classes of antigens expressed and in distribution of FCM scores may reflect distinctive stage characteristics of MDS during disease progression.
doi:10.1371/journal.pone.0088706
PMCID: PMC3928275  PMID: 24558415
11.  Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia 
Chinese Journal of Cancer  2014;33(2):80-86.
Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.
doi:10.5732/cjc.012.10285
PMCID: PMC3935009  PMID: 23845143
Bioreductive; prodrug; tumor hypoxia; clinical trial; oxidoreductase
12.  Evaluation of Varying Ductile Fracture Criteria for 42CrMo Steel by Compressions at Different Temperatures and Strain Rates 
The Scientific World Journal  2014;2014:579328.
Fracturing by ductile damage occurs quite naturally in metal forming processes, and ductile fracture of strain-softening alloy, here 42CrMo steel, cannot be evaluated through simple procedures such as tension testing. Under these circumstances, it is very significant and economical to find a way to evaluate the ductile fracture criteria (DFC) and identify the relationships between damage evolution and deformation conditions. Under the guidance of the Cockcroft-Latham fracture criteria, an innovative approach involving hot compression tests, numerical simulations, and mathematic computations provides mutual support to evaluate ductile damage cumulating process and DFC diagram along with deformation conditions, which has not been expounded by Cockcroft and Latham. The results show that the maximum damage value appears in the region of upsetting drum, while the minimal value appears in the middle region. Furthermore, DFC of 42CrMo steel at temperature range of 1123~1348 K and strain rate of 0.01~10 s−1 are not constant but change in a range of 0.160~0.226; thus, they have been defined as varying ductile fracture criteria (VDFC) and characterized by a function of temperature and strain rate. In bulk forming operations, VDFC help technicians to choose suitable process parameters and avoid the occurrence of fracture.
doi:10.1155/2014/579328
PMCID: PMC3925567  PMID: 24592175
13.  Sex-specific Association of the Zinc Finger Protein 259 rs2075290 Polymorphism and Serum Lipid Levels 
Background: Little is known about the association of ZNF259 rs2075290 single nucleotide polymorphism (SNP) and serum lipid levels in the Chinese population. This study aimed to detect the association of ZNF259 rs2075290 SNP and environmental factors with serum lipid levels between males and females in the Mulao and Han populations.
Methods and Results: Genotyping of ZNF259 rs2075290 SNP was performed in 788 of Mulao and 778 of Han participants using polymerase chain reaction and restriction fragment length polymorphism. The genotype frequencies were significantly different between Mulao and Han populations (AA, 50.1% Vs 58.9%; AG, 42.3% Vs 35.7%; GG, 7.6% Vs 5.4%, P = 0.002) and between Han males and females (AA, 64.5% Vs 55.2%; AG, 28.3% Vs 40.6%; GG, 7.2% Vs 4.2%, P = 0.001). Serum levels of triglyceride (TG) in Mulao males, and total cholesterol (TC), TG and low-density lipoprotein cholesterol (LDL-C) in Mulao females were different between the AA and AG/GG genotypes (P < 0.05-0.001). Serum TC, LDL-C and apolipoprotein (Apo) A1 levels in Han males, and TG and ApoB levels and ApoA1/ApoB ratio in Han females were different between the AA and AG/GG genotypes (P < 0.05-0.001). An interaction between ZNF259 rs2075290 polymorphism and male gender on serum TC, LDL-C, and ApoA1 levels was noted in Han population (P < 0.05-0.01) but not in Mulao's.
Conclusions: The subjects with AG/GG genotype in Mulao males and females and Han females have less favorable lipid profiles than those with AA genotype. In contrast, the subjects with AG/GG genotype in Han males have more favorable lipid profiles than those with AA genotype. These findings suggest that the association between ZNF259 rs2075290 SNP and serum lipid levels might have ethnic- and/or sex-specificity.
doi:10.7150/ijms.8489
PMCID: PMC3970100  PMID: 24688311
lipids; sex-specific association; zinc finger protein 259 (ZNF259); single nucleotide polymorphism; environmental factors.
14.  Ethyl Pyruvate Ameliorates Hepatic Ischemia-Reperfusion Injury by Inhibiting Intrinsic Pathway of Apoptosis and Autophagy 
Mediators of Inflammation  2013;2013:461536.
Background. Hepatic ischemia-reperfusion (I/R) injury is a pivotal clinical problem occurring in many clinical conditions such as transplantation, trauma, and hepatic failure after hemorrhagic shock. Apoptosis and autophagy have been shown to contribute to cell death in hepatic I/R injury. Ethyl pyruvate, a stable and simple lipophilic ester, has been shown to have anti-inflammatory properties. In this study, the purpose is to explore both the effect of ethyl pyruvate on hepatic I/R injury and regulation of intrinsic pathway of apoptosis and autophagy. Methods. Three doses of ethyl pyruvate (20 mg/kg, 40 mg/kg, and 80 mg/kg) were administered 1 h before a model of segmental (70%) hepatic warm ischemia was established in Balb/c mice. All serum and liver tissues were obtained at three different time points (4 h, 8 h, and 16 h). Results. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and pathological features were significantly ameliorated by ethyl pyruvate (80 mg/kg). The expression of Bcl-2, Bax, Beclin-1, and LC3, which play an important role in the regulation of intrinsic pathway of apoptosis and autophagy, was also obviously decreased by ethyl pyruvate (80 mg/kg). Furthermore, ethyl pyruvate inhibited the HMGB1/TLR4/ NF-κb axis and the release of cytokines (TNF-α and IL-6). Conclusion. Our results showed that ethyl pyruvate might attenuate to hepatic I/R injury by inhibiting intrinsic pathway of apoptosis and autophagy, mediated partly through downregulation of HMGB1/TLR4/ NF-κb axis and the competitive interaction with Beclin-1 of HMGB1.
doi:10.1155/2013/461536
PMCID: PMC3886226  PMID: 24453420
15.  Association of the KLF14 rs4731702 SNP and Serum Lipid Levels in the Guangxi Mulao and Han Populations 
BioMed Research International  2013;2013:231515.
The objective of the present study was to detect the association of the rs4731702 single nucleotide polymorphism (SNP) and serum lipid levels in the Guangxi Mulao and Han populations. A total of 727 subjects of Mulao and 740 subjects of Han Chinese were included. Serum low-density lipoprotein cholesterol (LDL-C) and apolipoprotein (Apo) B levels were higher in Mulao than in Han (P < 0.05). The T allele carriers had higher serum LDL-C and ApoAI levels in Mulao, whereas they had lower high-density lipoprotein cholesterol (HDL-C) levels and ratio of ApoAI to ApoB in Han (P < 0.05) than the T allele noncarriers. Subgroup analyses showed that the T allele carriers had higher HDL-C, LDL-C, and ApoAI levels in Mulao males and lower ApoAI levels and ratio of ApoAI to ApoB in Han males than the T allele noncarriers. The subjects with TT genotype in Han females also had higher total cholesterol, LDL-C, ApoAI, and ApoB levels than the subjects with CT or CC genotype. Serum lipid parameters were also correlated with several environmental factors in both ethnic groups. The differences in the association of KLF14 rs4731702 SNP and serum lipid levels between the two ethnic groups might partly result from different gene-environmental interactions.
doi:10.1155/2013/231515
PMCID: PMC3806325  PMID: 24195066
16.  Inhibition of Endoplasmic Reticulum Stress and Atherosclerosis by 2-Aminopurine in Apolipoprotein E-Deficient Mice 
ISRN Pharmacology  2013;2013:847310.
We previously reported that the apolipoprotein (apo) B48-carrying lipoproteins obtained from apoE knockout (apoE−/−) mice, so called E−/B48 lipoproteins, transformed mouse macrophages into foam cells and enhanced the phosphorylation of eukaryotic translation initiation factor 2α (eIF-2α). Furthermore, the eIF-2α phosphorylation inhibitor, 2-aminopurine (2-AP), attenuated E−/B48 lipoprotein-induced foam cell formation. The present report studied the effect of 2-AP on atherosclerosis in apoE−/− mice. Our results showed that the level of food intake, bodyweight, plasma cholesterol, and triglycerides was comparable in apoE−/− mice treated with or without 2-AP. However, the mean size of atherosclerotic lesions in the aorta sinus as well as the surface area of the entire aorta of 2-AP-treated apoE−/− mice were reduced by about 55% and 39%, respectively, compared to samples from untreated control apoE−/− mice. In addition, the 2-AP-treated apoE−/− mice showed a significant decrease in glucose-regulated protein 78 (GRP78) and phosphorylated eIF-2α in their aortic samples as compared to levels in untreated control apoE−/− mice. These observations suggest that endoplasmic reticulum stress is a causal mechanism for the development of atherosclerosis in apoE−/− mice and that therapeutic strategies can be developed for using eIF-2α phosphorylation inhibitors, such as 2-AP, to prevent or treat atherosclerosis.
doi:10.1155/2013/847310
PMCID: PMC3747385  PMID: 23984090
17.  Characterizing Venous Vasculatures of Hepatocellular Carcinoma Using a Multi-Breath-Hold Two-Dimensional Susceptibility Weighted Imaging 
PLoS ONE  2013;8(6):e65895.
The aim of our study is to characterize the venous vasculatures of hepatocellular carcinoma (HCC) using a multi-breath-hold two-dimensional (2D) susceptibility weighted imaging (SWI) in comparison with conventional Magnetic Resonance Imaging (MRI) sequences. Twenty-nine patients with pathologically confirmed HCC underwent MR examination at a 3.0 T scanner. The number of venous vascularity in or around the lesion was counted and the image quality was subjectively evaluated by two experienced radiologists independently based on four image sets: 1) SWI, 2) T1-weighted sequence, 3) T2-weighted sequence, and 4) T1-weighted dynamic contrast-enhanced (DCE) sequence. Of the 29 patients, a total of 33 liver lesions were detected by both SWI and conventional MR sequences. In the evaluation of the conspicuity of venous vascularity, a mean of 10.7 tumor venous vessels per mass was detected by the SWI and 3.9 tumor vasculatures were detected by T1-weighted DCE (P<0.0001), while none was detected by T1-, T2-weighted sequences. The Pearson correlation coefficients between the lesion sizes and the number of tumor vasculatures detected by T1-weighted DCE was 0.708 (P<0.001), and 0.883 by SWI (P<0.001). Our data suggest that SWI appears to be a more sensitive tool compared to T1-weighted DCE sequence to characterize venous vasculature in liver lesions.
doi:10.1371/journal.pone.0065895
PMCID: PMC3683022  PMID: 23799060
18.  A clinical trial report of autologous bone marrow-derived mesenchymal stem cell transplantation in patients with spinal cord injury 
Spinal cord injury (SCI) is a severe neurological disease. An effective strategy for the treatment of SCI is urgently required. Stem cell transplantation has emerged as a viable therapeutic option with great potential for restoring neurological function lost following SCI. From 2009 to 2010, a total of 20 SCI patients were enrolled in a clinical trial by Wuhan Hongqiao Brain Hospital; all patients completed and signed informed consent prior to autologous bone marrow-derived mesenchymal stem cell transplantation. Analysis of subsequent treatment results indicated significant improvements in sensory, motor and autonomic nerve function as assessed by the American Spinal Injury Association’s impairment scale. Thirty days after transplantation, a total of 15 patients (75%) demonstrated improvement, including four of the eight patients (50%) with grade A SCI, three of the four patients (75%) with grade B injury and all eight patients (100%) with grade C injury. The most common adverse events, fever and headache, disappeared within 24–48 h without treatment.
doi:10.3892/etm.2013.1083
PMCID: PMC3735529  PMID: 23935735
spinal cord injury; autologous bone marrow-derived mesenchymal stem cells; human bone marrow-derived mesenchymal stem cells; clinical trial
19.  Evidence of recent natural selection on the Southeast Asian deletion (--SEA) causing α-thalassemia in South China 
Background
The Southeast Asian deletion (--SEA) is the most commonly observed mutation among diverse α-thalassemia alleles in Southeast Asia and South China. It is generally argued that mutation --SEA, like other variants causing hemoglobin disorders, is associated with protection against malaria that is endemic in these regions. However, little evidence has been provided to support this claim.
Results
We first examined the genetic imprint of recent positive selection on the --SEA allele and flanking sequences in the human α-globin cluster, covering a genomic region spanning ~410 kb, by genotyping 28 SNPs in a Chinese population consisting of 76 --SEA heterozygotes and 138 normal individuals. The pattern of linkage disequilibrium (LD) and the long-range haplotype test revealed a signature of positive selection. The network of inferred haplotypes suggested a single origin of the --SEA allele.
Conclusions
Thus, our data support the hypothesis that the --SEA allele has been subjected to recent balancing selection, triggered by malaria.
doi:10.1186/1471-2148-13-63
PMCID: PMC3626844  PMID: 23497175
20.  Glomus tumor in the stomach: Computed tomography and endoscopic ultrasound findings 
A 57-year-old man presented with intermittent dull abdominal pain after a period of 1 year. Abdominal computed tomography (CT) was performed. Except for the endoscopy, the work-up for possible medical causes remained inconclusive. An open-abdomen, partial surgical excision of the stomach was performed after the unsuccessful endoscopic resection. The pathology report revealed a glomus tumor of the stomach. Importantly, glomus tumors of the stomach are rare and are almost always benign. Therefore, the most important current role of imaging associated with the diagnostic approach and therapeutic plan for a glomus tumor is to differentiate it from other gastric submucosal tumors (SMTs). We report this case with representative radiologic findings, including CT and endoscopic ultrasound (EUS) reports, and also correlate them with clinical and pathologic presentations that can help in the early detection and differentiation of gastric SMTs from other SMTs. As such, the purpose of this report is to provide a better understanding of relevant CT and EUS features. Alternative treatments should be considered carefully according to the imaging results.
doi:10.3748/wjg.v19.i8.1327
PMCID: PMC3587493  PMID: 23482388
Glomus tumor; Stomach; Diagnosis; Therapy
21.  Polymorphic Expression of UDP-Glucuronosyltransferase UGTlA Gene in Human Colorectal Cancer 
PLoS ONE  2013;8(2):e57045.
Background
Polymorphism of genes encoding drug-metabolizing enzymes is known to play an important role in increased susceptibility of colorectal cancer. UGT1A gene locus has been suggested to define tissue-specific glucuronidation activity. Reduced capacity of glucuronidation is correlated with the development of colorectal cancer. Therefore, we sought to explore polymorphism of UGTlA gene in human colorectal cancer.
Methods
Cancerous and healthy tissues were obtained from selectedpatients. Blood samples were collected and UGTlA mRNA transcriptions were analyzed. Genomic DNA was prepared and UGTlA8 exon-1 sequences were amplified, visualized and purified. The extracted DNA was subcloned and sequenced. Two-tailed Fisher's exact test, Odds ratios (ORs), confidence interval (CIs) and Logistics Regression Analysis were used for statistical analysis.
Results
UGTlA mRNA expression was reduced in cancerous tissues compared with healthy tissues from the same patient . The UGTlA mRNA expression of healthy tissue in study patients was lower than control . The mRNA expression of cancerous tissue was down-regulated in UGTlAl, 1A3, 1A4, lA6, 1A9 and up-regulated in UGTlA8 and UGTlAl0 UGT1A5 and UGT1A7 were not expressed in colonic tissue of either group. The allele frequency of WT UGTlA8*1 was higher (p = 0.000), frequency of UGTlA8*3 was lowered in control group (p = 0.000). The expression of homozygous UGTlA8*1 was higher in control group (p = 0.000). Higher frequency of both heterozygous UGTlA8*1/*3 and UGTlA8*2/*3 were found in study group (p = 0.000; p = 0.000). The occurrence of colorectal cancer was mainly related to the presence of polymorphic UGTlA8*3 alleles (p = 0.000).
Conclusion
Regulation of human UGT1A genes is tissue-specific. Individual variation in polymorphic expressions of UGTlA gene locus was noted in all types of colonic tissue tested, whereas hepatic tissue expression was uniform. The high incidence of UGTlA8 polymorphism exists in colorectal cancer patients. UGTlA8*1 allele is a protective factor and UGTlA8*3 allele is a risk factor.
doi:10.1371/journal.pone.0057045
PMCID: PMC3584141  PMID: 23468910
22.  Computational Approach to Seasonal Changes of Living Leaves 
This paper proposes a computational approach to seasonal changes of living leaves by combining the geometric deformations and textural color changes. The geometric model of a leaf is generated by triangulating the scanned image of a leaf using an optimized mesh. The triangular mesh of the leaf is deformed by the improved mass-spring model, while the deformation is controlled by setting different mass values for the vertices on the leaf model. In order to adaptively control the deformation of different regions in the leaf, the mass values of vertices are set to be in proportion to the pixels' intensities of the corresponding user-specified grayscale mask map. The geometric deformations as well as the textural color changes of a leaf are used to simulate the seasonal changing process of leaves based on Markov chain model with different environmental parameters including temperature, humidness, and time. Experimental results show that the method successfully simulates the seasonal changes of leaves.
doi:10.1155/2013/619385
PMCID: PMC3596921  PMID: 23533545
23.  Differential mRNA Expression Levels of Human Histone-Modifying Enzymes in Normal Karyotype B Cell Pediatric Acute Lymphoblastic Leukemia 
Histone modification enzymes regulate gene expression by altering the accessibility of promoters to transcription factors. We sought to determine whether the genes encoding histone modification enzymes are dysregulated in pediatric acute lymphoblastic leukemia (ALL). A real-time PCR array was designed, tested and used to profile the expression of 85 genes encoding histone modification enzymes in bone marrow mononuclear cells from 30 pediatric ALL patients and 20 normal controls. The expression profile of histone-modifying genes was significantly different between normal karyotype B cell pediatric ALL and normal controls. Eleven genes were upregulated in pediatric ALL, including the histone deacetylases HDAC2 and PAK1, and seven genes were downregulated, including PRMT2 and the putative tumor suppressor EP300. Future studies will seek to determine whether these genes serve as biomarkers of pediatric ALL. Ingenuity Pathway Analysis revealed that Gene Expression and Organ Morphology was the highest rated network, with 13 focus molecules (significance score = 35). Ingenuity Pathway Analysis also indicated that curcumin and miR-34 are upstream regulators of histone-modifying enzymes; future studies will seek to validate these results and examine the role of curcumin and miR-34 in leukemia. This study provides new clues into the molecular mechanisms of pediatric ALL.
doi:10.3390/ijms14023376
PMCID: PMC3588049  PMID: 23389039
histone-modifying enzymes; pediatric acute lymphoblastic leukemia; real-time PCR array
24.  Proprotein Convertase Subtilisin/Kexin Type 9 Gene E670G Polymorphism Interacts with Alcohol Consumption to Modulate Serum Lipid Levels 
Backgroud: Both alcohol consumption and the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene polymorphism modulate serum lipid levels, but their interactions on serum lipid profiles are still unknown. The present study was undertaken to detect the interactions of PCSK9 E670G polymorphism and alcohol consumption on serum lipid levels.
Methods: Genotypes of the PCSK9 E670G in 1352 unrelated subjects (785 non-drinkers and 567 drinkers) were determined by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. The interactions between PCSK9 E670G genotypes and alcohol consumption on serum lipid parameters were detected by using a factorial design covariance analysis after controlling for potential confounders.
Results: The levels of serum triglyceride, high-density lipoprotein cholesterol, apolipoprotein (Apo) A1, and the ratio of ApoA1 to ApoB were higher in drinkers than in non-drinkers (P < 0.01 for all), whereas the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and ApoB were lower in drinkers than in non-drinkers (P < 0.001 for all). The genotypic and allelic frequencies of PCSK9 E670G were not different between non-drinkers and drinkers (P > 0.05 for each). The subjects with AA genotype in non-drinkers had higher serum LDL-C levels than the subjects with AG genotype, whereas the subjects with AG genotype in drinkers had higher serum TC levels than the subjects with AA genotypes (P < 0.05 for each). The effects of alcohol consumption on TC and LDL-C levels depended upon genotypes, the subjects with AA genotype had lower serum TC and LDL-C levels in drinkers than in non-drinkers.
Conclusions: Alcohol consumption can modify the effects of the PCSK9 E670G polymorphism on serum TC and LDL-C levels. The subjects with AA genotype of the PCSK9 E670G benefit more from alcohol consumption than the subjects with AG genotype in decreasing serum TC and LDL-C levels.
doi:10.7150/ijms.5296
PMCID: PMC3547209  PMID: 23329883
proprotein convertase subtilisin/kexin type 9 gene; polymorphism; alcohol consumption; lipids; interaction.
25.  Scavenger Receptor Class B Type 1 Gene rs5888 Single Nucleotide Polymorphism and the Risk of Coronary Artery Disease and Ischemic Stroke: A Case-Control Study 
Background: Our previous studies have showed that the rs5888 single nucleotide polymorphism (SNP) in Scavenger receptor class B type 1 (SCARB1) gene is associated with serum lipid levels in the general Chinese populations. The present study was undertaken to detect the associations between rs5888 SNP and the risk of coronary artery disease (CAD) and ischemic stroke (IS).
Methods: A total of 1,716 unrelated subjects (CAD, 601; IS, 533; and healthy controls, 582) were included in this study. Genotyping of the rs5888 SNP were determined by polymerase chain reaction and restriction fragment length polymorphism.
Results: The genotypic frequencies of SCARB1 rs5888 SNP were different between CAD patients and controls, the subjects with TT genotype had high risk of CAD (OR = 1.76, P = 0.038 for TT vs. CC; and OR = 1.75, P = 0.036 for TT vs. CC/CT). There was no significant association between genotypes and the risk of IS. Further analysis showed that the subjects with TT genotype in the total population had lower levels of high-density lipoprotein cholesterol than the subjects with CC/CT genotypes (P < 0.05), the subjects with TT genotype in controls but not in CAD or IS patients had higher levels of serum LDL-C and ApoB than those with CC genotype (P < 0.05 for each).
Conclusions: The present study suggests that the SCARB1 rs5888 SNP influences serum lipid levels, and is associated with the risk of CAD.
doi:10.7150/ijms.7044
PMCID: PMC3804801  PMID: 24151447
Scavenger receptor class B type 1 gene; Single nucleotide polymorphism; Coronary artery disease; Ischemic stroke; Lipid

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