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1.  Non-medical use of prescription pain relievers among high school students in China: a multilevel analysis 
BMJ Open  2015;5(7):e007569.
Given the differences between general high school (GHS) and vocational high school (VHS) students, this study aimed to investigate the lifetime prevalence of non-medical use of prescription pain relievers (NMUPPR) among high school students as well as the associations between NMUPPR and individual-level factors and school category.
A cross-sectional study was conducted in GHS and VHS students in 2012 in Chongqing, and 11 906 students’ questionnaires were completed and qualified for the survey. Self-reported NMUPPR and information regarding individual-level determinants and school category were collected. A multilevel multivariate logistic regression model was fitted to explore independent predictors of NMUPPR.
The total lifetime prevalence of NMUPPR was 11.3%, and NMUPPR was more prevalent among VHS students (15.8%) compared with GHS students (9.8%). Overall, the results indicated that VHS students were more likely to be involved in NMUPPR (adjusted OR (AOR)=1.64, 95% CI 1.42 to 1.89). Regarding the individual-level predictors of NMUPPR, below-average family economic status was negatively correlated with NMUPPR (AOR=0.77, 95% CI 0.60 to 0.98), and students with more pocket money were more likely to be engaged in NMUPPR. Students who had difficult family relationships, had poor relationships with teachers, had parents or friends who engaged in non-medical prescription drug use, and considered or attempted suicide were more likely to be engaged in NMUPPR.
NMUPPR among high school students is a multidetermined phenomenon. The current findings indicate that VHS students are an important subgroup of adolescents and highlight the need for additional research as well as targeted prevention and intervention programmes for NMUPPR.
PMCID: PMC4513537  PMID: 26169805
EPIDEMIOLOGY; EDUCATION & TRAINING (see Medical Education & Training)
2.  Laparoscopic Versus Open Colorectal Resection Within Fast Track Programs: An Update Meta-Analysis Based on Randomized Controlled Trials 
The objective of the study was to assess the safety and efficacy of laparoscopic colorectal surgery by comparing open operation within fast track (FT) programs. The Cochrane Library, PubMed, Embase and Chinese Biological Medicine Database were searched to identify all available randomized controlled trials (RCTs) comparing laparoscopic with open colorectal resection within FT programs. A total of seven RCTs were finally included, enrolling 714 patients with colorectal cancer: 373 patients underwent laparoscopic surgery and FT programs (laparoscopic/FT group) and 341 patients received open operation and FT programs (open/FT group). Postoperative hospital stay (weighted mean difference (WMD): 0.66; 95% CI: 0.27 - 1.04; P < 0.05), total hospital stay (WMD: 1.46; 95% CI: 0.40 - 2.51; P < 0.05) and overall complications (RR: 1.31; 95% CI: 1.12 - 1.54; P < 0.05) were significantly lower in laparoscopic/FT group than in open/FT group. However, no statistically significant differences on mortality (risk ratio (RR): 2.26; 95% CI: 0.62 - 8.22; P = 0.21), overall surgical complications (RR: 1.19; 95% CI: 0.94 - 1.51; P = 0.15) and readmission rates (RR: 1.33; 95% CI: 0.79 - 2.22; P = 0.28) were found between both groups. The laparoscopic colorectal surgery combined with FT programs shows high-level evidence on shortening postoperative and total hospital stay, reducing overall complications without compromising patients’ safety.
PMCID: PMC4471745  PMID: 26124904
Fast track programs; Enhanced recovery after surgery; Laparoscopic surgery; Colorectal surgery; Meta-analysis
3.  Identification of Two Novel Compound Heterozygous PTPRQ Mutations Associated with Autosomal Recessive Hearing Loss in a Chinese Family 
PLoS ONE  2015;10(4):e0124757.
Mutations in PTPRQ are associated with deafness in humans due to defects of stereocilia in hair cells. Using whole exome sequencing, we identified responsible gene of family 1572 with autosomal recessively non-syndromic hearing loss (ARNSHL). We also used DNA from 74 familial patients with ARNSHL and 656 ethnically matched control chromosomes to perform extended variant analysis. We identified two novel compound heterozygous missense mutations, c. 3125 A>G p.D1042G (maternal allele) and c.5981 A>G p.E1994G (paternal allele), in the PTPRQ gene, as the cause of recessively inherited sensorineural hearing loss in family 1572. Both variants co-segregated with hearing loss phenotype in family 1572, but were absent in 74 familial patients. Heterozygosity for c. 3125 A>G was identified in two samples from unaffected Chinese individuals (656 chromosomes). Therefore, the hearing loss in this family was caused by two novel compound heterozygous mutations in PTPRQ.
PMCID: PMC4412678  PMID: 25919374
4.  Bullying as a Risk for Poor Sleep Quality among High School Students in China 
PLoS ONE  2015;10(3):e0121602.
To determine whether involvement in bullying as a bully, victim, or bully-victim was associated with a higher risk of poor sleep quality among high school students in China.
A cross-sectional study was conducted. A total of 23,877 high school students were surveyed in six cities in Guangdong Province. All students were asked to complete the adolescent health status questionnaire, which included the Chinese version of the Pittsburgh Sleep Quality Index (PSQI) and bullying involvement. Descriptive statistics were used to evaluate sleep quality and the prevalence of school bullying. Multi-level logistic regression analyses were conducted to examine the association between being victimized and bullying others with sleep quality.
Among the 23,877 students, 6,127 (25.66%) reported having poor sleep quality, and 10.89% reported being involved in bullying behaviors. Of the respondents, 1,410 (5.91%) were pure victims of bullying, 401 (1.68%) were bullies and 784 (3.28%) were bully-victims. Frequently being involved in bullying behaviors (being bullied or bullying others) was related to increased risks of poor sleep quality compared with adolescents who were not involved in bullying behaviors. After adjusting for age, sex, and other confounding factors, the students who were being bullied (OR=2.05, 95%CI=1.81-2.32), bullied others (OR=2.30, 95%CI=1.85-2.86) or both (OR=2.58, 95%CI=2.20-3.03) were at a higher risk for poor sleep quality.
Poor sleep quality among high school students is highly prevalent, and school bullying is prevalent among adolescents in China. The present results suggested that being involved in school bullying might be a risk factor for poor sleep quality among adolescents.
PMCID: PMC4374746  PMID: 25811479
5.  The Role of Distant Mutations and Allosteric Regulation on LovD Active Site Dynamics 
Nature chemical biology  2014;10(6):431-436.
Natural enzymes have evolved to perform their cellular functions under complex selective pressures, which often require their catalytic activities to be regulated by other proteins. We contrasted a natural enzyme, LovD, which acts on a protein-bound (LovF) acyl substrate, with a laboratory-generated variant that was transformed by directed evolution to accept instead a small free acyl thioester, and no longer requires the acyl carrier protein. The resulting 29-mutant variant is 1000-fold more efficient in the synthesis of the drug simvastatin than the wild-type LovD. This is the first non-patent report of the enzyme currently used for the manufacture of simvastatin, as well as the intermediate evolved variants. Crystal structures and microsecond molecular dynamics simulations revealed the mechanism by which the laboratory-generated mutations free LovD from dependence on protein-protein interactions. Mutations dramatically altered conformational dynamics of the catalytic residues, obviating the need for allosteric modulation by the acyl carrier LovF.
PMCID: PMC4028369  PMID: 24727900
7.  Genome-Wide Association Studies Using Haplotypes and Individual SNPs in Simmental Cattle 
PLoS ONE  2014;9(10):e109330.
Recent advances in high-throughput genotyping technologies have provided the opportunity to map genes using associations between complex traits and markers. Genome-wide association studies (GWAS) based on either a single marker or haplotype have identified genetic variants and underlying genetic mechanisms of quantitative traits. Prompted by the achievements of studies examining economic traits in cattle and to verify the consistency of these two methods using real data, the current study was conducted to construct the haplotype structure in the bovine genome and to detect relevant genes genuinely affecting a carcass trait and a meat quality trait. Using the Illumina BovineHD BeadChip, 942 young bulls with genotyping data were introduced as a reference population to identify the genes in the beef cattle genome significantly associated with foreshank weight and triglyceride levels. In total, 92,553 haplotype blocks were detected in the genome. The regions of high linkage disequilibrium extended up to approximately 200 kb, and the size of haplotype blocks ranged from 22 bp to 199,266 bp. Additionally, the individual SNP analysis and the haplotype-based analysis detected similar regions and common SNPs for these two representative traits. A total of 12 and 7 SNPs in the bovine genome were significantly associated with foreshank weight and triglyceride levels, respectively. By comparison, 4 and 5 haplotype blocks containing the majority of significant SNPs were strongly associated with foreshank weight and triglyceride levels, respectively. In addition, 36 SNPs with high linkage disequilibrium were detected in the GNAQ gene, a potential hotspot that may play a crucial role for regulating carcass trait components.
PMCID: PMC4203724  PMID: 25330174
8.  Acetylation Stabilizes ATP-Citrate Lyase to Promote Lipid Biosynthesis and Tumor Growth 
Molecular cell  2013;51(4):506-518.
Increased fatty acid synthesis is required to meet the demand for membrane expansion of rapidly growing cells. ATP-citrate lyase (ACLY) is upregulated or activated in several types of cancer, and inhibition of ACLY arrests proliferation of cancer cells. Here we show that ACLY is acetylated at lysine residues 540, 546, and 554 (3K). Acetylation at these three lysine residues is stimulated by P300/calcium-binding protein (CBP)-associated factor (PCAF) acetyltransferase under high glucose and increases ACLY stability by blocking its ubiquitylation and degradation. Conversely, the protein deacetylase sirtuin 2 (SIRT2) deacetylates and destabilizes ACLY. Substitution of 3K abolishes ACLY ubiquitylation and promotes de novo lipid synthesis, cell proliferation, and tumor growth. Importantly, 3K acetylation of ACLY is increased in human lung cancers. Our study reveals a crosstalk between acetylation and ubiquitylation by competing for the same lysine residues in the regulation of fatty acid synthesis and cell growth in response to glucose.
PMCID: PMC4180208  PMID: 23932781
9.  Function of SREBP1 in the Milk Fat Synthesis of Dairy Cow Mammary Epithelial Cells 
Sterol regulatory element-binding proteins (SREBPs) belong to a family of nuclear transcription factors. The question of which is the most important positive regulator in milk fat synthesis in dairy cow mammary epithelial cells (DCMECs) between SREBPs or other nuclear transcription factors, such as peroxisome proliferator-activated receptor γ (PPARγ), remains a controversial one. Recent studies have found that mTORC1 (the mammalian target of rapamycin C1) regulates SREBP1 to promote fat synthesis. Thus far, however, the interaction between the SREBP1 and mTOR (the mammalian target of rapamycin) pathways in the regulation of milk fat synthesis remains poorly understood. This study aimed to identify the function of SREBP1 in milk fat synthesis and to characterize the relationship between SREBP1 and mTOR in DCMECs. The effects of SREBP1 overexpression and gene silencing on milk fat synthesis and the effects of stearic acid and serum on SREBP1 expression in the upregulation of milk fat synthesis were investigated in DCMECs using immunostaining, Western blotting, real-time quantitative PCR, lipid droplet staining, and detection kits for triglyceride content. SREBP1 was found to be a positive regulator of milk fat synthesis and was shown to be regulated by stearic acid and serum. These findings indicate that SREBP1 is the key positive regulator in milk fat synthesis.
PMCID: PMC4200870  PMID: 25250914
SREBPs; mTOR; dairy cow mammary epithelial cells; milk fat synthesis
10.  FEN1 -69G>A and 4150G>T polymorphisms and cancer risk in Chinese population 
Scientific Reports  2014;4:6183.
Previous studies have investigated the associations between FEN1 -69G>A (rs174538) and 4150G>T (rs4246215) polymorphisms and cancer risk in Chinese population. However, the results were controversial. We therefore carried out a meta-analysis to derive a more precise estimation of the associations. PubMed Database was systematically searched to identify potentially eligible literatures. Crude odds ratios (ORs) and their 95% confidence intervals (CIs) were used to assess the strength of associations between FEN1 -69G>A and 4150G>T polymorphisms and cancer risk in Chinese population. A total of 4 articles, including 5,108 cases and 6,382 controls, were used to evaluate the effect of the two polymorphisms on cancer risk. The pooled ORs indicated that FEN1 -69G>A and 4150G>T polymorphisms were significantly associated with cancer risk in Chinese population. In stratified analyses by cancer type, significant associations were also observed in digestive system cancer. In addition, haplotypes consisting of -69G>A and 4150G>T polymorphisms were closely associated with cancer risk. Interestingly, significantly correlation between FEN1 -69G>A polymorphism and mRNA expression was observed. In conclusion, this meta-analysis suggests that FEN1 -69G>A and 4150G>T polymorphisms may be associated with cancer susceptibility in Chinese population. However, further investigation on large population and different ethnicities are warranted.
PMCID: PMC4143769  PMID: 25154853
11.  Novel Compound Heterozygous Mutations in MYO7A Associated with Usher Syndrome 1 in a Chinese Family 
PLoS ONE  2014;9(7):e103415.
Usher syndrome is an autosomal recessive disease characterized by sensorineural hearing loss, age-dependent retinitis pigmentosa (RP), and occasionally vestibular dysfunction. The most severe form is Usher syndrome type 1 (USH1). Mutations in the MYO7A gene are responsible for USH1 and account for 29–55% of USH1 cases. Here, we characterized a Chinese family (no. 7162) with USH1. Combining the targeted capture of 131 known deafness genes, next-generation sequencing, and bioinformatic analysis, we identified two deleterious compound heterozygous mutations in the MYO7A gene: a reported missense mutation c.73G>A (p.G25R) and a novel nonsense mutation c.462C>A (p.C154X). The two compound variants are absent in 219 ethnicity-matched controls, co-segregates with the USH clinical phenotypes, including hearing loss, vestibular dysfunction, and age-dependent penetrance of progressive RP, in family 7162. Therefore, we concluded that the USH1 in this family was caused by compound heterozygous mutations in MYO7A.
PMCID: PMC4117490  PMID: 25080338
12.  Prevalence and correlates of sleep disturbance and depressive symptoms among Chinese adolescents: a cross-sectional survey study 
BMJ Open  2014;4(7):e005517.
Study objective
To investigate the prevalence and the correlates of sleep disturbance and depressive symptoms among Chinese adolescents and to examine the association between the two problems.
Cross-sectional survey.
A total of 3186 school students in grades 7–12 were sampled from the schools in Guangdong. A stratified-cluster random-sampling strategy was used to select the schools.
Main outcome measures
A self-administered questionnaire was used. The Pittsburgh Sleep Quality index (PSQI) was used to assess the occurrence of sleep disturbance, and the Center for Epidemiology Scale for Depression (CES-D) was used to identify whether individuals had depressive symptoms.
The mean PSQI global score was 8.7 (±2.4) points, and 39.6% of the total sample had sleep disturbance. The mean CES-D score of students was 15.2 (±9.4) points, and 6.4% of the students had depressive symptoms. Additionally, girls and older adolescents were more likely to suffer from sleep disturbance, and the students who had depressive symptoms were 2.47 (95% CI 1.61 to 3.79) times more likely to suffer from sleep disturbance. Factors that were correlated with sleep disturbance and depressive symptoms were having a poor relationship with teachers, feeling lonely, suicide ideation and having run away from home.
Sleep disturbance was determined to be more prevalent among Chinese adolescents with depressive symptoms. Sleep disturbance and depressive symptoms were associated with each other, while school factors, family factors and psychosocial adjustment were comprehensively correlated with both.
PMCID: PMC4120320  PMID: 25079937
13.  An Iterative, Bimodular Nonribosomal Peptide Synthetase that Converts Anthranilate and Tryptophan into Tetracyclic Asperlicins 
Chemistry & biology  2013;20(7):870-878.
The bimodular 276 kDa nonribosomal peptide synthetase AspA from Aspergillus alliaceus, heterologously expressed in Saccharomyces cerevisiae, converts tryptophan and two molecules of the aromatic β-amino acid anthranilate (Ant) into a pair of tetracyclic peptidyl alkaloids asperlicin C and D in a ratio of 10:1. The first module of AspA activates and processes two molecules of Ant iteratively to generate a tethered Ant-Ant-Trp-S-enzyme intermediate on module two. Release is postulated to involve tandem cyclizations, in which the first step is the macrocyclization of the linear tripeptidyl-S-enzyme, by the terminal condensation (CT) domain to generate the regioisomeric tetracyclic asperlicin scaffolds. Computational analysis of the transannular cyclization of the 11-membered macrocyclic intermediate shows that asperlicin C is the kinetically favored product due to the high stability of a conformation resembling the transition state for cyclization, while asperlicin D is thermodynamically more stable.
PMCID: PMC3728708  PMID: 23890005
15.  Heterologous Expression and Manipulation of Three Tetracycline Biosynthetic Pathways** 
Three and one: Three tetracycline biosynthetic pathways have been overexpressed and manipulated in heterologous host Streptomyces lividans K4-114. New tetracycline modifying enzymes have been identified through a series of gene inactivation and intermediate characterization. The collection of newly discovered tailoring enzyme and the heterologous platform will promote our understanding of tetracycline biosynthesis, as well as our performance to engineer tetracycline biosynthesis in an efficient manner.
PMCID: PMC4070387  PMID: 23024027
heterologous expression; polyketide; tetracycline; biosynthesis
16.  Complexity generation in fungal peptidyl alkaloid biosynthesis: a two-enzyme pathway to the hexacyclic MDR export pump inhibitor ardeemin 
ACS chemical biology  2013;8(4):741-748.
Ardeemins are hexacyclic peptidyl alkaloids isolated from Aspergillus fischeri as agents that block efflux of anticancer drugs by (MultiDrug Resistance) MDR export pumps. To evaluate the biosynthetic logic and enzymatic machinery for ardeemin framework assembly, we sequenced the A. fischeri genome and identified the ardABC gene cluster. Through both genetic deletions and biochemical characterizations of purified ArdA and ArdB we show this ArdAB enzyme pair is sufficient to convert anthranilate (Ant), l-Ala and l-Trp to ardeemin. ArdA is a 430 kDa trimodular nonribosomal peptide synthase (NRPS) that converts the three building blocks into a fumiquinazoline (FQ) regioisomer termed ardeemin FQ. ArdB is a prenyltransferase that takes tricyclic ardeemin FQ and dimethylallyl diphosphate to the hexacyclic ardeemin scaffold via prenylation at C2 of the Trp-derived indole moiety with intramolecular capture by an amide NH of the fumiquinazoline ring. The two-enzyme ArdAB pathway reveals remarkable efficiency in construction of the hexacyclic peptidyl alkaloid scaffold.
PMCID: PMC3631443  PMID: 23330675
17.  A Novel Mutation in the TECTA Gene in a Chinese Family with Autosomal Dominant Nonsyndromic Hearing Loss 
PLoS ONE  2014;9(2):e89240.
TECTA-related deafness can be inherited as autosomal-dominant nonsyndromic deafness (designated DFNA) or as the autosomal-recessive version. The α-tectorin protein, which is encoded by the TECTA gene, is one of the major components of the tectorial membrane in the inner ear. Using targeted DNA capture and massively parallel sequencing (MPS), we screened 42 genes known to be responsible for human deafness in a Chinese family (Family 3187) in which common deafness mutations had been ruled out as the cause, and identified a novel mutation, c.257–262CCTTTC>GCT (p. Ser86Cys; p. Pro88del) in exon 3 of the TECTA gene in the proband and his extended family. All affected individuals in this family had moderate down-sloping hearing loss across all frequencies. To our knowledge, this is the second TECTA mutation identified in Chinese population. This study demonstrates that targeted genomic capture, MPS, and barcode technology might broaden the availability of genetic testing for individuals with undiagnosed DFNA.
PMCID: PMC3931719  PMID: 24586623
18.  Rational Improvement of Simvastatin Synthase Solubility in Escherichia coli Leads to Higher Whole-cell Biocatalytic Activity 
Biotechnology and bioengineering  2009;102(1):20-28.
Simvastatin is the active pharmaceutical ingredient of the blockbuster cholesterol lowering drug Zocor. We have previously developed an Escherichia coli based whole-cell biocatalytic platform towards the synthesis of simvastatin sodium salt (SS) starting from the precursor monacolin J sodium salt (MJSS). The centerpiece of the biocatalytic approach is the simvastatin synthase LovD, which is highly prone to misfolding and aggregation when overexpressed from E. coli. Increasing the solubility of LovD without decreasing its catalytic activity can therefore elevate the performance of the whole-cell biocatalyst. Using a combination of homology structural prediction and site-directed mutagenesis, we identified two cysteine residues in LovD that are responsible for nonspecific intermolecular crosslinking, which leads to oligomer formation and protein aggregation. Replacement of Cys40 and Cys60 with alanine residues resulted in marked gain in both protein solubility and whole-cell biocatalytic activities. Further mutagenesis experiments converting these two residues to small or polar natural amino acids showed that C40A and C60N are the most beneficial, affording 27% and 26% increase in whole cell activities, respectively. The double mutant C40A/C60N combines the individual improvements and displayed ~50% increase in protein solubility and whole-cell activity. Optimized fed-batch high-cell-density fermentation of the double mutant in an E. coli strain engineered for simvastatin production quantitatively (>99%) converted 45 mM MJSS to SS within 18 hours, which represents a significant improvement over the performance of wild type LovD under identical conditions. The high efficiency of the improved whole-cell platform renders the biocatalytic synthesis of SS an attractive substitute over the existing semisynthetic routes.
PMCID: PMC3928684  PMID: 18988191
Acyltransferase; simvastatin; site-directed mutagenesis; whole-cell biocatalyst; protein solubility
19.  Genetic mutations in nonsyndromic deafness patients of Chinese minority and han ethnicities in Yunnan, China 
Each year in China, 30,000 babies are born with congenital hearing impairment. However, the molecular etiology of hearing impairment in the Yunnan Province population where more than 52 minorities live has not been thoroughly investigated. To provide appropriate genetic testing and counseling to these families, we investigated the molecular etiology of nonsyndromic deafness in this population.
Unrelated students with hearing loss (n = 235) who attended Kunming Huaxia secondary specialized school in Yunnan enrolled in this study. Three prominent deafness-related genes, GJB2, SLC26A4 and mtDNA 12S rRNA, were analyzed. High-resolution temporal bone computed tomography (CT) scan examinations were performed in 100 cases, including 16 cases with SLC26A4 gene variants, and 37 minorities and 47 Han cases without any SLC26A4 gene mutation.
The GJB2 mutation was detected in 16.67% (7/42) of minority patients and 17.62% (34/193) of Chinese Han patients (P > 0.05). 235delC was the hotspot mutation in nonsyndromic hearing loss (NSHL) patients, whereas 35delG was not found. The 431_450del19 mutation was detected for the first time in Han NSHL patients, which resulted in a premature stop codon and changed the protein. The SLC26A4 mutation was found in 9.52% (4/42) of minority patients and 9.84% (19/193) of Han Chinese patients (P > 0.05). The frequencies of mtDNA 12S rRNA mutation in minority and Han Chinese patients were 11.90% (5/42) and 7.77% (15/193; P > 0.05), respectively. Sixteen (16/23, 69.57%) patients with SLC26A4 mutations received temporal bone CT scan, and 14 patients were diagnosed with enlarged vestibular aqueducts (EVAs); the other 2 patients had normal inner ear development. The ratio of EVA in the minorities was 14.63% (6/41).
In this study, a total of 35.74% deaf patients showed evidence of genetic involvement, based on either genetic screening or family history; 17.45%, 9.79%, and 8.51% of the patients were determined to have inherited hearing impairment caused by GJB2, SLC26A4, and mtDNA 1555A > G mutations. There was no significant difference in deafness associated gene mutational spectrum and frequency between the Yunnan minority and Han patients.
PMCID: PMC3878508  PMID: 24341454
Genetic mutations; Nonsyndromic deafness; Minority; Han; Yunnan
20.  High Glucose Induced Oxidative Stress and Apoptosis in Cardiac Microvascular Endothelial Cells Are Regulated by FoxO3a 
PLoS ONE  2013;8(11):e79739.
Cardiac microvascular endothelial cells (CMECs) dysfunction contributes to cardiovascular complications in diabetes, whereas, the underlying mechanism is not fully clarified. FoxO transcription factors are involved in apoptosis and reactive oxygen species (ROS) production. Therefore, the present study was designed to elucidate the potential role of FoxO3a on the CMECs injury induced by high glucose.
Materials and Methods
CMECs were isolated from hearts of adult rats and cultured in normal or high glucose medium for 6 h, 12 h and 24 h respectively. To down-regulate FoxO3a expression, CMECs were transfected with FoxO3a siRNA. ROS accumulation and apoptosis in CMECs were assessed by dihydroethidine (DHE) staining and TUNEL assay respectively. Moreover, the expressions of Akt, FoxO3a, Bim and BclxL in CMECs were assessed by Western blotting assay.
ROS accumulation in CMECs was significantly increased after high glucose incubation for 6 to 24 h. Meanwhile, high glucose also increased apoptosis in CMECs, correlated with decreased the phosphorylation expressions of Akt and FoxO3a. Moreover, high glucose incubation increased the expression of Bim, whereas increased anti-apoptotic protein BclxL. Furthermore, siRNA target FoxO3a silencing enhanced the ROS accumulation, whereas suppressed apoptosis in CMECs. FoxO3a silencing also abolished the disturbance of Bcl-2 proteins induced by high glucose in CMECs.
Our data provide evidence that high glucose induced FoxO3a activation which suppressed ROS accumulation, and in parallel, resulted in apoptosis of CMECs.
PMCID: PMC3832590  PMID: 24260294
21.  Novel compound heterozygous mutations in the MYO15A gene in autosomal recessive hearing loss identified by whole-exome sequencing 
Inherited genetic defects play an important role in congenital hearing loss, contributing to about 60% of deafness occurring in infants. Hereditary nonsyndromic hearing loss is highly heterogeneous, and most patients with a presumed genetic etiology lack a specific molecular diagnosis.
By whole exome sequencing, we identified responsible gene of family 4794 with autosomal recessively nonsyndromic hearing loss (ARNSHL). We also used DNA from 56 Chinese familial patients with ARNSHL (autosomal recessive nonsyndromic hearing loss) and 108 ethnicity-matched negative samples to perform extended variants analysis.
We identified MYO15A c.IVS25 + 3G > A and c.8375 T > C (p.V2792A) as the disease-causing mutations. Both mutations co-segregated with hearing loss in family 4794, but were absent in the 56 index patients and 108 ethnicity-matched controls.
Our results demonstrated that the hearing loss of family 4794 was caused by novel compound heterozygous mutations in MYO15A.
PMCID: PMC3828584  PMID: 24206587
Autosomal recessive sensorineural hearing loss; Whole-exome sequencing; MYO15A
22.  Assembly of Asperlicin Peptidyl Alkaloids from Anthranilate and Tryptophan: A Two-Enzyme Pathway Generates Heptacyclic Scaffold Complexity in Asperlicin E 
Journal of the American Chemical Society  2012;134(42):17444-17447.
Members of the asperlicin family of fungal metabolites produced by Aspergillus alliaceus are known potent CCKA antagonists. Herein we report the identification of the gene cluster responsible for directing their biosynthesis. We validate and probe the pathway by genetic manipulation, and provide the first biochemical characterization of the oxidative cyclization en route to the heptacyclic asperlicin E by reconstituting the activity of the FAD depend monooxygenase AspB. This report provides the first genetic characterization of a NRPS assembly line that efficiently activates two anthranilate building blocks and illustrates the remarkably efficient biosynthesis of the complex heptacyclic asperlicin E.
PMCID: PMC3500603  PMID: 23030663
23.  Primary angiosarcoma of the small intestine with metastasis to the liver: a case report and review of the literature 
Angiosarcoma is a rare disease with a poor prognosis; significantly, patients with intestinal angiosarcomas who survive over 1 year after diagnosis are extraordinarily rare. This article describes the case of a 33-year-old gentleman who presented with abdominal pain of 4 months duration, which had increased in severity 2 weeks prior to presentation. After a complicated diagnostic and therapeutic process, the diagnosis of primary angiosarcoma of the small intestine with metastasis to the liver was made by pathological and immunohistochemical examinations. We reviewed previous cases of angiosarcoma described in the English literature to determine their risk factors, diagnosis and treatment, and we found that angiosarcoma is extremely rare, especially in the small intestine. To the best of our knowledge, this may be the youngest case of primary angiosarcoma of the small intestine with metastasis to the liver reported in the English literature.
PMCID: PMC3851255  PMID: 24067058
Small intestine; Primary angiosarcoma; Hepatic metastasis
24.  Complexity Generation during Natural Product Biosynthesis using Redox Enzymes 
Current opinion in chemical biology  2012;16(3-4):362-369.
Redox enzymes such as FAD-dependent and cytochrome P450 oxygenases play indispensible roles in generating structural complexity during natural product biosynthesis. In the pre-assembly steps, redox enzymes can convert garden variety primary metabolites into unique starter and extender building blocks. In the post-assembly tailoring steps, redox cascades can transform nascent scaffolds into structurally complex final products. In this review, we will discuss several recently characterized redox enzymes in the biosynthesis of polyketides and nonribosomal peptides.
PMCID: PMC3415589  PMID: 22564679
25.  Tectorigenin Attenuates Palmitate-Induced Endothelial Insulin Resistance via Targeting ROS-Associated Inflammation and IRS-1 Pathway 
PLoS ONE  2013;8(6):e66417.
Tectorigenin is a plant isoflavonoid originally isolated from the dried flower of Pueraria thomsonii Benth. Although its anti-inflammatory and anti-hyperglycosemia effects have been well documented, the effect of tectorigenin on endothelial dysfunction insulin resistance involved has not yet been reported. Herein, this study aims to investigate the action of tectorigenin on amelioration of insulin resistance in the endothelium. Palmitic acid (PA) was chosen as a stimulant to induce ROS production in endothelial cells and successfully established insulin resistance evidenced by the specific impairment of insulin PI3K signaling. Tectorigenin effectively inhibited the ability of PA to induce the production of reactive oxygen species and collapse of mitochondrial membrane potential. Moreover, tectorigenin presented strong inhibition effect on ROS-associated inflammation, as TNF-α and IL-6 production in endothelial cells was greatly reduced with suppression of IKKβ/NF-κB phosphorylation and JNK activation. Tectorigenin also can inhibit inflammation-stimulated IRS-1 serine phosphorylation and restore the impaired insulin PI3K signaling, leading to a decreased NO production. These results demonstrated its positive regulation of insulin action in the endothelium. Meanwhile, tectorigenin down-regulated endothelin-1 and vascular cell adhesion molecule-1 overexpression, and restored the loss of insulin-mediated vasodilation in rat aorta. These findings suggested that tectorigenin could inhibit ROS-associated inflammation and ameliorated endothelial dysfunction implicated in insulin resistance through regulating IRS-1 function. Tectorigenin might have potential to be applied for the management of cardiovascular diseases involved in diabetes and insulin resistance.
PMCID: PMC3686685  PMID: 23840461

Results 1-25 (59)