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1.  Distinct different sensitivity of Treg and Th17 cells to Fas-mediated apoptosis signaling in patients with acute coronary syndrome 
Objective: An imbalance in CD4+CD25+ regulatory T (Treg) cells and Th17 cells has been found to correlate to occurrence of acute coronary syndrome [ACS, including unstable angina (UA) and acute myocardial infarction (AMI)]. However, the mechanisms of Th17/Treg imbalance in ACS patients are still unclear. The purpose of this study is to investigate the possibility of differences in sensitivity of Th17 and Tregs to Fas-mediated apoptosis which could lead to Th17/Treg imbalance in ACS patients. Methods: We examined the apoptosis of Th17 and Treg cells, apoptosis-related Fas/Fas ligand(FasL) pathway, and inflammatory markers in patients with AMI, UA, stable angina (SA) and controls by Flow cytometry and ELISA. Then we analysed the correlation of inflammatory markers and sFasL to Treg apoptosis, and the effect of anti-FasL antibody on Treg apoptois in vitro. Results: Our study demonstrated that apoptotic Tregs, Fas and FasL expression, Caspase-3 activity of Tregs were significantly higher in ACS patients than those in NCA and SA patients (all P < 0.05). The percentage of apoptotic Tregs is positively correlated with the levels of inflammatory markers and sFasL. In vitro incubation of peripheral blood mononuclear cells from ACS patients with anti-FasL antibody resulted in a markedly reduction of apoptotic Treg cells. However, there were no significant differences in apoptotic Th17 cells and in Fas and FasL expression for Th17 cells between the four groups (all P >0.05). Conclusions: Tregs, but not Th17 cells, become apoptotic through Fas/FasL pathway, which contributed to reduction of Tregs leading to an imbalance between Th17 and Treg cells. This could be the mechanism underlying Th17/Treg imbalance and occurrence of ACS.
PMCID: PMC3544239  PMID: 23330016
Apoptosis; Fas; Fas ligand; T helper 17; regulatory T cells; acute coronary syndrome
2.  Melatonin Inhibits the Migration of Human Lung Adenocarcinoma A549 Cell Lines Involving JNK/MAPK Pathway 
PLoS ONE  2014;9(7):e101132.
Melatonin, an indolamine produced and secreted predominately by the pineal gland, exhibits a variety of physiological functions, possesses antioxidant and antitumor properties. But, the mechanisms for the anti-cancer effects are unknown. The present study explored the effects of melatonin on the migration of human lung adenocarcinoma A549 cells and its mechanism.
MTT assay was employed to measure the viability of A549 cells treated with different concentrations of melatonin. The effect of melatonin on the migration of A549 cells was analyzed by wound healing assay. Occludin location was observed by immunofluorescence. The expression of occludin, osteopontin (OPN), myosin light chain kinase (MLCK) and phosphorylation of myosin light chain (MLC), JNK were detected by western blots.
After A549 cells were treated with melatonin, the viability and migration of the cells were inhibited significantly. The relative migration rate of A549 cells treated with melatonin was only about 20% at 24 h. The expression level of OPN, MLCK and phosphorylation of MLC of A549 cells were reduced, while the expression of occludin was conversely elevated, and occludin located on the cell surface was obviously increased. The phosphorylation status of JNK in A549 cells was also reduced when cells were treated by melatonin.
Melatonin significantly inhibits the migration of A549 cells, and this may be associated with the down-regulation of the expression of OPN, MLCK, phosphorylation of MLC, and up-regulation of the expression of occludin involving JNK/MAPK pathway.
PMCID: PMC4084631  PMID: 24992189
3.  Genetic variants in DNA repair pathway genes and risk of esophageal squamous cell carcinoma and gastric adenocarcinoma in a Chinese population 
Carcinogenesis  2013;34(7):1536-1542.
The DNA repair pathways help to maintain genomic integrity and therefore genetic variation in the pathways could affect the propensity to develop cancer. Selected germline single nucleotide polymorphisms (SNPs) in the pathways have been associated with esophageal cancer and gastric cancer (GC) but few studies have comprehensively examined the pathway genes. We aimed to investigate associations between DNA repair pathway genes and risk of esophageal squamous cell carcinoma (ESCC) and GC, using data from a genome-wide association study in a Han Chinese population where ESCC and GC are the predominant cancers. In sum, 1942 ESCC cases, 1758 GC cases and 2111 controls from the Shanxi Upper Gastrointestinal Cancer Genetics Project (discovery set) and the Linxian Nutrition Intervention Trials (replication set) were genotyped for 1675 SNPs in 170 DNA repair-related genes. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-level associations were determined using the resampling-based adaptive rank-truncated product approach. The DNA repair pathways overall were significantly associated with risk of ESCC (P = 6.37 × 10− 4), but not with GC (P = 0.20). The most significant gene in ESCC was CHEK2 (P = 2.00 × 10− 6) and in GC was CLK2 (P = 3.02 × 10− 4). We observed several other genes significantly associated with either ESCC (SMUG1, TDG, TP53, GTF2H3, FEN1, POLQ, HEL308, RAD54B, MPG, FANCE and BRCA1) or GC risk (MRE11A, RAD54L and POLE) (P < 0.05). We provide evidence for an association between specific genes in the DNA repair pathways and the risk of ESCC and GC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.
PMCID: PMC3697889  PMID: 23504502
4.  The Ron receptor tyrosine kinase activates c-Abl to promote cell proliferation through tyrosine phosphorylation of PCNA in breast cancer 
Oncogene  2013;33(11):1429-1437.
Multiple growth pathways lead to enhanced proliferation in malignant cells. However, how the core machinery of DNA replication is regulated by growth signaling remains largely unclear. The sliding clamp PCNA (Proliferating Cell Nuclear Antigen) is an indispensable component of the DNA machinery responsible for replicating the genome and maintaining genomic integrity. We previously reported that epidermal growth factor receptor (EGFR) triggered tyrosine 211 (Y211) phosphorylation of PCNA, which in turn stabilized PCNA on chromatin to promote cell proliferation. Here we show that the phosphorylation can also be catalyzed by the non-receptor tyrosine kinase c-Abl. We further demonstrate that, in the absence of EGFR, signaling to PCNA can be attained through the activation of the Ron receptor tyrosine kinase and the downstream non-receptor tyrosine kinase c-Abl. We show that Ron and c-Abl form a complex, and that activation of Ron by its ligand, HGFL, stimulates c-Abl kinase activity, which in turn directly phosphorylates PCNA at Y211 and leads to an increased level of chromatin-associated PCNA. Correspondingly, HGFL-induced Ron activation resulted in Y211 phosphorylation of PCNA while silencing of c-Abl blocked this effect. We show that cAbl and Y211 phosphorylation of PCNA is an important axis downstream of Ron, which is required for cell proliferation. Treatment with a specific peptide which inhibits Y211 phosphorylation of PCNA or with the c-Abl pharmacological inhibitor imatinib suppressed HGFL-induced cell proliferation. Our findings identify the pathway of Ron-cAbl-PCNA as a mechanism of oncogene-induced cell proliferation, with potentially important implications for development of combination therapy of breast cancer.
PMCID: PMC4064789  PMID: 23542172
PCNA; Ron; receptor tyrosine kinase; tyrosine phosphorylation; Y211; tyrosine kinase; c-Abl
5.  Spatial patterns of the congenital heart disease prevalence among 0- to 14-year-old children in Sichuan Basin, P. R China, from 2004 to 2009 
BMC Public Health  2014;14:595.
Congenital heart disease (CHD) is the most common type of major birth defects in Sichuan, the most populous province in China. The detailed etiology of CHD is unknown but some environmental factors are suspected as the cause of this disease. However, the geographical variations in CHD prevalence would be highly valuable in providing a clue on the role of the environment in CHD etiology. Here, we investigate the spatial patterns and geographic differences in CHD prevalence among 0- to 14-year-old children, discuss the possible environmental risk factors that might be associated with CHD prevalence in Sichuan Basin from 2004 to 2009.
The hierarchical Bayesian model was used to estimate CHD prevalence at the township level. Spatial autocorrelation statistics were performed, and a hot-spot analysis with different distance thresholds was used to identify the spatial pattern of CHD prevalence. Distribution and clustering maps were drawn using geographic information system tools.
CHD prevalence was significantly clustered in Sichuan Basin in different spatial scale. Typical hot/cold clusters were identified, and possible CHD causes were discussed. The association between selected hypothetical environmental factors of maternal exposure and CHD prevalence was evaluated.
The largest hot-spot clustering phenomena and the CHD prevalence clustering trend among 0- to 14-year-old children in the study area showed a plausibly close similarity with those observed in the Tuojiang River Basin. The high ecological risk of heavy metal(Cd, As, and Pb)sediments in the middle and lower streams of the Tuojiang River watershed and ammonia–nitrogen pollution may have contribution to the high prevalence of CHD in this area.
PMCID: PMC4073187  PMID: 24924350
Congenital heart disease(CHD); Hierarchical Bayesian model(HB); Spatial autocorrelation; Hot-spot analysis; Sichuan Basin
6.  Attitude and Impact of Perceived Depression in the Workplace 
Information concerning the occurrence and consequences of depression in the workplace is scarce. This study estimates how workers perceive depression, to investigate depression-related disabilities, and management of depression in the workplace. This investigation is based on a cross-sectional web-based survey of 1,000 workers recruited from online sources. The participants were Brazilian workers, aged 16–64 years, current workers and managers, or who have worked within the past year. Subjects answered a 13-item questionnaire about depression, its related consequences in the workplace, and available resources to handle depression. Common symptoms attributable to depression were crying, loss of interest, and sadness. Almost one in five participants reported having ever been labeled by a doctor/medical professional as suffering from depression. However, the majority of ever-depressed workers (73.5%) remained working. Performance-related impairments were reported by around 60% of depressed workers who continued working. Over half of them also complained about cognitive symptoms (concentration difficulties, indecisiveness, forgetfulness). One in three workers had taken off work due to depression (mean 65.7 out-of-role days), with these periods being lengthier for men than women. Managers underestimated the number of days out-of-role (29.5 days). The findings suggested that identification and management of symptoms of depression should be set as a priority in worker’s health care.
PMCID: PMC4078563  PMID: 24914639
depression; workplace; cognitive symptoms; productivity
7.  Extreme multidrug resistant HIV-1 protease with 20 mutations is resistant to novel protease inhibitors with P1′-pyrrolidinone or P2-tris-tetrahydrofuran 
Journal of medicinal chemistry  2013;56(10):4017-4027.
Extreme drug resistant mutant of HIV-1 protease (PR) bearing 20 mutations (PR20) has been studied with the clinical inhibitor amprenavir (1) and two potent antiviral investigational inhibitors GRL-02031 (2) and GRL-0519 (3). Clinical inhibitors are >1000-fold less active on PR20 than on wild type enzyme, which is consistent with dissociation constants (KL) from isothermal titration calorimetry of 40 nM for 3, 178 nM for amprenavir, and 960 nM for 2. High resolution crystal structures of PR20-inhibitor complexes revealed altered interactions compared with the corresponding wild-type PR complexes in agreement with relative inhibition. Amprenavir lacks interactions due to PR20 mutations in the S2/S2′ subsites relative to PR. Inhibitors 2 and 3 lose interactions with Arg8′ in PR20 relative to the wild type enzyme since Arg8′ shifts to interact with mutated L10F side chain. Overall, inhibitor 3 compares favorably with darunavir in affinity for PR20 and shows promise for further development.
PMCID: PMC3719844  PMID: 23590295
HIV/AIDS; aspartic protease; X-ray crystallography; drug resistance
8.  Effect of Chicken Egg Yolk Antibodies (IgY) against Diarrhea in Domesticated Animals: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(5):e97716.
IgY antibodies are serum immunoglobulin in birds, reptiles and amphibians, and are transferred from serum to egg yolk to confer passive immunity to their embryos and offspring. Currently, the oral passive immunization using chicken IgY has been focused as an alternative to antibiotics for the treatment and control of diarrhea in animals and humans. This systematic review was focused to determine the effect of IgY in controlling and preventing diarrhea in domesticated animals including Piglets, Mice, Poultry and Calves.
Methods and Results
Previous research reports focused on treatment effect of Chicken IgY against diarrhea were retrieved from different electronic data bases (MEDLINE, EMBASE, SPRINGER-LINK, WILEY, AGRICOLA, MEDWELL Journals, Scientific Publish, Chinese articles from Core periodicals in 2012). A total of 61 studies in 4 different animal classes met the inclusion criteria. Data on study characteristics and outcome measures were extracted. The pooled relative risk (RR) of 49 studies of different animals [Piglets – 22; Mice – 14; Poultry – 7 and Calves – 6] in meta-analyses revealed that, IgY significantly reduced the risk of diarrhea in treatment group when compare to the placebo. However, the 95% confidence intervals of the majority of studies in animal class piglets and calves embrace RR of one. The same results were obtained in sub group analyses (treatment regiment – prophylactic or therapeutic; pathogen type – bacterial or viral). Perhaps, this inconsistency in the effect of IgY at the individual study level and overall effect measures could be influenced by the methodological heterogeneity.
The present systematic review (SR) and meta-analysis demonstrated the beneficial effect of IgY. This supports the opinion that IgY is useful for prophylaxis and treatment. However, more intensive studies using the gold standard animal experiments with the focus to use IgY alone or in combination with other alternative strategies are indispensable.
PMCID: PMC4028221  PMID: 24846286
9.  A Randomized Trial of Chinese Diaoshi Jifa on Treatment of Dizziness in Meniere's Disease 
Background. Meniere's disease is characterized by refractory dizziness and hearing disturbance. We aimed to investigate the efficacy and tolerance of Diaoshi Jifa, a Chinese hand skill for treating dizziness in Meniere's disease. Methods. An open-labeled, randomized, controlled intervention trial was conducted. Twenty-seven patients diagnosed with Meniere's disease were randomly allocated to control group or experimental group. Both groups were assessed by DHI (dizziness handicap inventory (DHI)) questionnaire score before and within 24 hours of receiving treatment, respectively. Results. Twenty-six participants completed the study, and no adverse event was reported due to Diaoshi Jifa treatment. The difference in the DHI scores between baseline and posttreatment reached significant difference in both groups (63.88 ± 19.94 versus 10.25 ± 9.77 and 54.36 ± 17.97 versus 49.6 ± 20.50). Significant difference in DHI scores was observed between the two groups after treatment (10.25 ± 9.77 versus 49.6 ± 20.50). Further investigation of DHI subscales in the experimental group revealed significant improvement posttreatment in the physical domain, functional domain, and emotional domain. Although higher rate of improvement in the emotional domain compared to physical or functional domains was found, the difference was not statistically significant. Conclusions. Diaoshi Jifa might be a fast, effective, and well-tolerated method for alleviating dizziness in Meniere's disease.
PMCID: PMC4052476  PMID: 24955104
10.  Diagnosis and treatment of carcinosarcoma of the renal pelvis: A case report 
Oncology Letters  2014;8(1):467-469.
Carcinosarcoma is a rare type of renal pelvis malignancy, the diagnosis of which requires the presence of malignant epithelial and mesenchymal components. The prognosis of this disease is extremely poor due to its rapid progression and widespread metastases. The present study describes a case of carcinosarcoma involving the right renal pelvis in a 73-year-old female who presented with intermittent hematuria and right-flank pain that had persisted for one month. Computed tomography revealed a 2.4×2.5 cm mass in the right renal pelvis, which was diagnosed as a right renal pelvic tumor. Laparoscopic radical resection of the right kidney and ureter was performed. Following surgery, immunohistochemical analysis showed positive reactions for epithelial and mesenchymal markers. Based on these findings, the patient was diagnosed with carcinosarcoma. Thus, immunohistochemical analysis is a critical method for the accurate diagnosis of carcinosarcoma.
PMCID: PMC4063624  PMID: 24959298
carcinosarcoma; renal pelvis; squamous cell carcinoma; fibrosarcoma
11.  Elevated rates of force development and MgATP binding in F764L and S532P myosin mutations causing dilated cardiomyopathy 
Dilated cardiomyopathy (DCM) is a disease characterized by dilation of the ventricular chambers and reduced contractile function. We examined the contractile performance of chemically-skinned ventricular strips from two heterozygous murine models of DCM-causing missense mutations of myosin, F764L/+ and S532P/+, in an α-myosin heavy chain (MyHC) background. In Ca2+-activated skinned myocardial strips, the maximum developed tension in F764L/+ was only ~50% that of litter-mate controls (+/+). The F764L/+ also exhibited significantly reduced rigor stiffness, loaded shortening velocity and power output. Corresponding indices for S532P/+ strips were not different from controls. Manipulation of MgATP concentration in conjunction with measures of viscoelasticity, which provides estimates of myosin detachment rate 2πc, allowed us to probe the molecular basis of changes in crossbridge kinetics that occur with the myosin mutations. By examining the response of detachment rate to varying MgATP we found the rate of MgADP release was unaffected by the myosin mutations. However, MgATP binding rate was higher in the DCM groups compared to controls (422±109 mM−1.s−1 in F764L/+, 483±74 mM−1.s−1 in S532P/+ and 303± 18 mM−1.s−1 in +/+). In addition, the rate constant of force development, 2πb, was significantly higher in DCM groups compared to controls (at 5 mM MgATP: 36.9±4.9 s−1 in F764L/+, 32.9±4.5 s−1 in S532P/+ and 18.2±1.7 s−1 in +/+). These results suggest that elevated rates of force development and MgATP binding are features of cardiac myofilament function that underlie the development of DCM.
PMCID: PMC3594396  PMID: 23313350
hypertrophic cardiomyopathy; myocardium; detachment rate; time-on; sinusoidal analysis
12.  Molecular Epidemiology and Genetic Evolution of the Whole Genome of G3P[8] Human Rotavirus in Wuhan, China, from 2000 through 2013 
PLoS ONE  2014;9(3):e88850.
Rotaviruses are a major etiologic agent of gastroenteritis in infants and young children worldwide. Since the latter of the 1990s, G3 human rotaviruses referred to as “new variant G3” have emerged and spread in China, being a dominant genotype until 2010, although their genomic evolution has not yet been well investigated.
The complete genomes of 33 G3P[8] human rotavirus strains detected in Wuhan, China, from 2000 through 2013 were analyzed. Phylogenetic trees of concatenated sequences of all the RNA segments and individual genes were constructed together with published rotavirus sequences.
Genotypes of 11 gene segments of all the 33 strains were assigned to G3-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1, belonging to Wa genogroup. Phylogenetic analysis of the concatenated full genome sequences indicated that all the modern G3P[8] strains were assigned to Cluster 2 containing only one clade of G3P[8] strains in the US detected in the 1970s, which was distinct from Cluster 1 comprising most of old G3P[8] strains. While main lineages of all the 11 gene segments persisted during the study period, different lineages appeared occasionally in RNA segments encoding VP1, VP4, VP6, and NSP1-NSP5, exhibiting various allele constellations. In contrast, only a single lineage was detected for VP7, VP2, and VP3 genes. Remarkable lineage shift was observed for NSP1 gene; lineage A1-2 emerged in 2007 and became dominant in 2008–2009 epidemic season, while lineage A1-1 persisted throughout the study period.
Chinese G3P[8] rotavirus strains have evolved since 2000 by intra-genogroup reassortment with co-circulating strains, accumulating more reassorted genes over the years. This is the first large-scale whole genome-based study to assess the long-term evolution of common human rotaviruses (G3P[8]) in an Asian country.
PMCID: PMC3967987  PMID: 24676363
13.  Time-Efficient Myocardial Contrast Partition Coefficient Measurement from Early Enhancement with Magnetic Resonance Imaging 
PLoS ONE  2014;9(3):e93124.
Our purpose was to validate an early enhancement time point for accurately measuring the myocardial contrast partition coefficient (lambda) using dynamic-equilibrium magnetic resonance imaging.
Materials and Methods
The pre- and post-contrast longitudinal relaxation rates (reciprocal of T1) of the interventricular septum (R1m) and blood pool (R1b) were obtained from fifteen healthy volunteers and three diabetic patients with hypertension using two optimized T1 mapping sequences (modified Look-Locker inversion recovery) on a 3-Tesla magnetic resonance scanner. Reference lambda values were calculated as the slope of the regression line of R1m versus R1b at dynamic equilibrium (multi-point regression method). The simplified pre-/post-enhancement two-acquisition method (two-point method) was used to calculate lambda by relating the change in R1m and R1b using different protocols according to the acquisition stage of the post-enhancement data point. The agreement with the referential method was tested by calculating Pearson's correlation coefficient and the intra-class correlation coefficient.
The lambda values measured by the two-point method increased (from 0.479±0.041 to 0.534±0.043) over time from 6 to 45 minutes after contrast and exhibited good correlation with the reference at each time point (r≥0.875, p<0.05). The intra-class correlation coefficient on absolute agreement with the reference lambda was 0.946, 0.929 and 0.922 at the 6th, 7th and 8th minutes and dropped from 0.878 to 0.403 from the 9th minute on.
The time-efficient two-point method at 6–8 minutes after the Gd-DTPA bolus injection exhibited good agreement with the multi-point regression method and can be applied for accurate lambda measurement in normal myocardium.
PMCID: PMC3965516  PMID: 24667489
14.  Multifactorial Comparative Proteomic Study of Cytochrome P450 2E1 Function in Chronic Alcohol Administration 
PLoS ONE  2014;9(3):e92504.
With the use of iTRAQ technique, a multifactorial comparative proteomic study can be performed. In this study, to obtain an overview of ethanol, CYP2E1 and gender effects on liver injury and gain more insight into the underlying molecular mechanism, mouse liver proteomes were quantitatively analyzed using iTRAQ under eight conditions including mice of different genders, wild type versus CYP2E1 knockout, and normal versus alcohol diet. A series of statistical and bioinformatic analyses were explored to simplify and clarify multifactorial comparative proteomic data. First, with the Principle Component analysis, six proteins, CYP2E1, FAM25, CA3, BHMT, HIBADH and ECHS1, involved in oxidation reduction, energy and lipid metabolism and amino acid metabolism, were identified as the most differentially expressed gene products across all of the experimental conditions of our chronic alcoholism model. Second, hierarchical clustering analysis showed CYP2E1 knockout played a primary role in the overall differential protein expression compared with ethanol and gender factors. Furthermore, pair-wise multiple comparisons have revealed that the only significant expression difference lied in wild-type and CYP2E1 knockout mice both treated with ethanol. Third, K-mean clustering analysis indicated that the CYP2E1 knockout had the reverse effect on ethanol induced oxidative stress and lipid oxidation. More importantly, IPA analysis of proteomic data inferred that the gene expressions of two upstream regulators, NRF2 and PPARα, regulated by chronic alcohol feeding and CYP2E1 knockout, are involved in ethanol induced oxidative stress and lipid oxidation. The present study provides an effectively comprehensive data analysis strategy to compare multiple biological factors, contributing to biochemical effects of alcohol on the liver. The mass spectrometry proteomics data have been deposited to the ProteomeXchange with data set identifier of PXD000635.
PMCID: PMC3962406  PMID: 24658151
15.  Ethyl Acetate Extract of Artemisia anomala S. Moore Displays Potent Anti-Inflammatory Effect 
Artemisia anomala S. Moore has been widely used in China to treat inflammatory diseases for hundreds of years. However, mechanisms associated with its anti-inflammatory effect are not clear. In this study, we prepared ethyl acetate, petroleum ether, n-BuOH, and aqueous extracts from ethanol extract of Artemisia anomala S. Moore. Comparing anti-inflammatory effects of these extracts, we found that ethyl acetate extract of this herb (EAFA) exhibited the strongest inhibitory effect on nitric oxide (NO) production in LPS/IFNγ-stimulated RAW264.7 cells. EAFA suppressed the production of NO in a time- and dose-dependent manner without eliciting cytotoxicity to RAW264.7 cells. To understand the molecular mechanism underlying EAFA's anti-inflammatory effect, we showed that EAFA increased total cellular anti-oxidant capacity while reducing the amount of inducible nitric oxide synthase (iNOS) in stimulated RAW264.7 cells. EAFA also suppressed the expression of IL-1β and IL-6, whereas it elevates the level of heme oxygenase-1. These EAFA-induced events were apparently associated with NF-κB and MAPK signaling pathways because the DNA binding activity of p50/p65 was impaired and the activities of both ERK and JNK were decreased in EFEA-treated cells comparing to untreated cells. Our findings suggest that EAFA exerts its anti-inflammatory effect by inhibiting the expression of iNOS.
PMCID: PMC3972921  PMID: 24744815
16.  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.
PMCID: PMC3950214  PMID: 24618592
17.  Over-Expression of Platelet-Derived Growth Factor-D Promotes Tumor Growth and Invasion in Endometrial Cancer 
The platelet-derived growth factor-D (PDGF-D) was demonstrated to be able to promote tumor growth and invasion in human malignancies. However, little is known about its roles in endometrial cancer. In the present study, we investigated the expression and functions of PDGF-D in human endometrial cancer. Alterations of PDGF-D mRNA and protein were determined by real time PCR, western blot and immunohistochemical staining. Up-regulation of PDGF-D was achieved by stably transfecting the pcDNA3-PDGF-D plasmids into ECC-1 cells; and knockdown of PDGF-D was achieved by transient transfection with siRNA-PDGF-D into Ishikawa cells. The MTT assay, colony formation assay and Transwell assay were used to detect the effects of PDGF-D on cellular proliferation and invasion. The xenograft assay was used to investigate the functions of PDGF-D in vivo. Compared to normal endometrium, more than 50% cancer samples showed over-expression of PDGF-D (p < 0.001), and high level of PDGF-D was correlated with late stage (p = 0.003), deep myometrium invasion (p < 0.001) and lympha vascular space invasion (p = 0.006). In vitro, over-expressing PDGF-D in ECC-1 cells significantly accelerated tumor growth and promoted cellular invasion by increasing the level of MMP2 and MMP9; while silencing PDGF-D in Ishikawa cells impaired cell proliferation and inhibited the invasion, through suppressing the expression of MMP2 and MMP9. Moreover, we also demonstrated that over-expressed PDGF-D could induce EMT and knockdown of PDGF-D blocked the EMT transition. Consistently, in xenografts assay, PDGF-D over-expression significantly promoted tumor growth and tumor weights. We demonstrated that PDGF-D was commonly over-expressed in endometrial cancer, which was associated with late stage deep myometrium invasion and lympha vascular space invasion. Both in vitro and in vivo experiments showed PDGF-D could promote tumor growth and invasion through up-regulating MMP2/9 and inducing EMT. Thus, we propose targeting PDGF-D to be a potent strategy for endometrial cancer treatment.
PMCID: PMC3975424  PMID: 24646915
endometrial cancer; platelet-derived growth factor-D (PDGF-D); proliferation; invasion; matrix metalloproteinase (MMP); the epithelial-mesenchymal-transition (EMT)
18.  The effect of erectile dysfunction on quality of life in male kidney transplant recipients 
Objective : To assess how erectile dysfunction (ED) affects the quality of life in male kidney transplant recipients.
Methods: We randomly selected 150 cases of married male kidney transplant recipients. Using the International Index of Erectile Function (IIEF-5) Questionnaire, we divided our research subjects into ED group (n=63) and non-ED group (n = 87). The Short-Form health survey (SF-36) was used to evaluate the quality of life of the recipients. Hamilton Anxiety Rating Scale was used to compare the mental health status of the two groups.
Results: No significant differences (P > 0.05) were observed between the ED and non-ED groups in physical functioning (PF), role-physical (RP), or bodily pain (BP). However, the ED group exhibited a lower score (P < 0.05) than the non-ED group in general health (GH), vitality, social functioning (SF), role emotional (RE) and mental health (MH). There were 13 cases in the ED group with anxiety disorders (20.6%), which was clearly more than in the non-ED group (3.4%, P < 0.05).
Conclusion: Erectile dysfunction is an important factor in the quality of life of male kidney transplant recipients.
PMCID: PMC3999011  PMID: 24772144
Kidney; Male; Renal transplant; Erectile dysfunction; Quality of life
19.  Elevation of serum CXCL16 level correlates well with atherosclerotic ischemic stroke 
Currently there are no reliable biological markers for ischemic stroke. The novel chemokine CXCL16 is known to be involved in the development of atherosclerosis. Nevertheless, the real role of CXCL16 in atherosclerotic disorders remains uncertain. The goal of our study was to investigate the associations between serum-soluble CXCL16 level and atherosclerotic ischemic stroke, including large artery atherosclerosis (LAA) and small artery occlusion (SAO) subtypes, and to explore whether elevation in CXCL16 levels is correlated with the severity of large arterial stenosis.
Material and methods
The study recruited 227 subjects, including 74 controls and 153 consecutive patients with acute ischemic stroke from atherosclerosis of the carotid artery. The etiology of the acute ischemic strokes was classified into LAA (n = 86) subtype and SAO (n = 67) subtype according to the TOAST criteria, and the severity of carotid artery stenosis was assessed by the NASCET criteria. Serum-soluble CXCL16 concentration was measured by enzyme-linked immunosorbent assay.
Serum CXCL16 concentrations were significantly increased in both LAA (2.36 ng/ml) and SAO subtypes (2.13 ng/ml) when compared to that of the controls (2.04 ng/ml, p < 0.01 and p < 0.05, respectively), and it was significantly elevated in LAA subtype than in SAO subtype (p < 0.05). However, significant differences in CXCL16 levels between the high-grade stenosis group (2.36 ng/ml) and moderate-grade stenosis group (2.24 ng/ml) of LAA subtype were not found (p > 0.05). A correlation of serum levels of CXCL16 with serum levels of hs-CRP, fibrinogen and lipid parameters was not observed (p > 0.05).
Increased serum level of soluble CXCL16 was independently associated with atherosclerotic ischemic stroke, particularly LAA subtype.
PMCID: PMC3953970  PMID: 24701213
CXCL16; chemokine; atherosclerosis; ischemic stroke; inflammation
20.  Chinese Herbal Medicine for Aspirin Resistance: A Systematic Review of Randomized Controlled Trials 
Aspirin resistance (AR) is a prevalent phenomenon and leads to significant clinical consequences, but the current evidence for effective interventional strategy is insufficient. The objective of this systematic review is thus to assess the efficacy and safety of Chinese herbal medicine (CHM) for AR. A systematical literature search was conducted in 6 databases until December 2012 to identify randomized controlled trials (RCTs) of CHM for AR. As a result, sixteen RCTs with a total of 1011 subjects were identified, suggesting that the interests of the medical profession and the public in the use of CHM for AR have grown considerably in the recent years. Tongxinluo capsule and Danshen-based prescriptions were the most frequently used herbal prescriptions, while danshen root, milkvetch root, Leech, and Rosewood were the most frequently used single herbs. Despite the apparent reported positive findings, it is premature to determine the efficacy and safety of CHM for the treatment of AR due to poor methodological quality and insufficient safety data. However, CHMs appeared to be well tolerated in all included studies. Thus, CHM as a promising candidate is worthy of improvement and development for further clinical AR trials. Large sample-size and well-designed rigorous RCTs are needed.
PMCID: PMC3950618  PMID: 24701247
21.  Novel P2 tris-tetrahydrofuran group in antiviral compound 1 (GRL-0519) fills the S2 binding pocket of selected mutants of HIV-1 protease 
Journal of medicinal chemistry  2013;56(3):1074-1083.
GRL-0519 (1) is a potent antiviral inhibitor of HIV-1 protease (PR) possessing tris-tetrahydrofuran (tris-THF) at P2. The high resolution X-ray crystal structures of inhibitor 1 in complexes with single substitution mutants PRR8Q, PRD30N, PRI50V, PRI54M, and PRV82A were analyzed in relation to kinetic data. The smaller valine side chain in PRI50V eliminated hydrophobic interactions with inhibitor and the other subunit consistent with 60-fold worse inhibition. Asn30 in PRD30N showed altered interactions with neighboring residues and 18-fold worse inhibition. Mutations V82A and I54M showed compensating structural changes consistent with 6-7-fold lower inhibition. Gln8 in PRR8Q replaced the ionic interactions of wild type Arg8 with hydrogen bond interactions without changing the inhibition significantly. The carbonyl oxygen of Gly48 showed two alternative conformations in all structures likely due to the snug fit of the large tris-THF group in the S2 subsite in agreement with high antiviral efficacy of 1 on resistant virus.
PMCID: PMC3574189  PMID: 23298236
HIV / AIDS; aspartic protease; X-ray crystallography; drug resistance
22.  Similar to Spironolactone, Oxymatrine Is Protective in Aldosterone-Induced Cardiomyocyte Injury via Inhibition of Calpain and Apoptosis-Inducing Factor Signaling 
PLoS ONE  2014;9(2):e88856.
Accumulating evidence indicates that oxymatrine (OMT) possesses variously pharmacological properties, especially on the cardiovascular system. We previously demonstrated that activated calpain/apoptosis-inducing factor (AIF)-mediated pathway was the key molecular mechanism in aldosterone (ALD) induces cardiomyocytes apoptosis. In the present study, we extended the experimentation by investigating the effect of OMT on cardiomyocytes exposed to ALD, as compared to spironolactone (Spiro), a classical ALD receptor antagonist. Cardiomyocytes were pre-incubated with OMT, Spiro or vehicle for 1 h, and then, cardiomyocytes were exposed to ALD 24 h. The cell injury was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) leakage ratio. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, annexin V/PI staining, and relative caspase-3 activity assay. Furthermore, expression of pro-apoptotic proteins including truncated Bid (tBid), calpain and AIF were evaluated by western blot analysis. ALD stimulation increased cardiomyocytes apoptosis, caspase-3 activity and protein expression of calpain, tBid and AIF in the cytosol (p<0.05). Pre-incubated with cardiomyocytes injury and increased caspase-3 activity were significantly attenuated (p<0.05). Furthermore, OMT suppressed ALD-induced high expression of calpain and AIF. And these effects of OMT could be comparable to Spiro. These findings indicated that OMT might be a potential cardioprotective-agent against excessive ALD-induced cardiotoxicity, at least in part, mediated through inhibition of calpain/AIF signaling.
PMCID: PMC3923837  PMID: 24551180
23.  Clinical Significance of Survivin Expression in Patients with Urothelial Carcinoma 
Disease Markers  2014;2014:574985.
Background. Survivin is a member of the inhibitors of apoptosis protein family that plays an important role in carcinogenesis. Here, we examined the association between survivin expression and clinical outcome in urothelial carcinoma of the bladder (UCB). Methods. A total of 56 histopathologically confirmed UCB patients were recruited from the Department of Urology of Chiayi Christian Hospital from August 2007 to May 2009. Immunohistochemistry (IHC) was used to detect the survivin expression in tumor tissues. The –31 C/G polymorphism in survivin promoter region was determined by polymerase chain reaction-restricted fragment length polymorphism. Results. The frequency of high survivin expression was significantly higher in muscle-invasive tumors (66.6%) than in non-muscle-invasive tumors (34.2%) (P = 0.042) and in poorly differentiated (85.7%) tumors than in moderately differentiated tumors (30.8%) (P = 0.0014). The higher frequency of risk genotypes (C/C and C/G) was found in the median (72.7%) and high (68.0%) survivin expression groups. The multivariate analysis showed that a high survivin expression level was a potential predictive biomarker of poor overall survival (P = 0.02). Conclusion. Our results suggest that the high survivin expression was associated with tumor stage and grade and may present a predictive marker of overall survival in UCB.
PMCID: PMC3933524  PMID: 24648609
24.  Numerical Simulation on Zonal Disintegration in Deep Surrounding Rock Mass 
The Scientific World Journal  2014;2014:379326.
Zonal disintegration have been discovered in many underground tunnels with the increasing of embedded depth. The formation mechanism of such phenomenon is difficult to explain under the framework of traditional rock mechanics, and the fractured shape and forming conditions are unclear. The numerical simulation was carried out to research the generating condition and forming process of zonal disintegration. Via comparing the results with the geomechanical model test, the zonal disintegration phenomenon was confirmed and its mechanism is revealed. It is found to be the result of circular fracture which develops within surrounding rock mass under the high geostress. The fractured shape of zonal disintegration was determined, and the radii of the fractured zones were found to fulfill the relationship of geometric progression. The numerical results were in accordance with the model test findings. The mechanism of the zonal disintegration was revealed by theoretical analysis based on fracture mechanics. The fractured zones are reportedly circular and concentric to the cavern. Each fracture zone ruptured at the elastic-plastic boundary of the surrounding rocks and then coalesced into the circular form. The geometric progression ratio was found to be related to the mechanical parameters and the ground stress of the surrounding rocks.
PMCID: PMC3925544  PMID: 24592166
25.  Prognostic significance of B-cell lymphoma 2 expression in acute leukemia: A systematic review and meta-analysis 
Molecular and Clinical Oncology  2014;2(3):411-414.
A number of studies have provided estimates of the correlation between B-cell lymphoma 2 (Bcl-2) expression and its clinical significance in acute leukemia (AL); however, the results have been heterogeneous. In order to clarify the prognostic significance of Bcl-2 status in patients with AL, a systematic review and meta-analysis of 5 published studies including a total of 665 subjects was performed. The reported frequency of Bcl-2 expression was 0–99.00%. Bcl-2-positive patients had a higher median white blood cell count compared to Bcl-2-negative patients. Additionally, Bcl-2-negative patients had >2-fold higher odds of achieving complete remission (CR) compared to Bcl-2-positive patients. The summary hazard ratio of Bcl-2 negativity/positivity for CR was 0.62 [95% confidence interval: 0.53–0.81, P<0.001]. Although this meta-analysis was based on data abstracted from observational studies, our results may justify the use of risk-adapted therapeutic strategies for AL according to the Bcl-2 expression status.
PMCID: PMC3999138  PMID: 24772309
acute leukemia; B-cell lymphoma 2 protein; clinical significance; meta-analysis

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