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1.  Interleukin-16 Polymorphism Is Associated with an Increased Risk of Ischemic Stroke 
Mediators of Inflammation  2013;2013:564750.
Clinical and experimental data have demonstrated that inflammation plays fundamental roles in the pathogenesis of ischemic stroke. Interleukin-16 (IL-16) is identified as a proinflammatory cytokine that is a key element in the ischemic cascade after cerebral ischemia. We aimed to examine the relationship between the IL-16 polymorphisms and the risk of ischemic stroke in a Chinese population. A total of 198 patients with ischemic stroke and 236 controls were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing method. We found that the rs11556218TG genotype and G allele of IL-16 were associated with significantly increased risks of ischemic stroke (TG versus TT, adjusted OR = 1.88; 95% CI, 1.15–3.07; G versus T, adjusted OR = 1.54; 95% CI, 1.05–2.27, resp.). However, there were no significant differences in the genotype and allele frequencies of IL-16 rs4778889 T/C and rs4072111 C/T polymorphisms between the two groups, even after stratification analyses by age, gender, and the presence or absence of hypertension, diabetes mellitus, hypercholesterolemia, and hypertriglyceridemia. These findings indicate that the IL-16 polymorphism may be related to the etiology of ischemic stroke in the Chinese population.
PMCID: PMC3833071  PMID: 24288444
2.  Cigarette smoke affects dendritic cell maturation in the small airways of patients with chronic obstructive pulmonary disease 
Molecular Medicine Reports  2014;11(1):219-225.
The aim of the present study was to characterize and quantify the numbers and expression levels of cells markers associated with dendritic cell (DC) maturation in small airways in current smokers and non-smokers with or without chronic obstructive pulmonary disease (COPD). Lung tissues from the following 32 patients were obtained during resection for lung cancer: Eight smokers with COPD, eight non-smokers with COPD, eight current smokers without COPD and eight non-smokers without COPD, serving as a control. The tissue sections were immunostained for cluster of differentiation (CD)83+ and CD1a+ to delineate mature and immature DCs, and chemokine receptor type 7 (CCR7+) to detect DC migratory ability. Myeloid DCs were collected from the lung tissues, and subsequently the CD83+ and CCR7+ expression levels in the lung myeloid DCs were detected using flow cytometry. The expression levels of CD83+, CD1a+ and CCR7+ mRNA in total lung RNA were evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Evident chronic bronchitis and emphysema pathological changes were observed in the lung tissues of patients with COPD. The results revealed that the numbers of CD83+ and CCR7+ DCs were reduced but the numbers of CD1a+ DCs were significantly increased in the COPD group as compared with the control group (P<0.05, respectively). Using RT-qPCR, the expression levels of CCR7+ and CD83+ mRNA were found to be reduced in the smokers with COPD as compared with the non-smokers without COPD group (P<0.05, respectively). Excessive local adaptive immune responses are key elements in the pathogenesis of COPD. Cigarette smoke may stimulate immune responses by impairing the homing of airway DCs to the lymph nodes and reduce the migratory potential of DCs. The present study revealed that COPD is associated with reduced numbers of mature CD83+ DCs and lower CCR7+ expression levels in small airways.
PMCID: PMC4237095  PMID: 25338516
chronic obstructive pulmonary disease; reverse transcription polymerase chain reaction; chemokine receptor type 7; dendritic cells; cluster of differentiation 83; cluster of differentiation 1a
3.  Effect of Abnormal Fasting Plasma Glucose Level on All-Cause Mortality in Older Patients With Acute Myocardial Infarction: Results From the Beijing Elderly Acute Myocardial Infarction Study (BEAMIS) 
Mayo Clinic Proceedings  2011;86(2):94-104.
OBJECTIVE: To assess whether the relationship between abnormal fasting plasma glucose (FPG) levels and patient outcomes holds for both older men and older women with acute myocardial infarction (AMI).
PATIENTS AND METHODS: From April 1, 2004, to October 31, 2006, a total of 2016 consecutive older patients (age ≥65 years) presenting with AMI were screened. Of these patients, 1854 were consecutively enrolled in the study. Patients were categorized into 4 groups: the hypoglycemic group (FPG, ≤90.0 mg/dL [to convert to mmol/L, multiply by 0.0555]; n=443, 23.9%), the euglycemic group (FPG, 90.1-126.0 mg/dL; n=812, 43.8%), the mildly hyperglycemic group (FPG, 126.1-162.0 mg/dL; n=308, 16.6%), and the severely hyperglycemic group (FPG, ≥162.1 mg/dL; n=291, 15.7%). The primary outcomes were rates of in-hospital and 3-year mortality.
RESULTS: Female patients were older and had a higher incidence of diabetes mellitus but lower rates of smoking and use of invasive therapy. Men tended to have a higher frequency of hypoglycemia, whereas women tended to have a higher frequency of hyperglycemia. No significant difference was found in in-hospital (10.9% vs 9.1%; P=.36) or 3-year (24.5% vs 24.5%; P=.99) mortality between male and female patients, and FPG-associated mortality did not vary significantly by sex.
CONCLUSION: An increased FPG level was associated with a relatively higher risk of in-hospital mortality in men but not in women. Nonetheless, increased and decreased FPG levels at admission could predict higher mortality rates regardless of sex. There was a striking U-shaped relationship between FPG levels and in-hospital and 3-year mortality. The effect of abnormal FPG level on outcomes among older patients with AMI did not vary significantly by sex.
An increased fasting plasma glucose level was associated with a relatively higher risk of in-hospital mortality in men but not in women. Nonetheless, increased and decreased fasting plasma glucose levels at admission could predict higher mortality rates regardless of sex.
PMCID: PMC3031433  PMID: 21282483
4.  Identification and Genetic Analysis of a Factor IX Gene Intron 3 Mutation in a Hemophilia B Pedigree in China 
Turkish Journal of Hematology  2014;31(3):226-230.
Objective: Hemophilia B is caused by coagulation defects in the factor IX gene located in Xq27.1 on the X chromosome. A wide range of mutations, showing extensive molecular heterogeneity, have been described in hemophilia B patients. Our study was aimed at genetic analysis and prenatal diagnosis of hemophilia B in order to further elucidate the pathogenesis of the hemophilia B pedigree in China.
Materials and Methods: Polymerase chain reaction amplification and direct sequencing of all the coding regions was conducted in hemophilia B patients and carriers. Prenatal diagnosis of the proband was conducted at 20 weeks.
Results: We identified the novel point mutation 10.389 A>G, located upstream of the intron 3 acceptor site in hemophilia B patients. The fetus of the proband’s cousin was identified as a carrier.
Conclusion: Our identification of a novel mutation in the F9 gene associated with hemophilia B provides novel insight into the pathogenesis of this genetically inherited disorder and also represents the basis of prenatal diagnosis.
PMCID: PMC4287022  PMID: 25330515
Hemophilia B; Factor IX; mutation; Intron 3; mRNA splice site
5.  Alteration of Lipid Profile in Subclinical Hypothyroidism: A Meta-Analysis 
Previous studies yielded controversial results about the alteration of lipid profiles in patients with subclinical hypothyroidism. We performed a meta-analysis to investigate the association between subclinical hypothyroidism and lipid profiles.
We searched PubMed, Cochrane Library, and China National Knowledge Infrastructure articles published January 1990 through January 2014. Dissertation databases (PQDT and CDMD) were searched for additional unpublished articles. We included articles reporting the relationship between subclinical hypothyroidism and at least 1 parameter of lipid profiles, and calculated the overall weighted mean difference (WMD) with a random effects model. Meta-regression was used to explore the source of heterogeneity among studies, and the Egger test, Begg test, and the trim and fill method were used to assess potential publication bias.
Sixteen observational studies were included in our analysis. Meta-analysis suggested that the serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and total triglyceride levels were significantly increased in patients with subclinical hypothyroidism compared with euthyroidism individuals; the WMD were 12.17 mg/dl, 7.01 mg/dl, and 13.19 mg/dl, respectively (P<0.001 for all). No significant difference was observed for serum high-density lipoprotein cholesterol (HDL-C). Match strategy was the main source of heterogeneity among studies in TC and LDL-C analysis. Potential publication bias was found in TC and LDL-C analysis by the Egger test or Begg test and was not confirmed by the trim and fill method.
Subclinical hypothyroidism may correlate with altered lipid profile. Previous studies had limitations in the control of potential confounding factors and further studies should consider those factors.
PMCID: PMC4144946  PMID: 25124461
Hypothyroidism; Lipid Metabolism; Meta-Analysis
6.  Quantitative analysis of real-time tissue elastography for evaluation of liver fibrosis 
The present study aimed to investigate the feasibility of quantitative analysis of liver fibrosis using real-time tissue elastography (RTE) and its pathological and molecule biological basis. Methods: Fifty-four New Zealand rabbits were subcutaneously injected with thioacetamide (TAA) to induce liver fibrosis as the model group, and another eight New Zealand rabbits served as the normal control group. Four rabbits were randomly taken every two weeks for real-time tissue elastography (RTE) and quantitative analysis of tissue diffusion. The obtained twelve characteristic quantities included relative mean value (MEAN), standard deviation (SD), blue area % (% AREA), complexity (COMP), kurtosis (KURT), skewness (SKEW), contrast (CONT), entropy (ENT), inverse different moment (IDM), angular secon moment (ASM), correlation (CORR) and liver fibrosis index (LF Index). Rabbits were executed and liver tissues were taken for pathological staging of liver fibrosis (grouped by pathological stage into S0 group, S1 group, S2 group, S3 group and S4 group). In addition, the collagen I (Col I) and collagen III (Col III) expression levels in liver tissue were detected by Western blot. Results: Except for KURT, there were significant differences among the other eleven characteristic quantities (P < 0.05). LF Index, Col I and Col III expression levels showed a rising trend with increased pathological staging of liver fibrosis, presenting a positive correlation with the pathological staging of liver fibrosis (r = 0.718, r = 0.693, r = 0.611, P < 0.05). Conclusion: RTE quantitative analysis is expected for noninvasive evaluation of the pathological staging of liver fibrosis.
PMCID: PMC4057854  PMID: 24955175
Ultrasound; elastography; liver fibrosis; non-invasive diagnosis
7.  Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease 
Nature genetics  2012;44(8):890-894.
We performed a meta-analysis of 2 genome-wide association studies of coronary artery disease comprising 1,515 cases with coronary artery disease and 5,019 controls, followed by de novo replication studies in 15,460 cases and 11,472 controls, all of Chinese Han descent. We successfully identified four new loci for coronary artery disease reaching genome-wide significance (P < 5 × 10−8), which mapped in or near TTC32-WDR35, GUCY1A3, C6orf10-BTNL2 and ATP2B1. We also replicated four loci previously identified in European populations (PHACTR1, TCF21, CDKN2A/B and C12orf51). These findings provide new insights into biological pathways for the susceptibility of coronary artery disease in Chinese Han population.
PMCID: PMC3927410  PMID: 22751097
8.  Low-dose heparin as treatment for early disseminated intravascular coagulation during sepsis: A prospective clinical study 
The present study aimed to investigate whether low-dose heparin improves the condition of patients suffering from early disseminated intravascular coagulation (pre-DIC) during sepsis. In total, 37 patients were randomly divided into low-dose heparin intervention and control groups. The heparin group received a low-dose of heparin for 5–7 days, while the other group received only saline. The two groups were treated for sepsis. Blood samples were collected at various times and acute physiology and chronic health evaluation (APACHE)-II scores were recorded at day 1 and 7. In addition, the number of days applying mechanical ventilation and in the intensive care unit (ICU) were recorded, as well as the 28-day mortality rate. APACHE-II scores in the two groups decreased following treatment, however, scores in the heparin group decreased more significantly. Prothrombin fragment and thrombin-antithrombin complex levels in the heparin group were significantly decreased. In addition, the number of days applying a ventilator was fewer and the total stay in ICU was significantly shorter compared with the control group. Significantly fewer complications were observed in the heparin group, however, there was no significant difference in the 28-day mortality rate. In conclusion, low-dose heparin improves the hypercoagulable state of sepsis, which subsequently reduces the incidence of DIC or multiple organ dysfunction syndrome, decreasing the number of days of mechanical ventilation and hospitalization.
PMCID: PMC3919907  PMID: 24520253
sepsis; low-dose heparin; coagulation; treatment; clinical trial; disseminated intravascular coagulation
9.  Plasmon-Enhanced Light Harvesting of Chlorophylls on Near-Percolating Silver Films via One-Photon Anti-Stokes Upconversion 
Scientific Reports  2013;3:1861.
There exists a wealth of means of efficient utilization of solar energy in nature, with photosynthesis of chlorophylls as a prime example. Separately, artificially structured plasmonic materials are versatile in light harvesting and energy conversion. Using a simple and scalable design of near-percolating silver nanostructures, we demonstrate that the light-harvesting efficiency of chlorophylls can be drastically enhanced by tuning the plasmon frequency of the constituent silver nanoparticles to coincide with the maximal photon flux of sunlight. In particular, we show that the photon upconversion efficiency can be readily enhanced by over 20 folds, with the room-temperature fluorescence quantum yield increased by a factor of 2.63. The underlying mechanism for the upconversion enhancement is attributed to a one-electron-per-photon anti-Stokes process, involving absorption of a characteristic phonon mode of the chlorophylls. These findings suggest that chlorophylls can serve as molecular building blocks for high-efficiency light harvesting and solar energy conversion.
PMCID: PMC3659322  PMID: 23689426
10.  Regulation of synoviocyte activity by resveratrol in rats with adjuvant arthritis 
The aim of this study was to investigate the preventive effects of resveratrol (Res) on rats with adjuvant arthritis (AA) and the mechanism(s) of action. An AA model was established by injection of Freund’s complete adjuvant (FCA). Vascular endothelial growth factor (VEGF) was visualized in joint specimens using immunohistochemistry. IL-1β and TNF-α production in synoviocytes was determined by radioimmunoassay (RIA). The mRNA expression of IL-1β and TNF-α was observed in synoviocytes using the reverse transcription (RT)-PCR method. The synoviocytes of the AA model were stimulated by Res or treated with the protein kinase C (PKC) inhibitor chelerythrine prior to stimulation. The expression of phosphorylated ERK1/2 (p-ERK1/2) was detected by western blotting. Res was able to reduce the elevated levels of IL-1β and TNF-α, and inhibit the mRNA expression of IL-1β and TNF-α in the synoviocytes of the AA model rats. VEGF expression in the Res-treated group was significantly lowered. The protein expression levels of p-ERK1/2 were significantly higher in the Res-treated group compared with those of the model group, while p-ERK1/2 was markedly lower in the group pretreated with chelerythrine. Res has a therapeutic effect on AA rats, which may be correlated with its immunoregulatory actions, and may activate p-ERK1/2 in synoviocytes via PKC.
PMCID: PMC3735719  PMID: 23935741
adjuvant arthritis; resveratrol; rat; extracellular signal regulated protein kinase1/2
11.  Contemporary Management and Attainment of Cholesterol Targets for Patients with Dyslipidemia in China 
PLoS ONE  2013;8(4):e47681.
It is well-established that lipid disorder is an important cardiovascular risk factor, and failure to reach optimal lipid levels significantly contributes to the residual cardiovascular risks. However, limited information is available on the management and the attainment of recommended cholesterol targets in real-world practice in China.
Methods and Results
A nationally representative sample of 12,040 patients with dyslipidemia from 19 provinces and 84 hospitals across China were consecutively enrolled in this survey. Risk stratification and individual cholesterol target was established for all participants. This survey identified a high-risk cohort, with over 50% of patients had hypertension, 37.5% had coronary artery disease, and more than 30% had peripheral artery disease. Thirty-nine percent of all participants received lipid lowering medications. And the majority of them (94.5%) had statins (42.5% with atorvastatin, 29.0% with simvastatin, and 15.2% with rosuvastatin). However, the overall attainment for low-density lipoprotein cholesterol (LDL-C) target is low (25.8%), especially, in female (22.2%), and in patients with increased body mass index (BMI) (38.3% for BMI<18.5, 28.1% for BMI 18.5–24.9, 26.0% for BMI 25.0–29.9, and 17.4% for BMI≥30, P<0.0001). Subgroup analysis also showed the attainment is significantly lower in patients who were stratified into high (19.9%) and very high (21.1%) risk category. In logistic regression analysis, eight factors (BMI, gender, coronary artery disease, systolic and diastolic blood pressure, hypertension, family history of premature coronary artery disease and current smoking) were identified as independent predictors of LDL-C attainment.
Despite the proven benefits of lipid-lowering therapies, current management of dyslipidemia continues to be unsatisfied. A considerable proportion of patients failed to achieve guideline-recommended targets in China, and this apparent treatment gap was more pronounced among patients with increased BMI, higher risk stratification and women.
PMCID: PMC3621908  PMID: 23593110
12.  Effects of exposure to bisphenol A during pregnancy and lactation on the testicular morphology and caspase-3 protein expression of ICR pups 
Biomedical Reports  2013;1(3):420-424.
Bisphenol A (BPA), a xenoestrogen and endocrine-disrupting chemical, is a cause for concern due to its being a potential human carcinogen. The aim of this study was to investigate the effects of continued maternal exposure to BPA on the testicular structures and expression of caspase-3 protein in male ICR offspring during pregnancy and lactation and explore its possible mechanism. Pregnant ICR mice were divided into two control groups, which were either given or not given the solvent dimethyl sulfoxide (DMSO) and three treatment groups, which were gavaged with water-soluble BPA dissolved in DMSO at three different concentrations from gestational day 0 to weaning on postnatal day (PND) 21. The number of mice pups and ratios of males to females were recorded. On PND 21, male offspring were sacrificed to measure their wet weights and testicular coefficients. Electron microscopy was used to observe testicular morphological changes, Hoechst 33258 staining to detect cell apoptosis and immunohistochemistry to measure caspase-3 expression. Although there was no significant difference between offspring of the control group and the treatment group in litter size and male-female ratio (P>0.05), the testicular viscera coefficient in the latter decreased (P<0.01). Specifically, compared with offspring of the control group, in addition to increased cell apoptosis, those of the treatment groups were found to have changes in mitochondrial and endoplasmic reticulum in their spermatogenous, Sertoli, Leydig and peritubular myoid cells, which were concomitant with an elevated expression of caspase-3 in the cytoplasm (P<0.01). In conclusion, exposure of pregnant mice to BPA during pregnancy and lactation has some toxic effects on the testes of male ICR offspring and these may originate from increased apoptosis.
PMCID: PMC3917723  PMID: 24648961
bisphenol A; offspring mice; caspase-3
13.  Synergy between Proteasome Inhibitors and Imatinib Mesylate in Chronic Myeloid Leukemia 
PLoS ONE  2009;4(7):e6257.
Resistance developed by leukemic cells, unsatisfactory efficacy on patients with chronic myeloid leukemia (CML) at accelerated and blastic phases, and potential cardiotoxity, have been limitations for imatinib mesylate (IM) in treating CML. Whether low dose IM in combination with agents of distinct but related mechanisms could be one of the strategies to overcome these concerns warrants careful investigation.
Methods and Findings
We tested the therapeutic efficacies as well as adverse effects of low dose IM in combination with proteasome inhibitor, Bortezomib (BOR) or proteasome inhibitor I (PSI), in two CML murine models, and investigated possible mechanisms of action on CML cells. Our results demonstrated that low dose IM in combination with BOR exerted satisfactory efficacy in prolongation of life span and inhibition of tumor growth in mice, and did not cause cardiotoxicity or body weight loss. Consistently, BOR and PSI enhanced IM-induced inhibition of long-term clonogenic activity and short-term cell growth of CML stem/progenitor cells, and potentiated IM-caused inhibition of proliferation and induction of apoptosis of BCR-ABL+ cells. IM/BOR and IM/PSI inhibited Bcl-2, increased cytoplasmic cytochrome C, and activated caspases. While exerting suppressive effects on BCR-ABL, E2F1, and β-catenin, IM/BOR and IM/PSI inhibited proteasomal degradation of protein phosphatase 2A (PP2A), leading to a re-activation of this important negative regulator of BCR-ABL. In addition, both combination therapties inhibited Bruton's tyrosine kinase via suppression of NFκB.
These data suggest that combined use of tyrosine kinase inhibitor and proteasome inhibitor might be helpful for optimizing CML treatment.
PMCID: PMC2705802  PMID: 19606213
14.  Ouabain protects against adverse developmental programming of the kidney 
Nature Communications  2010;1(4):1-7.
The kidney is extraordinarily sensitive to adverse fetal programming. Malnutrition, the most common form of developmental challenge, retards the formation of functional units, the nephrons. The resulting low nephron endowment increases susceptibility to renal injury and disease. Using explanted rat embryonic kidneys, we found that ouabain, the Na,K-ATPase ligand, triggers a calcium–nuclear factor-κB signal, which protects kidney development from adverse effects of malnutrition. To mimic malnutrition, kidneys were serum deprived for 24 h. This resulted in severe retardation of nephron formation and a robust increase in apoptosis. In ouabain-exposed kidneys, no adverse effects of serum deprivation were observed. Proof of principle that ouabain rescues development of embryonic kidneys exposed to malnutrition was obtained from studies on pregnant rats given a low-protein diet and treated with ouabain or vehicle throughout pregnancy. Thus, we have identified a survival signal and a feasible therapeutic tool to prevent adverse programming of kidney development.
Poor maternal nutrition is known to affect fetal kidney development. This study shows that the sodium potassium ATPase ligand, ouabain, protects kidneys from cell death induced by serum starvation in vitro and from abnormal kidney development due to a low-protein diet in vivo.
PMCID: PMC2963829  PMID: 20975704

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