Search tips
Search criteria

Results 1-25 (135)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
1.  Nafamostat mesilate attenuates neuronal damage in a rat model of transient focal cerebral ischemia through thrombin inhibition 
Scientific Reports  2014;4:5531.
Evidence suggests that thrombin, a blood coagulation serine protease, mediates neuronal injury in experimental cerebral ischemia. Here, we test the hypothesis that nafamostat mesilate, a serine protease inhibitor, may ameliorate ischemia-induced neuronal damage through thrombin inhibition after ischemic stroke. Focal ischemia was induced in adult Sprague-Dawley rats by occlusion of the middle cerebral artery for 2 hours followed by 22 hours of reperfusion. The administration of nafamostat mesilate during ischemia and reperfusion reduced the brain infarct volume, edema volume and neurological deficit. Thrombin expression and activity in the ipsilateral striatum were increased after ischemia, whereas the administration of nafamostat mesilate significantly inhibited thrombin expression and activity. Immunostaining showed that the majority of thrombin was expressed in neurons. TUNEL staining showed that nafamostat mesilate reduced the number of dying cells during ischemia. A rat behavioral test showed that nafamostat mesilate treatment significantly improved the learning ability of ischemic rats. These results suggest that nafamostat mesilate may have a potential therapeutic role for neuroprotection against focal cerebral ischemia through thrombin inhibition.
PMCID: PMC4078306  PMID: 24985053
2.  Elevated Urinary Levels of Cystatin C and Neutrophil Gelatinase-Associated Lipocalin in Henoch-Schönlein Purpura Patients with Renal Involvement 
PLoS ONE  2014;9(6):e101026.
Henoch-Schönlein purpura (HSP) is a commonest systemic vasculitis in childhood. The long-term prognosis of HSP is determined by the degree of renal involvement. The aim of this study is to search novel clinically applicable biomarkers to evaluate renal involvement in HSP patients. 20 bio-indexes in urine samples were simultaneously screened by antibody array assay. We indicated that urinary levels of cystatin C (Cys C) and neutrophil gelatinase-associated lipocalin (NGAL) in HSP patients with renal involvement were significantly higher than those without renal involvement and healthy controls. Furthermore, ELISA was used to analyze urinary Cys C and NGAL levels in HSP patients with or without renal involvement, atopic dermatitis (AD) patients and healthy controls. Our results demonstrated that urinary Cys C and NGAL levels in HSP patients with renal involvement were significantly elevated, when compared with those without renal involvement, AD patients and control subjects. In addition, by receiver operating characteristic (ROC) curve analysis, we demonstrated that the area under the ROC curve of NGAL (0.789) was larger than that of Cys C (0.692). Taken together, we show firstly that urinary Cys C and NGAL levels is abnormally elevated in HSP patients with renal involvement. We suggest that urinary Cys C and NGAL are novel useful biomarkers of renal involvement in HSP patients.
PMCID: PMC4070996  PMID: 24963810
3.  Evaluation of the POSSUM, P-POSSUM and E-PASS scores in the surgical treatment of hilar cholangiocarcinoma 
The Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) model, its Portsmouth (P-POSSUM) modification and the Estimation of physiologic ability and surgical stress (E-PASS) are three surgical risk scoring systems used extensively to predict postoperative morbidity and mortality in general surgery. The aim was to undertake the first study of the predictive value of these models in patients undergoing surgical treatment of hilar cholangiocarcinoma.
A retrospective analysis was performed on data collected prospectively over a 10-year interval from January 2003 to December 2012. The morbidity and mortality risks were calculated using the POSSUM, P-POSSUM and E-PASS equations.
One hundred patients underwent surgical treatment of hilar cholangiocarcinoma. Complications were seen in 52 of 100 patients (52.0%). There were 10 postoperative in-hospital deaths (10.0%). Of 31 preoperative and intraoperative variables studied, operative type (P = 0.000), preoperative serum albumin (P = 0.003) and aspartate aminotransferase (P = 0.029) were found to be factors multivariate associated with postoperative complications. Intraoperative blood loss (P = 0.015), Bismuth-Corlette classification (P = 0.033) and preoperative hemoglobin (P = 0.041) were independent factors multivariate associated with in-hospital death. The POSSUM system predicted morbidity risk effectively with no significant lack of fit (P = 0.488) and an area under the ROC curve (AUC) of 0.843. POSSUM, P-POSSUM and E-PASS scores showed no significant lack of fit in calculating the mortality risk (P >0.05) and all yielded an AUC value exceeding 0.8. POSSUM had significantly more accuracy in predicting morbidity after major and major plus operations (O:E (observed/expected) ratio 0.98 and AUC 0.901) than after minor and moderate operations (O:E ratio 1.13 and AUC 0.759).
POSSUM, P-POSSUM and E-PASS scores effectively predict morbidity and mortality in surgical treatment of hilar cholangiocarcinoma. However, improvements are still needed in the future because none of these scoring systems yielded an AUC value exceeding 0.9 for operations with all different levels of severity. Only POSSUM had more accuracy in predicting postoperative morbidity after operations with higher severity.
Trial registration
This study was undertaken after obtaining approval from the ethics committee of School of Medicine, Shanghai Jiao Tong University with a trial registration number of http://09411960800.
PMCID: PMC4079624  PMID: 24961847
POSSUM; P-POSSUM; E-PASS; Morbidity; Mortality; Hilar cholangiocarcinoma
4.  Metastasis-Associated in Colon Cancer 1 Is a Novel Survival-Related Biomarker for Human Patients with Renal Pelvis Carcinoma 
PLoS ONE  2014;9(6):e100161.
Metastasis-associated in colon cancer 1 (MACC1) has recently been identified as a novel independent prognostic indicator for metastasis occurrence, overall survival and cancer-free survival for patients with colon cancer and other solid tumors. In this study, we investigated the role of MACC1 in the development and progression of renal pelvis carcinoma, a form of upper tract urothelial carcinomas. MACC1 protein has been found in the cytoplasm as well as in the nucleus of the transitional epithelial cells of the normal renal pelvis in immunohistochemical (IHC) assays. Quantitative IHC examinations revealed that MACC1 abnormal abundance in cancerous tissues might represent a biological indicator clinically suggestive of tumor malignancy in the renal pelvis. Furthermore, investigation of the association of MACC1 protein levels with clinicopathological parameters in this study has suggested a correlation of MACC1 expression with tumor-node-metastasis stage and histopathological grade of patients with renal pelvis carcinoma, with elevated MACC1 protein levels frequently associated with higher aggressiveness of the disease. Moreover, both disease-free survival and overall survival for the patients in the high MACC1 expression group were significantly lower than those in the low expression group. Multivariate analysis with a Cox proportional-hazards model suggested that MACC1 is indeed an independent prognostic indicator of overall survival and cancer-free survival for patients with renal pelvis carcinoma. Thus, MACC1 may represent a promising prognostic biomarker candidate, as well as a potential therapeutic target for this disease.
PMCID: PMC4064998  PMID: 24949951
5.  The Biocompatibility of Titanium Cardiovascular Devices Seeded With Autologous Blood-Derived Endothelial Progenitor Cells 
Biomaterials  2010;32(1):10-18.
Implantable and extracorporeal cardiovascular devices are commonly made from titanium (Ti) (e.g. Ti-coated Nitinol stents and mechanical circulatory assist devices). Endothelializing the blood-contacting Ti surfaces of these devices would provide them with an antithrombogenic coating that mimics the native lining of blood vessels and the heart. We evaluated the viability and adherence of peripheral blood-derived porcine endothelial progenitor cells (EPCs), seeded onto thin Ti layers on glass slides under static conditions and after exposure to fluid shear stresses. EPCs attached and grew to confluence on Ti in serum-free medium, without preadsorption of proteins. After attachment to Ti for 15 min, less than 5 % of the cells detached at a shear stress of 100 dyne/cm2. Confluent monolayers of EPCs on smooth Ti surfaces (Rq of 10 nm), exposed to 15 or 100 dyne/cm2 for 48 hours, aligned and elongated in the direction of flow and produced nitric oxide dependent on the level of shear stress. EPC-coated Ti surfaces had dramatically reduced platelet adhesion when compared to uncoated Ti surfaces. These results indicate that peripheral blood-derived EPCs adhere and function normally on Ti surfaces. Therefore EPCs may be used to seed cardiovascular devices prior to implantation to ameliorate platelet activation and thrombus formation.
PMCID: PMC4062098  PMID: 20926131
Biocompatibility; Cell adhesion; Progenitor cell; Titanium; Thrombogenicity; Endothelialisation
6.  Effects of NB001 and gabapentin on irritable bowel syndrome-induced behavioral anxiety and spontaneous pain 
Molecular Brain  2014;7:47.
Irritable bowel syndrome (IBS) is characterized by recurrent abdominal discomfort, spontaneous pain, colorectal hypersensitivity and bowel dysfunction. Patients with IBS also suffer from emotional anxiety and depression. However, few animal studies have investigated IBS-induced spontaneous pain and behavioral anxiety. In this study, we assessed spontaneous pain and anxiety behaviors in an adult mouse model of IBS induced by zymosan administration. By using Fos protein as a marker, we found that sensory and emotion related brain regions were activated at day 7 after the treatment with zymosan; these regions include the prefrontal cortex, anterior cingulate cortex, insular cortex and amygdala. Behaviorally, zymosan administration triggered spontaneous pain (decreased spontaneous activities in the open field test) and increased anxiety-like behaviors in three different tests (the open field, elevated plus maze and light/dark box tests). Intraperitoneal injection of NB001, an adenylyl cyclase 1 (AC1) inhibitor, reduced spontaneous pain but had no significant effect on behavioral anxiety. In contrast, gabapentin reduced both spontaneous pain and behavioral anxiety. These results indicate that NB001 and gabapentin may inhibit spontaneous pain and anxiety-like behaviors through different mechanisms.
PMCID: PMC4071154  PMID: 24935250
Irritable bowel syndrome; Zymosan; Visceral pain; Spontaneous pain; Anxiety
7.  Postsynaptic potentiation of corticospinal projecting neurons in the anterior cingulate cortex after nerve injury 
Molecular Pain  2014;10:33.
Long-term potentiation (LTP) is the key cellular mechanism for physiological learning and pathological chronic pain. In the anterior cingulate cortex (ACC), postsynaptic recruitment or modification of AMPA receptor (AMPAR) GluA1 contribute to the expression of LTP. Here we report that pyramidal cells in the deep layers of the ACC send direct descending projecting terminals to the dorsal horn of the spinal cord (lamina I-III). After peripheral nerve injury, these projection cells are activated, and postsynaptic excitatory responses of these descending projecting neurons were significantly enhanced. Newly recruited AMPARs contribute to the potentiated synaptic transmission of cingulate neurons. PKA-dependent phosphorylation of GluA1 is important, since enhanced synaptic transmission was abolished in GluA1 phosphorylation site serine-845 mutant mice. Our findings provide strong evidence that peripheral nerve injury induce long-term enhancement of cortical-spinal projecting cells in the ACC. Direct top-down projection system provides rapid and profound modulation of spinal sensory transmission, including painful information. Inhibiting cortical top-down descending facilitation may serve as a novel target for treating neuropathic pain.
PMCID: PMC4060852  PMID: 24890933
8.  Elevated Serum Levels of Visfatin in Patients with Henoch-Schönlein Purpura 
Annals of Dermatology  2014;26(3):303-307.
Henoch-Schönlein purpura (HSP) is an immune complex-mediated disease predominantly characterized by the deposition of circulating immune complexes containing immunoglobulin A (IgA) on the walls of small vessels. Although the pathogenesis of HSP is not yet fully understood, some researchers proposed that B-cell activation might play a critical role in the development of this disease.
To investigate the serum levels of visfatin (pre-B-cell colony-enhancing factor), B-cell-activating factor (BAFF), and CXCL13, and to analyze their association with disease severity.
The serum levels of visfatin, BAFF, and CXCL13 were measured by using a double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) in 43 patients with HSP and 45 controls. The serum levels of IgA anticardiolipin antibodies (ACA) were detected by using a double-antigen sandwich ELISA.
Levels of visfatin but not BAFF and CXCL13 were significantly elevated in the sera of patients with HSP in the acute stage, and restored to normal levels in the convalescent stage. Furthermore, serum levels of visfatin were significantly higher in patients with HSP having renal involvement than in those without renal involvement. Serum levels of visfatin were correlated with the severity of HSP and serum concentration of ACA-IgA.
We show for the first time that the serum levels of visfatin are abnormally elevated in patients with HSP. Visfatin may be associated with the pathogenesis of HSP.
PMCID: PMC4069639  PMID: 24966628
B-cell activating factor; Chemokine CXCL13; Henoch-Schoenlein purpura; Immunoglobulin A; Nicotinamide phosphoribosyltransferase
9.  Circulating Proteolytic Products of Carboxypeptidase N for Early Detection of Breast Cancer 
Clinical chemistry  2013;60(1):233-242.
Carboxypeptidase N (CPN) plays an important role in regulating vasoactive peptide hormones, growth factors, and cytokines by specifically cleaving their C-terminal basic residues. Herein we demonstrated that the circulating peptides specifically cleaved by CPN in the tumor microenvironment can indeed be stage-specific indicators of breast cancer.
The activity of CPN was evaluated using an ex-vivo peptide cleavage assay, in which synthesized C3f peptide (His6-C3f_S1304-R1320-His6) is incubated in interstitial fluids of breast tumor and adjacent normal breast tissues in mice with orthotopic implantation of the human cell line MDA-MB-231. Fragment profiling, by an approach combining nanopore fractionation and mass spectrometry, revealed the nature and extent of cleavage by CPN. These results correlated with the level of CPN-catalyzed peptides in blood specimens taken from the tumor-bearing mice, healthy women and breast cancer patients. CPN expression in the same set of samples was further examined by immunohistochemistry and immunoblotting.
We showed that generation of C3f_R1310-L1319 specifically correlated with the CPN expression level. In both the mouse and clinical patient samples, the amount of CPN was clearly increased in tumor tissues compared to that seen in normal breast tissue, while its counterpart in blood remained constant. The amount of 6 CPN-catalyzed peptides predominantly increased in sera taken from the mice (n=8) at 2 weeks after orthotropic implantation. Six homologous peptides displayed the significantly higher expression in the patients’ plasma as early as the first pathologic stage of breast cancer.
The amount of circulating CPN-catalyzed peptides reported here reflects the extent of this enzyme’s activity in tumors, and our results clearly indicate their strong potential as biomarkers for non-invasive and early diagnosis of breast cancer.
PMCID: PMC4038544  PMID: 24146311
Circulating peptides; Nanopore-based assay; Breast cancer; Early detection; Carboxypeptidase N
10.  Association of Hepatitis B Virus Pre-S Deletions with the Development of Hepatocellular Carcinoma in Qidong, China 
PLoS ONE  2014;9(5):e98257.
To investigate the roles of mutations in pre-S and S regions of hepatitis B virus (HBV) on the progression of hepatocellular carcinoma (HCC) in Qidong, China.
We conducted an age matched case-control study within a cohort of 2387 male HBV carriers who were recruited from August, 1996. The HBV DNA sequence in pre-S/S regions was successfully determined in 96 HCC cases and 97 control subjects. In addition, a consecutive series of samples from 11 HCC cases were employed to evaluate the pre-S deletion patterns before and after the occurrence of HCC.
After adjustment for age, history of cigarette smoking and alcohol consumption, HBeAg positivity, pre-S deletions, pre-S2 start codon mutations, and T53C mutation were significantly associated with HCC, showing adjusted odds ratios (ORs) from 1.914 to 3.199. HCC patients also had a lower frequency of T31C mutation in pre-S2 gene, compared with control subjects (0.524; 95% CI 0.280-0.982). HBV pre-S deletions were clustered mainly in the 5′ end of pre-S2 region. Multivariate analysis showed that pre-S deletions and pre-S2 start codon mutations were independent risk factors for HCC. The OR (95% CI) were 2.434 (1.063–5.573) and 3.065 (1.099–8.547), respectively. The longitudinal observation indicated that the pre-S deletion mutations were not acquired at the beginning of HBV infection, but that the mutations occurred during the long course of liver disease.
Pre-S deletions and pre-S2 start codon mutations were independently associated with the development of HCC. The results also provided direct evidence that pre-S deletion mutations were not acquired from the beginning of infection but arose de novo during the progression of liver disease.
PMCID: PMC4029943  PMID: 24849936
11.  Proteasomal interaction as a critical activity modulator of the human constitutive androstane receptor 
The Biochemical journal  2014;458(1):95-107.
The CAR (constitutive androstane receptor; NR1I3) is a critical xenobiotic sensor that regulates xenobiotic metabolism, drug clearance, energy and lipid homoeostasis, cell proliferation and development. Although constitutively active, in hepatocytes CAR is normally held quiescent through a tethering mechanism in the cytosol, anchored to a protein complex that includes several components, including heat-shock protein 90. Release and subsequent nuclear translocation of CAR is triggered through either direct binding to ligand activators such as CITCO {6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime} or through indirect chemical activation, such as with PB (phenobarbital). In the present study, we demonstrate that proteasomal inhibition markedly disrupts CAR function, repressing CAR nuclear trafficking, disrupting CAR’s interaction with nuclear co-activators and inhibiting induction of CAR target gene responses in human primary hepatocytes following treatment with either PB or CITCO. Paradoxically, these effects occur following accumulation of ubiquitinated hCAR (human CAR). Furthermore, a non-proteolytic function was indicated by its interaction with a SUG1 (suppressor for Gal1), a subunit of the 26S proteasome. Taken together, these data demonstrate that the proteasome complex functions at multiple levels to regulate the functional biology of hCAR activity.
PMCID: PMC4019979  PMID: 24224465
constitutive androstane receptor; hepatocyte; human; lactacystin; MG-132; NR1I3; proteasome
12.  Diabetes Attitude Scale: Validation in Type-2 Diabetes Patients in Multiple Centers in China 
PLoS ONE  2014;9(5):e96473.
The aim of the paper is to report the development and psychometric testing of Diabetes Attitude Scale.
A prospective study was performed. The cultural equivalency and content validity of the Diabetes Attitude Scale were determined by panels of endocrinologists, physiologists, nurses and dieticians. An accurate and usable translation was obtained for each of five subscales examining attitudes on need for special training, the seriousness of type-2 diabetes, the need for controlling the condition, its psychosocial impact and the degree of autonomy given to patients in decision making. The validation was derived from 5961 patients with type-2 diabetes, recruited from 50 centers in 29 provinces throughout China between March 1st and September 30th, 2010.
The modified Diabetes Attitude Scale showed an acceptable level of internal consistency. The strength of the inter-correlations among the domains of five subscales suggests that the instrument measures related but separate domains of patients' attitudes toward diabetes. Moreover, the test-retest intraclass correlation coefficients were high enough to support the stability of the Chinese version of the third version of the scale.
The psychometric properties of the Chinese version of Diabetes Attitude Scale demonstrated satisfactory validity and reliability and appeared to effectively evaluate attitudes toward diabetes in patients with type-2 diabetes.
PMCID: PMC4011833  PMID: 24802805
13.  Female breast cancer survival in Qidong, China, 1972–2011: a population-based study 
BMC Cancer  2014;14:318.
Based on data from the population-based Qidong Cancer Registry, we report a survival analysis for female breast cancer patients diagnosed during 1972–2011 in order to assess the long-term trends for the prognosis of this cancer.
The last follow-up for survival status of the 3,398 registered female breast cancer cases was April, 2012. Cumulative observed survival (OS) and relative survival (RS) rates were calculated using Hakulinen’s method performed by the SURV3.01 Software developed at the Finnish Cancer Registry.
The one-, three-, five-, ten-, fifteen-, twenty-, thirty-, and forty- year OS rates were 83.61%, 67.53%, 58.75%, 48.56%, 42.57%, 38.30%, 29.19%, 19.35%; and the RS rates were 84.76%, 70.45%, 63.12%, 56.81%, 55.26%, 56.36%, 62.59%, 84.00%, respectively. Five-year RS rates of age groups 15–34, 35–44, 45–54, 55–64, 65–74, and 75+ were 60.17%, 68.27%, 67.79%, 56.03%, 55.50%, and 57.28%; 10-year RS rates were 54.16%, 59.59%, 61.34%, 47.78%, 51.30%, and 59.28%, respectively. There were statistical differences among the age groups (RS: χ2 = 152.15, P = 0.000). Remarkable improvement could be seen for the 5-year RS rates from 52.08% in 1972 to 69.26% in 2003–2007, and the 10-year RS rates from 43.16% in 1972 to 60.85% in 1998–2002, respectively.
Survival outcomes from Qidong registered cases with breast cancer have shown gradual progress during the past 40 years. The disparities between survival rates of this area and developed countries are getting narrower, but there is still great need for improving survival in Qidong.
PMCID: PMC4016778  PMID: 24886526
Breast cancer; Cancer registration; Observed survival; Relative survival; Qidong
14.  The Effect of XPD Polymorphisms on Digestive Tract Cancers Risk: A Meta-Analysis 
PLoS ONE  2014;9(5):e96301.
The Xeroderma pigmento-sum group D gene (XPD) plays a key role in nucleotide excision repair. Single nucleotide polymorphisms (SNP) located in its functional region may alter DNA repair capacity phenotype and cancer risk. Many studies have demonstrated that XPD polymorphisms are significantly associated with digestive tract cancers risk, but the results are inconsistent. We conducted a comprehensive meta-analysis to assess the association between XPD Lys751Gln polymorphism and digestive tract cancers risk. The digestive tract cancers that our study referred to, includes oral cancer, esophageal cancer, gastric cancer and colorectal cancer.
We searched PubMed and EmBase up to December 31, 2012 to identify eligible studies. A total of 37 case-control studies including 9027 cases and 16072 controls were involved in this meta-analysis. Statistical analyses were performed with Stata software (version 11.0, USA). Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association.
The results showed that XPD Lys751Gln polymorphism was associated with the increased risk of digestive tract cancers (homozygote comparison (GlnGln vs. LysLys): OR = 1.12, 95% CI = 1.01–1.24, P = 0.029, P heterogeneity = 0.133). We found no statistical evidence for a significantly increased digestive tract cancers risk in the other genetic models. In the subgroup analysis, we also found the homozygote comparison increased the susceptibility of Asian population (OR = 1.28, 95% CI = 1.01–1.63, P = 0.045, P heterogeneity = 0.287). Stratified by cancer type and source of control, no significantly increased cancer risk was found in these subgroups. Additionally, risk estimates from hospital-based studies and esophageal studies were heterogeneous.
Our meta-analysis suggested that the XPD 751Gln/Gln genotype was a low-penetrate risk factor for developing digestive tract cancers, especially in Asian populations.
PMCID: PMC4008560  PMID: 24787743
15.  DNA-Guided-Metal Nanoparticle Formation on Graphene Oxide Surface 
PMCID: PMC3779546  PMID: 23436286
Metal Nanoparticles; DNA guided; graphene oxide
16.  Investigation of Avian Influenza Infections in Wild Birds, Poultry and Humans in Eastern Dongting Lake, China 
PLoS ONE  2014;9(4):e95685.
We investigated avian influenza infections in wild birds, poultry, and humans at Eastern Dongting Lake, China. We analyzed 6,621 environmental samples, including fresh fecal and water samples, from wild birds and domestic ducks that were collected from the Eastern Dongting Lake area from November 2011 to April 2012. We also conducted two cross-sectional serological studies in November 2011 and April 2012, with 1,050 serum samples collected from people exposed to wild birds and/or domestic ducks. Environmental samples were tested for the presence of avian influenza virus (AIV) using quantitative PCR assays and virus isolation techniques. Hemagglutination inhibition assays were used to detect antibodies against AIV H5N1, and microneutralization assays were used to confirm these results. Among the environmental samples from wild birds and domestic ducks, AIV prevalence was 5.19 and 5.32%, respectively. We isolated 39 and 5 AIVs from the fecal samples of wild birds and domestic ducks, respectively. Our analysis indicated 12 subtypes of AIV were present, suggesting that wild birds in the Eastern Dongting Lake area carried a diverse array of AIVs with low pathogenicity. We were unable to detect any antibodies against AIV H5N1 in humans, suggesting that human infection with H5N1 was rare in this region.
PMCID: PMC3995770  PMID: 24755911
17.  Sodium Tanshinone IIA Silate Inhibits High Glucose-Induced Vascular Smooth Muscle Cell Proliferation and Migration through Activation of AMP-Activated Protein Kinase 
PLoS ONE  2014;9(4):e94957.
The proliferation of vascular smooth muscle cells may perform a crucial role in the pathogenesis of diabetic vascular disease. AMPK additionally exerts several salutary effects on vascular function and improves vascular abnormalities. The current study sought to determine whether sodium tanshinone IIA silate (STS) has an inhibitory effect on vascular smooth muscle cell (VSMC) proliferation and migration under high glucose conditions mimicking diabetes without dyslipidemia, and establish the underlying mechanism. In this study, STS promoted the phosphorylation of AMP-activated protein kinase (AMPK) at T172 in VSMCs. VSMC proliferation was enhanced under high glucose (25 mM glucose, HG) versus normal glucose conditions (5.5 mM glucose, NG), and this increase was inhibited significantly by STS treatment. We utilized western blotting analysis to evaluate the effects of STS on cell-cycle regulatory proteins and found that STS increased the expression of p53 and the Cdk inhibitor, p21, subsequent decreased the expression of cell cycle-associated protein, cyclin D1. We further observed that STS arrested cell cycle progression at the G0/G1 phase. Additionally, expression and enzymatic activity of MMP-2, translocation of NF-κB, as well as VSMC migration were suppressed in the presence of STS. Notably, Compound C (CC), a specific inhibitor of AMPK, as well as AMPK siRNA blocked STS-mediated inhibition of VSMC proliferation and migration. We further evaluated its potential for activating AMPK in aortas in animal models of type 2 diabetes and found that Oral administration of STS for 10 days resulted in activation of AMPK in aortas from ob/ob or db/db mice. In conclusion, STS inhibits high glucose-induced VSMC proliferation and migration, possibly through AMPK activation. The growth suppression effect may be attributable to activation of AMPK-p53-p21 signaling, and the inhibitory effect on migration to the AMPK/NF-κB signaling axis.
PMCID: PMC3989257  PMID: 24739942
18.  Radix Astragali Improves Dysregulated Triglyceride Metabolism and Attenuates Macrophage Infiltration in Adipose Tissue in High-Fat Diet-Induced Obese Male Rats through Activating mTORC1-PPARγ Signaling Pathway 
PPAR Research  2014;2014:189085.
Increased levels of free fatty acids (FFAs) and hypertriglyceridemia are important risk factors for cardiovascular disease. The effective fraction isolated from radix astragali (RA) has been reported to alleviate hypertriglyceridemia. The mechanism of this triglyceride-lowering effect of RA is unclear. Here, we tested whether activation of the mTORC1-PPARγ signaling pathway is related to the triglyceride-lowering effect of RA. High-fat diet-induced obese (DIO) rats were fed a high-fat diet (40% calories from fat) for 9-10 weeks, and 4 g/kg/d RA was administered by gavage. RA treatment resulted in decreased fasting triglyceride levels, FFA concentrations, and adipocyte size. RA treated rats showed improved triglyceride clearance and fatty acid handling after olive oil overload. RA administration could also decrease macrophage infiltration and expression of MCP-1 and TNFα, but it may also increase the expression of PPARγ in epididymal adipose tissue from RA treated rats. Consistently, expressions of PPARγ and phospho-p70S6K were increased in differentiated 3T3-L1 adipocytes treated with RA. Moreover, RA couldnot upregulate the expression of PPARγ at the presence of rapamycin. In conclusion, the mTORC1-PPARγ signaling pathway is a potential mechanism through which RA exerts beneficial effects on the disturbance of triglyceride metabolism and dysfunction of adipose tissue in DIO rats.
PMCID: PMC4000987  PMID: 24817881
19.  Involvement of RbAp48 in erythroid differentiation of murine erythroleukemia cells induced by sodium butyrate 
Oncology Letters  2014;7(6):1785-1789.
Normal mammalian terminal erythroid differentiation is a precisely regulated process during which the progenitor cells execute particular programs to form a mature erythrocytic phenotype. In the present study, it was found that RbAp48, a histone-binding protein associated with retinoblastoma protein, was upregulated during terminal erythroid maturation in vivo and in vitro. This indicated that RbAp48, at least in part, participated in the regulation of murine erythropoiesis. Following sodium butyrate (SB) induction, murine erythroleukemia (MEL) cells began to re-enter erythroid differentiation and the ratio of differentiated cells reached ~80% at 72 h. The erythroid maturation-related mRNA expression of α-globin, β-globin and glycophorin A (GPA) was increased markedly, which indicated that SB induced MEL differentiation. During MEL differentiation, the RbAp48 level showed a 1.5-fold increase at 72 h, and the globin transcription factor (GATA)-1 level was also upregulated in the early stage of differentiation. By contrast, the c-Myc level was gradually downregulated in MEL differentiation. Using an immunofluorescence assay, the results of the study directly showed that the average fluorescence intensity of RbAp48 in each cell reached an almost 1.7-fold increase at 72 and 96 h. This was consistent with the western blot results of RbAp48 during MEL differentiation. In addition, reduced expression of RbAp48 by RNA inference decreased SB-induced MEL differentiation by ~20%, indicating that a high level of RbAp48 was essential for MEL differentiation. Taken together, these results established a functional link between RbAp48 and erythroid differentiation.
PMCID: PMC4049757  PMID: 24932233
RbAp48; murine erythroleukemia cell; sodium butyrate; erythroid differentiation
20.  Engineering a Cell-surface Aptamer Circuit for Targeted and Amplified Photodynamic Cancer Therapy 
ACS nano  2013;7(3):2312-2319.
Photodynamic therapy (PDT) is one of the most promising and noninvasive methods for clinical treatment of different malignant diseases. Here, we present a novel strategy of designing an aptamer-based DNA nanocircuit capable of the selective recognition of cancer cells, controllable activation of photosensitizer and amplification of photodynamic therapeutic effect. The aptamers can selectively recognize target cancer cells and bind to the specific proteins on cell membranes. Then the overhanging catalyst sequence on aptamer can trigger a toehold-mediated catalytic strand displacement to activate photosensitizer and achieve amplified therapeutic effect. The specific binding-induced activation allows the DNA circuit to distinguish diseased cells from healthy cells, reducing damage to nearby healthy cells. Moreover, the catalytic amplification reaction will only take place close to the target cancer cells, resulting in a high local concentration of singlet oxygen to selectively kill the target cells. The principle employed in this study demonstrated the feasibility of assembling a DNA circuit on cell membranes and could further broaden the utility of DNA circuits for applications in biology, biotechnology, and biomedicine.
PMCID: PMC3609929  PMID: 23397942
DNA nanocircuit; aptamer; photosensitizer; cancer therapy
21.  HMGB1-Promoted and TLR2/4-Dependent NK Cell Maturation and Activation Take Part in Rotavirus-Induced Murine Biliary Atresia 
PLoS Pathogens  2014;10(3):e1004011.
Recent studies show that NK cells play important roles in murine biliary atresia (BA), and a temporary immunological gap exists in this disease. In this study, we found high-mobility group box-1 (HMGB1) and TLRs were overexpressed in human and rotavirus-induced murine BA. The overexpressed HMGB1 released from the nuclei of rotavirus-infected cholangiocytes, as well as macrophages, activated hepatic NK cells via HMGB1-TLRs-MAPK signaling pathways. Immature NK cells had low cytotoxicity on rotavirus-injured cholangiocytes due to low expression of TLRs, which caused persistent rotavirus infection in bile ducts. HMGB1 up-regulated the levels of TLRs of NK cells and promoted NK cell activation in an age-dependent fashion. As NK cells gained increasing activation as mice aged, they gained increasing cytotoxicity on rotavirus-infected cholangiocytes, which finally caused BA. Adult NK cells eliminated rotavirus-infected cholangiocytes shortly after infection, which prevented persistent rotavirus infection in bile ducts. Moreover, adoptive transfer of mature NK cells prior to rotavirus infection decreased the incidence of BA in newborn mice. Thus, the dysfunction of newborn NK cells may, in part, participate in the immunological gap in the development of rotavirus induced murine BA.
Author Summary
Biliary atresia (BA) is the most common precipitating factor for liver transplantation in infants. BA is caused by the obstruction of hepatic bile ducts, leading to progressive obstructive jaundice and liver fibrosis. A well-recognized theory is that rotavirus injures biliary epithelia in a mouse model of BA, followed by attack of immunocytes, such as NK cells. We performed this research to investigate whether maturation and activation of NK cells take part in the development of BA. We identified that rotavirus induced HMGB1 release from injured bile ducts. HMGB1 induced NK cell activation in an age-dependent fashion via HMGB1-TLRs-MAPK signaling pathways. Newborn NK cells were unable to eliminate rotavirus-infected cholangiocytes, which caused persistent biliary infection; maturated NK cells were activated gradually and caused persistent biliary injury, which finally led to BA. We identify HMGB1 as an important pro-inflammatory initiator and a critical inducer for maturation of NK cells in the development of BA. HMGB1-induced activation of NK cells may, in part, plays crucial roles in the development of murine BA. Novel therapies targeting HMGB1 or TLRs in patients with BA may be applied in the future to decrease the activity of NK cells in order to inhibit the progression of BA.
PMCID: PMC3961347  PMID: 24651485
22.  Increased Plasma DPP4 Activity Is an Independent Predictor of the Onset of Metabolic Syndrome in Chinese over 4 Years: Result from the China National Diabetes and Metabolic Disorders Study 
PLoS ONE  2014;9(3):e92222.
To determine whether fasting plasma Dipeptidyl Peptidase 4 (DPP4) activity and active Glucagon-Like Peptide-1 (GLP-1) were predictive of the onset of metabolic syndrome.
A prospective cohort study was conducted of 2042 adults (863 men and 1,179 women) aged 18-70 years without metabolic syndrome examined in 2007(baseline) and 2011(follow-up). Baseline plasma DPP4 activity was determined as the rate of cleavage of 7-amino-4- methylcoumarin (AMC) from the synthetic substrate H-glycyl-prolyl-AMC and active GLP-1 was determined by enzymoimmunoassay.
During an average of 4 years of follow-up, 131 men (15.2%) and 174 women (14.8%) developed metabolic syndrome. In multiple linear regression analysis, baseline DPP4 activity was an independent predictor of an increase in insulin resistance over a 4-year period (P<0.01). In multivariable-adjusted models, the odds ratio (OR) for incident metabolic syndrome comparing the highest with the lowest quartiles of DPP4 activity and active GLP-1 were 2.82, 0.45 for men and 2.48, 0.36 for women respectively. Furthermore, plasma DPP4 activity significantly improved the area under the ROC curve for predicting new-onset metabolic syndrome based on information from metabolic syndrome components (Both P<0.01).
DPP4 activity is an important predictor of the onset of insulin resistance and metabolic syndrome in apparently healthy Chinese men and women. This finding may have important implications for understanding the aetiology of metabolic syndrome.
Trial Registration
#TR-CCH-Chi CTR-CCH-00000361
PMCID: PMC3960228  PMID: 24647445
23.  A novel mycobacterial Hsp70-containing fusion protein targeting mesothelin augments antitumor immunity and prolongs survival in murine models of ovarian cancer and mesothelioma 
Although dendritic cell (DC) vaccines are considered to be promising treatments for advanced cancer, their production and administration is costly and labor-intensive. We developed a novel immunotherapeutic agent that links a single-chain antibody variable fragment (scFv) targeting mesothelin (MSLN), which is overexpressed on ovarian cancer and mesothelioma cells, to Mycobacterium tuberculosis (MTB) heat shock protein 70 (Hsp70), which is a potent immune activator that stimulates monocytes and DCs, enhances DC aggregation and maturation and improves cross-priming of T cells mediated by DCs.
Binding of this fusion protein with MSLN on the surface of tumor cells was measured by flow cytometry and fluorescence microscopy. The therapeutic efficacy of this fusion protein was evaluated in syngeneic and orthotopic mouse models of papillary ovarian cancer and malignant mesothelioma. Mice received 4 intraperitoneal (i.p.) treatments with experimental or control proteins post i.p. injection of tumor cells. Ascites-free and overall survival time was measured. For the investigation of anti-tumor T-cell responses, a time-matched study was performed. Splenocytes were stimulated with peptides, and IFNγ- or Granzyme B- generating CD3+CD8+ T cells were detected by flow cytometry. To examine the role of CD8+ T cells in the antitumor effect, we performed in vivo CD8+ cell depletion. We further determined if the fusion protein increases DC maturation and improves antigen presentation as well as cross-presentation by DCs.
We demonstrated in vitro that the scFvMTBHsp70 fusion protein bound to the tumor cells used in this study through the interaction of scFv with MSLN on the surface of these cells, and induced maturation of bone marrow-derived DCs. Use of this bifunctional fusion protein in both mouse models significantly enhanced survival and slowed tumor growth while augmenting tumor-specific CD8+ T-cell dependent immune responses. We also demonstrated in vitro and in vivo that the fusion protein enhanced antigen presentation and cross-presentation by targeting tumor antigens towards DCs.
This new cancer immunotherapy has the potential to be cost-effective and broadly applicable to tumors that overexpress mesothelin.
PMCID: PMC3943805  PMID: 24565018
Mycobacterial Hsp70; Mesothelin; Single chain variable fragment; Cancer immunotherapy; Murine tumor model
24.  Full Genome Sequence of a Recombinant H1N2 Avian Influenza Virus Isolated from Wild Waterfowl in the East Dongting Lake Wetland 
Genome Announcements  2014;2(1):e00023-14.
Here, we report the full genome sequence of an H1N2 avian influenza virus (AIV) isolated from wild waterfowl in Dongting Lake. Phylogenetic analysis showed that it was a novel recombinant AIV between domestic ducks and wild waterfowl. Investigation of this virus is helpful for our understanding of the ecology of AIV in this region.
PMCID: PMC3931351  PMID: 24558230
25.  Few-Layer MoSe2 Possessing High Catalytic Activity towards Iodide/Tri-iodide Redox Shuttles 
Scientific Reports  2014;4:4063.
Due to the two-dimensional confinement of electrons, single- and few-layer MoSe2 nanostructures exhibit unusual optical and electrical properties and have found wide applications in catalytic hydrogen evolution reaction, field effect transistor, electrochemical intercalation, and so on. Here we present a new application in dye-sensitized solar cell as catalyst for the reduction of I3− to I− at the counter electrode. The few-layer MoSe2 is fabricated by surface selenization of Mo-coated soda-lime glass. Our results show that the few-layer MoSe2 displays high catalytic efficiency for the regeneration of I− species, which in turn yields a photovoltaic energy conversion efficiency of 9.00%, while the identical photoanode coupling with “champion” electrode based on Pt nanoparticles on FTO glass generates efficiency only 8.68%. Thus, a Pt- and FTO-free counter electrode outperforming the best conventional combination is obtained. In this electrode, Mo film is found to significantly decrease the sheet resistance of the counter electrode, contributing to the excellent device performance. Since all of the elements in the electrode are of high abundance ratios, this type of electrode is promising for the fabrication of large area devices at low materials cost.
PMCID: PMC3924216  PMID: 24525919

Results 1-25 (135)