Harbin, China

Harbin Medical University is a public university located in Harbin, Heilongjiang, China. Wikipedia.


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Li S.-S.,Harbin Medical University | Ran Y.-J.,Harbin Medical University | Zhang D.-D.,Harbin Medical University | Li S.-Z.,Harbin Medical University | Zhu D.,Harbin Medical University
Journal of Cellular Biochemistry | Year: 2014

Pulmonary arterial hypertension (PAH) is associated with sustained vasoconstriction, profound structural remodeling of vasculatures and alterations in Ca2+ homeostasis in arterial smooth muscle cells (SMCs), while the underlying mechanisms are still elusive. By regulating the expression of proteins, microRNAs (miRNAs) are known to play an important role in cell fates including differentiation, apoptosis and proliferation, and may be involved in the development of PAH. Based on our previous study, hypoxia produced a significant increase of the miR-190 level in the pulmonary artery (PA), here, we used synthetic miR-190 to mimic the increase in hypoxic conditions and showed evidence for the effects of miR-190 on pulmonary arterial vasoconstriction and Ca2+ influx in arterial SMCs. Synthetic miR-190 remarkably enhanced the vasoconstriction responses to phenylephrine (PE) and KCl. The voltage-gated K+ channel subfamily member, Kcnq5, mRNA was shown to be a target for miR-190. Meanwhile, miR-190 antisense oligos can partially reverse the effects of miR-190 on PASMCs and PAs. Therefore, these results suggest that miR-190 appears to be a positive regulator of Ca2+ influx, and plays an important role in hypoxic pulmonary vascular constriction. © 2014 Wiley Periodicals, Inc.


Lu B.,University of Groningen | Lu B.,Harbin Medical University | Tigchelaar W.,University of Groningen | Ruifrok W.P.T.,University of Groningen | And 3 more authors.
European Journal of Heart Failure | Year: 2012

Aims Although cardiac diseases account for the highest mortality and morbidity rates in Western society, there is still a considerable gap in our knowledge of genes that contribute to cardiac (dys)function. Here we screened for gene expression profiles correlated to heart failure. Methods and results By expression profiling we identified a novel gene, termed DHRS7c, which was significantly down-regulated by adrenergic stimulation and in heart failure models. Dhrs7c is a short chain dehydrogenase/reductase (SDR) and is localized to the endo/sarcoplasmic reticulum. Dhrs7c is strongly conserved in vertebrates, and mRNA and protein expression levels were highest in heart and skeletal muscle followed by skin, but were not detectable in other organs. In vitro, both α-and β-adrenergic stimulation repressed Dhrs7c expression in neonatal cardiomyocytes and this could be mimicked by the direct activation of protein kinase C and adenylate cyclase, the respective intracellular targets of these hormones. In contrast, endothelin-1, which also provoked strong hypertrophy development in vitro, did not repress Dhrs7c expression. The latter suggests adrenergic specificity and indicates that down-regulation is not a prerequisite for hypertrophy development. In vivo adrenergic stimulation could also down-regulate Dhrs7c expression. Finally, we confirmed that expression was also down-regulated in two different models of failure and, importantly, also in biopsies from human heart failure patients. Conclusion Our results show that the expression of Dhrs7c, a novel endo/sarcoplasmic reticulum-localized SDR, is inversely correlated with adrenergic stimulation and heart failure development. © 2011 The Author.


Zhang L.,Harbin Medical University | Zhang L.,Shanghai University | Wang N.,Shanghai University | Shen Q.,Shanghai University | And 2 more authors.
PLoS ONE | Year: 2013

The aim of this study was to investigate the therapeutic efficacy of percutaneous radiofrequency (RF) ablation versus microwave (MW) ablation for hepatocellular carcinoma (HCC) measuring ≤5 cm in greatest diameter. From January 2006 to December 2006, 78 patients had undergone RF ablation whereas 77 had undergone MW ablation. Complete ablation (CA), local tumour progression (LTP) and distant recurrence (DR) were compared. The overall survival curves were calculated with the Kaplan-Meier technique and compared with the log-rank test. The CA rate was 83.4% (78/93) for RF ablation and 86.7%(91/105 for MW ablation. The LTP rate was 11.8% (11/93) for RF ablation and 10.5% (11/105) for MW ablation. DR was found in 51 (65.4%) in the RF ablation and 62 (80.5%) in the MW ablation. There was no significant difference in the 1-, 3-, and 5-year overall survival rates (P = 0.780) and the 1-, 3-, and 5-year disease-free survival rates (P = 0.123) between RF and MW ablation. At subgroup analyses, for patients with tumors ≤3.0 cm, there was no significant difference in the 1-, 3-, and 5-year overall survival rates (P = 0.067) and the corresponding disease-free survival rates(P = 0.849). For patients with tumor diameters of 3.1-5.0 cm, the 1-, 3-, and 5-year overall survival rates were 87.1%, 61.3%, and 40.1% for RF ablation and 85.4%, 36.6%, and 22% for MW ablation, with no significant difference (P = 0.068). The corresponding disease-free survival rates were 74.2%, 54.8%, and 45.2% for the RF ablation group and 53.3%, 26.8%, and 17.1% for the MW ablation group. The disease-free survival curve for the RF ablation group was significantly better than that for the MW ablation group (P = 0.018). RF ablation and MW ablation are both effective methods in treating hepatocellular carcinomas, with no significant differences in CA, LTP, DR, and overall survival. © 2013 Zhang et al.


Wang T.,Peking University | Gou Z.,Harbin Medical University | Wang F.,University of Connecticut | Nling M.,Harbin Medical University | Zhai S.-D.,Peking University
PLoS ONE | Year: 2014

Background: Incretin-based therapies which include glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are recommended by several practice guidelines as second-line agents for add-on therapy to metformin in patients with type 2 diabetes (T2DM) who do not achieve glycemic control with metformin plus lifestyle interventions alone. The purpose of this study is to perform a systematic review with meta-analysis of existing head to head studies to compare the efficacy and safety of GLP-1 analogues with DPP-4 inhibitors. Methods: We performed a systematic review and meta-analysis of head-to-head studies to compare GLP-1 analogues with DPP-4 inhibitors in the management of type 2 diabetes. A random effects model was selected to perform the meta-analyses, results were expressed as weighted mean differences for continuous outcomes and relative risks for dichotomous outcomes, both with 95% confidence intervals, and with I2 values and P values as markers of heterogeneity. Results: Four head-to-head randomized controlled studies with 1755 patients were included. Compared to sitagliptin, GLP-1 analogues are more effective in reducing HbA1C (weight mean difference -0.41%, 95% CI -0.51 to -0.31) and body weight (weight mean difference -1.55 kg, 95% CI -1.98 to -1.12). Conversely, GLP-1 analogues are associated with a higher incidence of gastrointestinal adverse events compared to sitagliptin: nausea (relative risk 3.14, 95% CI 2.15 to 4.59), vomiting (relative risk 2.60, 95% CI 1.48 to 4.56), diarrhea (relative risk 1.82, 95% CI 1.24 to 2.69), and constipation (relative risk 2.50, 95% CI 1.33 to 4.70). Conclusions: The result of this meta-analysis demonstrates that compared to sitagliptin, GLP-1 analogues are more effective for glycemic control and weight loss, but have similar efficacy in reducing blood pressure and lipid parameters, however, GLP-1 analogues are associated with a higher incidence of gastrointestinal adverse events and a similar incidence of hypoglycemia compared to sitagliptin. © 2014 Wang et al.


Li X.,Nanjing Medical University | Zhang J.,Peking Union Medical College | Huang J.,Nanjing Medical University | Ma A.,Xi'an Jiaotong University | And 8 more authors.
Journal of the American College of Cardiology | Year: 2013

Objectives The purpose of this study was to assess the effects of qili qiangxin capsules in patients with chronic heart failure (CHF). Background Qili qiangxin capsules are a traditional Chinese medicine that has been approved in China for the treatment of CHF, but the evidence supporting its efficacy remains unclear. Methods A total of 512 patients with CHF were enrolled and randomly assigned to receive the placebo or qili qiangxin capsules in addition to their standard medications for the treatment of CHF. The primary endpoint was the reduction or percent change in the plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) level during 12 weeks of treatment. Results At the 12-week follow-up, a significant reduction in the NT-proBNP level from baseline was observed in both groups, but the qili qiangxin capsule group demonstrated a significantly greater reduction than the placebo group (p = 0.002); 47.95% of patients in the qili qiangxin capsule group demonstrated reductions in NT-proBNP levels of at least 30% compared with 31.98% of patients in the placebo group (p < 0.001). Treatment with qili qiangxin capsules also demonstrated superior performance in comparison to the placebo with respect to New York Heart Association functional classification, left ventricular ejection fraction, 6-min walking distance, and quality of life. Conclusions On a background of standard treatment, qili qiangxin capsules further reduced the levels of NT-proBNP. Together, our data suggest that qili qiangxin capsules could be used in combination therapy for CHF. © 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.


Wang T.,Peking University | Wang F.,University of Connecticut | Gou Z.,Harbin Medical University | Tang H.,Peking University | And 3 more authors.
Diabetes, Obesity and Metabolism | Year: 2015

To investigate the real-world incidence of acute pancreatitis (AP) associated with incretin-based therapy (IBT). Methods: We carried out a systematic review and meta-analysis of observational studies using Medline, PubMed, Embase, the Cochrane Database, ClinicalTrials.gov and conference proceedings. We included: those studies in which AP was a pre-defined clinical outcome; longitudinal studies (case-control, cohort); studies that adjusted for confounders; studies that reported on a population exposed to IBT; studies in which non-IBT users or past users (who received IBTs >90days before the index date) were used as the control group; studies that reported risk estimates [relative risks, odds ratios (ORs) or hazard ratios] with 95% confidence intervals (CIs) for AP event with IBT use, or that reported sufficient data to estimate these; and publications in the English language. Data were extracted by two independent investigators, and a consensus was reached with involvement of a third. Study-specific ORs from seven cohort studies and two case-control studies were meta-analysed using random-effects models. Associations were tested in subgroups representing different patient characteristics and study quality. Results: A total of nine studies that included 1324515 patients and 5195 cases of AP were included in our meta-analysis. The summary estimate of OR for an association between IBT and AP was 1.03 (95% CI 0.87-1.20). Conclusions: The present meta-analysis of real-world data does not suggest that IBT is associated with AP. Although we should continue to remain vigilant, IBTs should be regarded as reasonable options to consider adding to the regimen of a patient with type 2 diabetes. © 2014 John Wiley & Sons Ltd.


Zhu W.,Harbin Medical University | Han B.,Harbin Medical University | Sun Y.,Peking University | Wang Z.,Shenyang Medical College | Yang X.,Harbin Medical University
Carbohydrate Polymers | Year: 2012

In this research we purified one homogeneous glucogalactan from the roots of Panax quinquefolium, with a molecular weight of 54 kDa estimated by high-performance gel permeation chromatography (HPGPC). The monosaccharide composition of PPQ was composed of Glc (glucose) and Gal (galactose) in a molar ratio of 2.1:1, as determined by gas chromatography (GC). In order to evaluate the anti-lung carcinoma and immunoregulatory effects of this glucogalactan in mice, we established a Lewis lung carcinoma model in C57BL/6 mouse. The results showed that PPQ not only could inhibit the growth of lung tumor, but also enhance the thymus and spleen indices, as well as the level of IFN-γ, IL-10 and IL-2, indicating PPQ could have a possible cancer therapeutic potential. © 2011 Elsevier Ltd.


Li Y.,Harbin Medical University | Tian X.-X.,Harbin Medical University | Wang R.-T.,Harbin Medical University
Endocrine | Year: 2015

Type 2 diabetes mellitus (DM) carries an increased risk for cardiovascular complications. The brachial-ankle pulse wave velocity (baPWV) is an index for early atherosclerotic changes. Recently, the effect of altered blood rheology on atherosclerosis has received attention. Therefore, this study aimed to examine the association of hemorheological parameters with baPWV in patients with DM. In this cross-sectional study, we investigated the relationship between rheological parameters and baPWV in 323 control subjects (160 men and 163 women) and 382 patients with DM (170 men and 212 women). The participants with DM had higher whole blood viscosity (WBV) levels both at low shear rate (3 s−1) and at high shear rate (200 s−1) than those without DM. Different metabolic parameters were compared across WBV (3 s−1) quartiles. The mean values of baPWV gradually increased with WBV (3 s−1) quartiles. In addition, there was a positive correlation between baPWV and WBV 3 s−1 in patients with DM after adjusting confounding factors (r = 0.285, p = 0.039). Stepwise multiple linear regression analysis further revealed that WBV (3 s−1) is a significant determinant for increased baPWV in DM (β = 0.184; p < 0.001). However, there were no association between WBV (3 s−1) and baPWV in control subjects. The findings showed that baPWV increased as WBV (3 s−1) elevated in DM. Moreover, WBV (3 s−1) is independently associated with baPWV even after adjusting other cardiovascular risk factors. Early detection of abnormal WBV levels at low shear rate should warrant for early search of undetected arterial stiffness in patients with DM. © 2014, Springer Science+Business Media New York.


Jia Y.,Monash University | Jia Y.,Peking University | Morand E.F.,Monash University | Song W.,Monash University | And 4 more authors.
Journal of Cellular Physiology | Year: 2013

Annexin-A1 (AnxA1) is a glucocorticoid-induced protein with multiple actions in the regulation of inflammatory cell activation. The contribution of AnxA1 to human cell biology is not well understood. We investigated the contribution of AnxA1 and its receptor, formyl-peptide receptor 2 (FPR2), to the regulation of inflammatory responses in human normal lung fibroblasts (NLF). Silencing constitutive AnxA1 expression in NLF using small interfering RNA (siRNA) was associated with moderate but significant increases in tumor necrosis factor (TNF)-induced proliferation and interleukin (IL)-6 production, accompanied by reduction of ERK and NF-κB activity. AnxA1 regulation of ERK and NF-κB activation was associated with effects on proliferation. Blocking FPR2 using the specific antagonist WRW4 mimicked the effects of AnxA1 silencing on TNF-induced proliferation, IL-6, ERK, and NF-κB activation. AnxA1 silencing also impaired inhibitory effects of glucocorticoid on IL-6 production and on the expression of glucocorticoid-induced leucine zipper (GILZ), but blocking FPR2 failed to mimic these effects of AnxA1 silencing. These data suggest that AnxA1 regulates TNF-induced proliferation and inflammatory responses in lung fibroblasts, via effects on the ERK and NF-κB pathways, which depend on FPR2. AnxA1 also mediates effects of glucocorticoids and GILZ expression, but these effects appear independent of FPR2. These findings suggest that mimicking AnxA1 actions might have therapeutic potential in chronic inflammatory lung diseases. © 2012 Wiley Periodicals, Inc.


Gao R.,Chinese Academy of Sciences | Yang Y.,Chinese Academy of Sciences | Han Y.,General Hospital of Shenyang Military Command | Huo Y.,Peking University | And 12 more authors.
Journal of the American College of Cardiology | Year: 2015

Background The everolimus-eluting bioresorbable vascular scaffold (BVS) is designed to achieve results comparable to metallic drug-eluting stents at 1 year, with improved long-term outcomes. Whether the 1-year clinical and angiographic results of BVS are noninferior to current-generation drug-eluting stents has not been established. Objectives This study sought to evaluate the angiographic efficacy and clinical safety and effectiveness of BVS in a randomized trial designed to enable approval of the BVS in China. Methods Eligible patients with 1 or 2 de novo native coronary artery lesions were randomized to BVS or cobalt-chromium everolimus-eluting stents (CoCr-EES) in a 1:1 ratio stratified by diabetes and the number of lesions treated. Angiographic and clinical follow-up were planned at 1 year in all patients. The primary endpoint was angiographic in-segment late loss (LL), powered for noninferiority with a margin of 0.15 mm. Results A total of 480 patients were randomized (241 BVS vs. 239 CoCr-EES) at 24 sites. Acute clinical device success (98.0% vs. 99.6%; p = 0.22) and procedural success (97.0% and 98.3%; p = 0.37) were comparable in BVS- and CoCr-EES-treated patients, respectively. The primary endpoint of in-segment LL at 1 year was 0.19 ± 0.38 mm for BVS versus 0.13 ± 0.38 mm for CoCr-EES; the 1-sided 97.5% upper confidence limit of the difference was 0.14 mm, achieving noninferiority of BVS compared with CoCr-EES (pnoninferiority = 0.01). BVS and CoCr-EES also had similar 1-year rates of target lesion failure (cardiac death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization; 3.4% vs. 4.2%, respectively; p = 0.62) and definite/probable scaffold/stent thrombosis (0.4% vs. 0.0%, respectively; p = 1.00). Conclusions In the present multicenter randomized trial, BVS was noninferior to CoCr-EES for the primary endpoint of in-segment LL at 1 year. (A Clinical Evaluation of Absorb Bioresorbable Vascular Scaffold [Absorb BVS] System in Chinese Population - ABSORB China Randomized Controlled Trial [RCT]; NCT01923740) © 2015 American College of Cardiology Foundation.


Lu B.,University of Groningen | Mahmud H.,University of Groningen | Maass A.H.,University of Groningen | Yu B.,Harbin Medical University | And 3 more authors.
PLoS ONE | Year: 2010

BI 2536 is a new anti-mitotic drug that targets polo-like kinase 1 (Plk1) and is currently under clinical development for cancer therapy. The effect of this drug on cancer cells has been extensively investigated, but information about the effects on primary dividing cells and differentiated non-dividing cells is scarce. We have investigated the effects of this drug on primary neonatal rat cardiac fibroblasts and on differentiated cardiomyocytes and explored the possibility to use this drug to enrich differentiated cell populations in vitro. BI 2536 had a profound effect on cardiac fibroblast proliferation in vitro and arrested these cells in mitosis with an IC50 of about 43 nM. Similar results were observed with primary human cells (HUVEC, IC50 = 30 nM), whereas the cancer cell line HeLa was more sensitive (IC50 of 9 nM). Further analysis revealed that prolonged mitotic arrest resulted in cell death for about 40% of cardiac fibroblasts. The remaining cells showed an interphase morphology with mostly multi- and micro-nucleated nuclei. This indicates that a significant number of primary fibroblasts are able to escape BI 2536 induced mitotic arrest and apparently become aneuploid. No effects were observed on cardiomyocytes and hypertrophic response (growth) upon endothelin-1 and phenylephrine stimulation was normal in the presence of BI 2536. This indicates that BI 2536 has no adverse effects on terminally differentiated cells and still allows proliferation independent growth induction in these cells. In conclusion, cardiomyocytes could be enriched using BI 2536, but the formation of aneuploidy in proliferating cells most likely limits this in vitro application and does not allow its use in putative cell based therapies. © 2010 Lu et al.


Shen L.,Qiqihar Medical School | Wang P.,Harbin Medical University | Yang J.,Jilin Province Tumor Hospital | Li X.,Jiamusi University
PLoS ONE | Year: 2014

Osteosarcoma is the most common type of primary tumor of bone which mainly affects adolescents and young adults. Osteosarcoma causes large number of deaths because of its complex pathogenesis and resistance to conventional treatment. MicroRNAs are a class of small noncoding RNAs that function as critical gene regulators through targeting mRNAs, causing translational repression or degradation. In this study, we showed that miR-217 was down-regulated in osteosarcoma cell lines and tissues in comparison to that in normal bone cells or tissues. Meanwhile, the lower level of miR-217 was associated with metastasis in clinical osteosarcoma patients. Furthermore, we found that overexpession of miR-217 markedly suppressed cell proliferation, migration, and invasion of osteosarcoma cells. Conversely, the inhibition of miR-217 expression significantly accelerated the cell proliferation, migration, and invasion. Moreover, we identified WASF3 as a novel functional downstream target of miR-217. The ectopic expression of WASF3 can partially reverse the inhibition of cell proliferation and invasion caused by miR-217. Take together, our results demonstrate that miR-217 functions as a tumor-suppressive miRNA and inhibits the osteosarcoma tumorigenesis through targeting WASF3. Copyright: © 2014 Bischoff et al.


Li Z.,Harbin Medical University | Xie K.,University of Houston
Current Pharmaceutical Design | Year: 2015

Pancreatic ductal adenocarcinoma (PDAC) still remains one of the most fatal human malignant tumors. Long-term survival rate is still extremely pathetic even for patients who receive surgery. Epithelial-to-mesenchymal transition (EMT), which is a physiologic process of morphological as well as genetic changes in carcinoma cells, plays a vital role in aggressiveness of PDAC. Meanwhile EMT is also the reason why pancreatic cancer cells achieve such huge metastatic potentials. Many tumor microenvironmental factors such as cytokines, growth factors, as well as chemotherapeutic agents may induce EMT. Our study provides evidence regarding effects of EMT on pancreatic cancer progression, focusing on the correlation between EMT and other pathways which are crucial to tumor progression, especially vitamin D receptor signaling pathway. Research on signal pathways resulting in EMT inactivation during these disease processes may offer innovative ideas on plasticity of cellular phenotypes as well as possible therapeutic interventions. © 2015 Bentham Science Publishers.


Tian J.,Harbin Medical University | Tian J.,Harvard University | Dauerman H.,University of Vermont | Toma C.,University of Pittsburgh | And 15 more authors.
Journal of the American College of Cardiology | Year: 2014

Background The relationship between features of vulnerable plaque and angiographic coronary stenosis is unknown. Objectives The purpose of this study was to systematically investigate the absolute number, relative prevalence, and characteristics of thin-cap fibroatheroma (TCFA) at different degrees of stenosis using optical coherence tomography (OCT), intravascular ultrasound, and coronary angiography. Methods We identified 643 plaques from 255 subjects who underwent OCT imaging in all 3 coronary arteries. They were divided into 3 groups on the basis of angiographic diameter stenosis: Group A (30% to 49%, n = 325), Group B (50% to 69%, n = 227), and Group C (>70%, n = 91). Results OCT showed that the absolute number of TCFA was greatest in Group A (n = 58), followed by Groups B (n = 40) and C (n = 33). However, the relative prevalence of TCFA was higher in Group C (36%) than in Groups A (18%) or B (18%) (p = 0.003 and p = 0.002, respectively). Fibrous cap of TCFA was thinner in Group C than in Groups A (p < 0.001) or B (p = 0.001). intravascular ultrasound showed that the plaque burden of TCFA was largest in Group C (80.1 ± 7.4%), compared with Groups B (67.5 ± 9.4%) and A (58.1 ± 8.4%). TCFA in Group C had a higher remodeling index than those in Group A (p = 0.002). Conclusions The absolute number of TCFA is 3 times greater in nonsevere stenosis than in severe stenosis. It is, however, twice as likely for a lesion to be TCFA in cases of severe stenosis than in nonsevere stenosis. Moreover, TCFA in severely-stenotic areas had more features of plaque vulnerability. © 2014 by the American College of Cardiology Foundation.


Li N.,Harbin Medical University | Zhang G.-W.,Harbin Medical University | Zhang J.-R.,Harbin Medical University | Jin D.,Harbin Medical University | And 2 more authors.
Nutrition, Metabolism and Cardiovascular Diseases | Year: 2015

Background and aims: NAFLD is an independent risk factor for increased cardiovascular disease. Arterial stiffness is an index of subclinical atherosclerosis. The aims of this study were to examine prospectively the relationship between Non-alcoholic fatty liver disease (NAFLD) and the progression of arterial stiffness. Methods and results: A prospective study of 728 men and 497 women free of hypertension, and diabetes at the baseline were conducted. The subjects were followed for 5 years. The progression rate of arterial stiffness was measured by calculating the increase in brachial-ankle pulse wave velocity (baPWV) the changes of the baPWV (adjusted for age) during the study period was significantly greater in the patients with NAFLD (172.4±42.1cm/s for men, 95.8±36.7cm/s for women) than in the subjects without NAFLD (70.3±56.5cm/s for men, 55.4±42.2cm/s for women). For the subjects with metabolic syndrome, after adjusting for multiple risk factors, NAFLD was a significant predictor of baPWV progression (for male, β=0.843; P<0.001; for female, β=0.575; P<0.001, respectively). In addition, results were unmodified in subjects without metabolic syndrome. Conclusions: NAFLD was found to be an independent predictor of faster progression of baPWV even after adjusting other cardiovascular risk factors. These prospective data support a pathogenic role for NAFLD in the development of arterial stiffness. © 2014 Elsevier B.V.


Huang X.,Medical College of Wisconsin | Huang X.,Harbin Medical University | Yuan T.,Medical College of Wisconsin | Liang M.,Harbin Medical University | And 18 more authors.
European Urology | Year: 2015

Background Extracellular microRNAs (miRNAs) embedded in circulating exosomes may serves as prognostic biomarkers in cancer. Objective To identify and evaluate plasma exosomal miRNAs for prognosis in castration-resistant prostate cancer (CRPC). Design, setting, and participants RNA sequencing was performed to identify candidate exosomal miRNAs associated with overall survival in a screening cohort of 23 CRPC patients. Candidate miRNAs were further evaluated for prognosis using quantitative real-time polymerase chain reaction in a follow-up cohort of 100 CRPC patients. Outcome measurements and statistical analysis Cox regression and Kaplan-Meier survival analyses were used to evaluate survival association using candidate miRNAs along with clinical prognostic factors. Results and limitations RNA sequencing in screening cohort generated approximately 6.80 million mappable reads per patient. Of those with normalized read counts ≥5, 43% were mapped to miRNAs for a total of 375 known and 57 novel miRNAs. Cox regression analysis identified an association of miR-1290, -1246, and -375 with overall survival (false discover rate < 0.05). Of those, higher levels of miR-1290 and -375 were significantly associated with poor overall survival (p < 0.004) in the follow-up cohort. Incorporation of miR-1290/-375 into putative clinical prognostic factors-based models in CRPC stage significantly improved predictive performance with a time-dependent area under the curve increase from 0.66 to 0.73 (p = 6.57 × 10-6). Conclusions Plasma exosomal miR-1290 and miR-375 are promising prognostic biomarkers for CRPC patients. Prospective validation is needed for further evaluation of these candidate miRNAs. Patient summary In this study, we evaluated whether small RNAs circulating in blood could be used to predict clinical outcomes in late-stage prostate cancer patients. We identified two blood-based small RNAs whose levels showed significant association with survival. Our results warrant further investigation because the noninvasive blood-based test has great potential in the management of late-stage prostate cancer. © 2014 European Association of Urology.


Gao X.,Harbin Medical University | Jiang S.,Harbin Medical University | Tian H.,Harbin Medical University | Jiang C.,Georgia State University | Zhu D.,Harbin Medical University
Hypertension | Year: 2012

Chronic hypoxia is the most common cause of secondary pulmonary hypertension, for which the mechanisms are still unclear. Recent studies implicated an important role for microRNAs (miRNAs) in hypoxia-mediated responses in various cellular processes, including cell apoptosis and proliferation. Therefore, we hypothesized that these regulatory molecules might be implicated in the etiology of hypoxic pulmonary hypertension. Here we show that miRNA-328, a posttranscriptional regulator, was drastically downregulated in the pulmonary artery (PA) after a hypoxic assault. PA rings, Western blot, quantitative real-time PCR, in situ hybridization, and luciferase assay were used to investigate the role of miRNA-328 in hypoxic pulmonary hypertension. We found that hypoxia produced a significant inhibition of miRNA-328 expression, which was involved in PA vasoconstriction and remodeling. Overexpressing miRNA-328 in the transgenic mice remarkably decreased the right ventricular systolic pressure and PA wall thickness under both normoxia and hypoxia. MiRNA-328 inhibited L-type calcium channel-α1C expression through a miRNA-328 binding site within the 3′ untranslational region of L-type calcium channel-α1C. The L-type calcium channel-α1C inhibition attenuated the PA response to KCl. Furthermore, miRNA-328 suppressed the insulin growth factor 1 receptor, ultimately leading to apoptosis of pulmonary arterial smooth muscle cells. The posttranscriptional repression of L-type calcium channel-α1C and insulin growth factor 1 receptor was further confirmed by luciferase reporter assay. These results showed that miRNA-328, an important protecting factor, plays a significant role in PA constriction and remodeling by regulating multiple gene targets in hypoxic pulmonary hypertension. © 2012 American Heart Association, Inc.


Yang W.,China Japan Friendship Hospital | Lu J.,Chinese People's Liberation Army | Weng J.,Sun Yat Sen University | Jia W.,Shanghai JiaoTong University | And 16 more authors.
New England Journal of Medicine | Year: 2010

BACKGROUND: Because of the rapid change in lifestyle in China, there is concern that diabetes may become epidemic. We conducted a national study from June 2007 through May 2008 to estimate the prevalence of diabetes among Chinese adults. METHODS: A nationally representative sample of 46,239 adults, 20 years of age or older, from 14 provinces and municipalities participated in the study. After an overnight fast, participants underwent an oral glucose-tolerance test, and fasting and 2-hour glucose levels were measured to identify undiagnosed diabetes and prediabetes (i.e., impaired fasting glucose or impaired glucose tolerance). Previously diagnosed diabetes was determined on the basis of self-report. RESULTS: The age-standardized prevalences of total diabetes (which included both previously diagnosed diabetes and previously undiagnosed diabetes) and prediabetes were 9.7% (10.6% among men and 8.8% among women) and 15.5% (16.1% among men and 14.9% among women), respectively, accounting for 92.4 million adults with diabetes (50.2 million men and 42.2 million women) and 148.2 million adults with prediabetes (76.1 million men and 72.1 million women). The prevalence of diabetes increased with increasing age (3.2%, 11.5%, and 20.4% among persons who were 20 to 39, 40 to 59, and ≥60 years of age, respectively) and with increasing weight (4.5%, 7.6%, 12.8%, and 18.5% among persons with a body-mass index [the weight in kilograms divided by the square of the height in meters] of <18.5, 18.5 to 24.9, 25.0 to 29.9, and ≥30.0, respectively). The prevalence of diabetes was higher among urban residents than among rural residents (11.4% vs. 8.2%). The prevalence of isolated impaired glucose tolerance was higher than that of isolated impaired fasting glucose (11.0% vs. 3.2% among men and 10.9% vs. 2.2% among women). CONCLUSIONS: These results indicate that diabetes has become a major public health problem in China and that strategies aimed at the prevention and treatment of diabetes are needed. Copyright © 2010 Massachusetts Medical Society. All rights reserved.


Zhou C.,Tongji University | Wu Y.-L.,Guangdong Academy of Medical science | Chen G.,Harbin Medical University | Feng J.,Jiangsu Province Cancer Hospital | And 19 more authors.
The Lancet Oncology | Year: 2011

Background: Activating mutations in EGFR are important markers of response to tyrosine kinase inhibitor (TKI) therapy in non-small-cell lung cancer (NSCLC). The OPTIMAL study compared efficacy and tolerability of the TKI erlotinib versus standard chemotherapy in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC. Methods: We undertook an open-label, randomised, phase 3 trial at 22 centres in China. Patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received either oral erlotinib (150 mg/day) until disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin. Patients were randomly assigned (1:1) with a minimisation procedure and were stratified according to EGFR mutation type, histological subtype (adenocarcinoma vs non-adenocarcinoma), and smoking status. The primary outcome was progression-free survival, analysed in patients with confirmed disease who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT00874419, and has completed enrolment; patients are still in follow-up. Findings: 83 patients were randomly assigned to receive erlotinib and 82 to receive gemcitabine plus carboplatin; 82 in the erlotinib group and 72 in the chemotherapy group were included in analysis of the primary endpoint. Median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy (13.1 [95% CI 10.58-16.53] vs 4.6 [4.21-5.42] months; hazard ratio 0.16, 95% CI 0.10-0.26; p<0.0001). Chemotherapy was associated with more grade 3 or 4 toxic effects than was erlotinib (including neutropenia in 30 [42%] of 72 patients and thrombocytopenia in 29 [40%] patients on chemotherapy vs no patients with either event on erlotinib); the most common grade 3 or 4 toxic effects with erlotinib were increased alanine aminotransferase concentrations (three [4%] of 83 patients) and skin rash (two [2%] patients). Chemotherapy was also associated with increased treatment-related serious adverse events (ten [14%] of 72 patients [decreased platelet count, n=8; decreased neutrophil count, n=1; hepatic dysfunction, n=1] vs two [2%] of 83 patients [both hepatic dysfunction]). Interpretation: Compared with standard chemotherapy, erlotinib conferred a significant progression-free survival benefit in patients with advanced EGFR mutation-positive NSCLC and was associated with more favourable tolerability. These findings suggest that erlotinib is important for first-line treatment of patients with advanced EGFR mutation-positive NSCLC. Funding: F Hoffmann-La Roche Ltd (China); Science and Technology Commission of Shanghai Municipality. © 2011 Elsevier Ltd.


Liu G.,Guangdong Medical College | Liu G.,CAS Tianjin Institute of Industrial Biotechnology | Yao L.,Harbin Medical University | Liu J.,The First Hospital of Harbin | And 5 more authors.
Neurobiology of Aging | Year: 2014

Alzheimer's disease (AD) is the most common and complex neurodegenerative disease in the elderly individuals. Recently, genome-wide association studies (GWAS) have been used to investigate AD pathogenesis. These GWAS have yielded important new insights into the genetic mechanisms of AD. However, these newly identified AD susceptibility loci exert only very small risk effects and cannot fully explain the underlying AD genetic risk. We hypothesize that combining the findings from different AD GWAS may have greater power than genetic analysis alone. To identify new AD risk factors, we integrated findings from 3 previous large-scale AD GWAS (n= 14,138) using a gene-based meta-analysis and subsequently conducted a pathway analysis using the kyoto encyclopedia of genes and genomes and gene ontology databases. Interestingly, we not only confirmed previous findings, but also highlighted, for the first time, the involvement of cardiovascular disease-related pathways in AD. Our results provided the clues as to the link between these diseases using pathway analysis methods. We believe that these findings will be very useful for future genetic studies of AD. © 2014 Elsevier Inc.


Song H.,Harbin Medical University | Li C.,Harbin Medical University | Li R.,Peking University | Geng J.,Harbin Medical University
International Journal of Colorectal Disease | Year: 2010

Background: Astrocyte elevated gene-1 (AEG-1), as an HIV-1 or TNF-α-inducible transcript, is associated with various aspects of tumor malignancy. However, relatively little knowledge is available related to the role of AEG-1 in colorectal carcinoma. Methods: By immunohistochemical and western blot analysis, we investigated AEG-1 expression in normal mucosa, adenomas, and carcinomas of colorectum. By statistical analysis, we determined its relationship with clinicopathological parameters and overall survival in colorectal carcinoma. Results: We found that AEG-1 expression levels were gradually elevated in normal tissues, low-grade adenoma, high-grade adenoma, and colorectal carcinoma, respectively. Though AEG-1 staining mainly emerged in the cytoplasm, we observed that nuclear staining of AEG-1 tends to become more common in lesions from patients with more advanced disease stages. Furthermore, there was a similar trend for Ki67 expression (as a proliferative index) from normal mucous to adenoma and carcinoma. Statistical analysis revealed that AEG-1 expression was markedly correlated with the UICC stage (P<0.001), T classification (P=0.002), N classification (P=0.015), M classification (P=0.010), Ki67 expression (P=0.012), and histological differentiation (P=0.037) in the colorectal cancer patients. Besides, those patients with high AEG-1 levels had shorter survival time (P<0.001). Conclusions: High AEG-1 expression correlates with poor overall survival in the colorectal carcinoma patients. In addition, AEG-1 expression in colorectal carcinoma may be associated with tumor progression, indicating that AEG-1 may be a potential preventive and chemotherapeutic target in the patients. © 2010 Springer-Verlag.


Hua Z.,Harbin Medical University | Li D.,Harbin Medical University | Xiang G.,Harbin Medical University | Xu F.,Harbin Medical University | And 4 more authors.
Breast Cancer Research and Treatment | Year: 2011

The programmed death-1 (PD-1) is a potent immunoregulatory molecule which is responsible for the negative regulation of T-cell activation and peripheral tolerance. In order to investigate the association between polymorphisms of PD-1 and breast cancer, a case-control study was conducted in Chinese female population consisting of 490 cases with breast cancer and 512 age-matched healthy individuals from Heilongjiang Province of China. Four polymorphisms of the PD-1 gene, including rs36084323 (PD-1.1), rs7421861, rs2227982 (PD-1.9), and rs2227981 (PD-1.5), were selected and genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The frequencies of PD-1.1 GG genotype and PD-1.5 CT genotype were significantly lower in cases compared with controls (P = 0.020 and 0.004, respectively), and PD-1.5 CC genotype and C allele had higher frequencies in cases (P = 0.003 and 0.010). In haplotype analysis, we observed that the frequencies of ATTC and GTCT haplotypes were lower in cases than those of in controls (P = 0.0055 and 0.0012, respectively), whereas the GTCC and ATCC haplotypes had higher frequencies in cases (P = 0.0040 and 0.00008037, respectively). Additionally, strong association was showed between PD-1.1 and P53, and haplotype CCTA was associated with ER status. These results primarily suggest that PD-1 gene polymorphisms may affect the breast cancer risk and prognosis in Chinese Han females of Heilongjiang Province in Northeast China. © 2011 Springer Science+Business Media, LLC.


Yin M.,Harbin Medical University | Xu Y.,Harbin Medical University | Lou G.,Harbin Medical University | Hou Y.,Harbin Medical University | And 4 more authors.
International Journal of Cancer | Year: 2011

LAPTM4B is a novel tumor-associated gene. To date, there have been no published data regarding the role of LAPTM4B expression in epithelial ovarian carcinoma metastasis. Therefore, this study was performed to determine whether LAPTM4B overexpression is a new predictor of epithelial ovarian carcinoma metastasis. LAPTM4B expression was evaluated in 22 normal ovarian specimens and 139 ovarian carcinomas by western blotting analyses and immunohistochemistry. Univariate and multivariate analyses were used to determine the association between LAPTM4B expression and epithelial ovarian carcinoma metastasis. Western blotting analysis demonstrated that LAPTM4B was overexpressed in metastatic tissues from patients with ovarian cancers, and immunohistochemistry results revealed that among 59 patients with LAPTM4B overexpression, 57 (96.6%) presented intraperitoneal metastasis and 31 (52.5%) had lymph node metastasis. The results of the univariate and multivariate analyses demonstrated that LAPTM4B overexpression correlated with metastasis. The odds ratio of high-to-low expression for intraperitoneal metastasis was 11.410 (95% CI: 2.357, 55.239) and that for lymph node metastasis was 6.332 (95% CI: 2.533, 15.831). For intraperitoneal metastasis, the sensitivity and specificity of LAPTM4B overexpression were 48.7% and 90.9%; for lymph node metastasis, they were 73.8%% and 71.1%, respectively. LAPTM4B overexpression is a new predictor of epithelial ovarian carcinoma metastasis and an important potential biomarker for the early diagnosis of ovarian carcinoma. Copyright © 2010 UICC.


Yuan L.,Harbin Medical University | Yuan L.,State Province Key Laboratories of Biomedicine Pharmaceutics of China | Zhao H.,Daqing Oilfield General Hospital | Zhang L.,Harbin Medical University | Liu X.,Harbin Medical University
Tumor Biology | Year: 2013

Multigene-based combination therapy is an effective practice in cancer gene therapy. Apoptin is a chicken anemia virus-derived, p53-independent, Bcl-2-insensitive apoptotic protein with the ability to specifically induce apoptosis in various human tumor cells. Interleukin-24 (IL-24) displays ubiquitous antitumor property and tumor-specific killing activity. Adeno-associated virus (AAV) is a promising gene delivery vehicle due to its advantage of low pathogenicity and long-term gene expression. In this study, we assessed the efficacy of combination therapy using AAV-mediated co-expression of apoptin and interleukin-24 on hepatocellular carcinoma in vitro and in vivo. Our results showed that AAV-mediated co-expression of IL-24 and apoptin significantly suppressed the growth and induced the apoptosis of HepG2 cells in vitro. Furthermore, AAV-mediated combined treatment of IL-24 and apoptin significantly suppressed tumor growth and induced apoptosis of tumor cells in xenograft nude mice. These data suggest that AAV vectors that co-express apoptin and IL-24 have great potential in cancer gene therapy. © 2013 International Society of Oncology and BioMarkers (ISOBM).


Tang L.,Harbin Medical University | Liu S.-L.,Harbin Medical University | Liu S.-L.,University of Calgary | Liu S.-L.,Peking University
Antonie van Leeuwenhoek, International Journal of General and Molecular Microbiology | Year: 2012

A key issue troubling bacterial taxonomy and systematics is the lack of a biological species definition. Criteria to be used for defining bacterial species on genetic and biological bases should be able to reveal clear-cut boundaries among clusters of bacteria. To date, DNA-DNA re-association assays and ribosomal RNA sequence comparison have been useful in determining relative evolutionary distances among bacteria but the data are continuous and thus cannot define bacterial clusters as taxonomic units to be called species. Using Salmonella as models, we have looked for definite genetic and biologic uniqueness of clusters of bacteria. Based on our findings that each Salmonella lineage has a unique genome structure shared by strains of the same lineage but not overlapping with strains of other Salmonella lineages, we conclude that this is a result of genetic isolation following divergence of the bacteria. We propose that there should be genetic boundaries between different species of bacteria at the genomic level, which awaits further genomic information for validation. © Springer Science+Business Media B.V. 2011.


Meng F.,Harbin Medical University | Song H.,Harbin Medical University | Luo C.,Red Cross | Yin M.,Harbin Medical University | And 4 more authors.
Cancer | Year: 2011

BACKGROUND: Lysosome-associated protein transmembrane 4 beta (LAPTM4B), a novel oncoprotein, is overexpressed in several carcinomas. Previous studies revealed that LAPTM4B polymorphisms contribute to the risk of certain types of cancers. The purpose of this study was to investigate the association between different LAPTM4B alleles and the risk of cervical carcinoma. METHODS: A case-control analysis was performed in 317 patients with cervical cancer and 416 control subjects. Genomic DNA was extracted from peripheral blood lymphocytes in all participants. LAPTM4B genotypes were determined using polymerase chain reaction. Odds ratios and 95% confidence intervals (CIs) were computed using an unconditional logistic regression model. RESULTS: There was a significant difference (P<.001) in LAPTM4B*2 allele frequency between cervical cancer cases (35.8%) and controls (26.3%). There was also a significant difference in the overall genotypic distribution between patients and controls (P <.001). Using the LAPTM4B*1/1 genotype as a reference, we found that LAPTM4B allelic variation was associated with a significantly increased risk of cervical cancer, with adjusted odds ratios of 1.60 (95% CI, 1.15-2.22) and 2.12 (95% CI, 1.20-3.76) for the*1/2 and*2/2 genotype, respectively. Stratification analysis indicated that the association was more pronounced in younger subjects, smokers, premenopausal women, and women with more parities. Moreover, multiplicative joint effects were found between the*1/2 or*2/2 genotype and smoking. CONCLUSIONS: The findings of this study indicated that the LAPTM4B*2 allele might be a cervical cancer risk factor and may play an important role in genetic susceptibility to cervical cancer in the Chinese population. Copyright © 2011 American Cancer Society.


Zhang W.,Capital Medical University | Zhang J.,CAS Beijing Institute of Genomics | Yan W.,Capital Medical University | You G.,Capital Medical University | And 9 more authors.
Cancer | Year: 2013

Background: More reliable clinical outcome prediction is required to better guide more personalized treatment for patients with primary glioblastoma multiforme (GBM). The objective of this study was to identify a microRNA expression signature to improve outcome prediction for patients with primary GBM. METHODS: A cohort of Chinese patients with primary GBM (n = 82) was analyzed using whole-genome microRNA expression profiling with patients divided into a training set and a testing set. Cox regression and risk-score analyses were used to develop a 5-microRNA signature using 41 training samples. The signature was validated in 41 other test samples, in an independent cohort of 35 patients with GBM, and in the Cancer Genome Atlas data set. RESULTS: Patients who had high risk scores according to the 5-microRNA signature had poor overall survival and progression-free survival compared with patients who had low risk scores. Multivariate Cox analysis indicated that the 5-microRNA signature was an independent prognostic biomarker after adjusting for other clinicopathologic and genetic factors, such as extent of resection, temozolomide chemotherapy, preoperative Karnofsky performance status score, isocitrate dehydrogenase 1 (IDH1) mutation, and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. CONCLUSIONS: The 5-microRNA signature was identified as an independent risk predictor that identified patients who had a high risk of unfavorable outcome, demonstrating its potential for personalizing cancer management. The authors concluded that this signature should be evaluated in further prospective studies. © 2012 American Cancer Society.


Feng Y.,Harbin Medical University | Chen Z.,Zhejiang Hospital of Traditional Chinese Medicine | Liu S.-L.,Harbin Medical University | Liu S.-L.,Peking University | Liu S.-L.,University of Calgary
PLoS ONE | Year: 2011

Background: Many facultative bacterial pathogens have undergone extensive gene decay processes, possibly due to lack of selection pressure during evolutionary conversion from free-living to intracellular lifestyle. Shigella, the causative agents of human shigellosis, have arisen from different E. coli-like ancestors independently by convergent paths. As these bacteria all have lost large numbers of genes by mutation or deletion, they can be used as ideal models for systematically studying the process of gene function loss in different bacteria living under similar selection pressures. Methodologies/Principal Findings: We compared the sequenced Shigella genomes and re-defined decayed genes (pseudogenes plus deleted genes) in these bacteria. Altogether, 85 genes are commonly decayed in the five analyzed Shigella strains and 1456 genes are decayed in at least one Shigella strain. Genes coding for carbon utilization, cell motility, transporter or membrane proteins are prone to be inactivated. Decayed genes tend to concentrate in certain operons rather than distribute averagely across the whole genome. Genes in the decayed operon accumulated more non-synonymous mutations than the rest genes and meanwhile have lower expression levels. Conclusions: Different Shigella lineages underwent convergent gene decay processes, and inactivation of one gene would lead to a lesser selection pressure for the other genes in the same operon. The pool of superfluous genes for Shigella may contain at least two thousand genes and the gene decay processes may still continue in Shigella until a minimum genome harboring only essential genes is reached. © 2011 Feng et al.


Liu G.,CAS Tianjin Institute of Industrial Biotechnology | Jiang Y.,Harbin Medical University | Wang P.,CAS Tianjin Institute of Industrial Biotechnology | Feng R.,Harbin Medical University | And 4 more authors.
Journal of Neurochemistry | Year: 2012

Alzheimer's disease (AD) is a kind of complex neurological disorder. The complex genetic architecture of AD makes genetic analysis difficult. Fortunately, a pathway-based method to study the existing genome-wide association studies datasets has been applied into AD. However, no shared Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway was reported. In this study, we performed multiple pathway analyses of French AD genome-wide association studies dataset (discovery dataset, n = 7360, 2032 cases and 5328 controls) and Pfizer dataset (validation dataset, n = 2220, 1034 cases and 1186 controls). First, we performed multiple pathway analyses by Hypergeometric test, improved gene set enrichment analysis (IGSEA) and Z-statistic test in KEGG. Using Hypergeometric test, we identified 54 and 25 significant pathways (p < 0.05) in discovery dataset and validation dataset, respectively. Using IGSEA method, we identified three significant pathways in both discovery and validation datasets, respectively. Using Z-statistic test, we identified 19 significant pathways in validation dataset. Among the significant pathways, cell adhesion molecules (CAM) pathway was identified to be the only consistent signal emerging across multiple analyses in KEGG. After permutation and multiple testing corrections, CAM pathway was significant with p = 2.40E-05 (Hypergeometric test) and p = 3.00E-03 (IGSEA) in discovery dataset. In validation dataset, CAM pathway was significant with p = 1.84E-06 (Hypergeometric test), p = 1.00E-02 (IGSEA) and p = 2.81E-03 (Z-statistic test). We replicated the association by multiple pathway analyses in Gene Ontology using Hypergeometric test (WebGestalt), modified Fisher's exact test (DAVID) and Binomial test (PANTHER). Our findings provided further evidence on the association between CAM pathway and AD susceptibility, which would be helpful to study the genetic mechanisms of AD and may significantly assist in the development of therapeutic strategies. © 2011 International Society for Neurochemistry.


Goldstein I.J.,University of Groningen | Van Veldhuisen D.J.,University of Groningen | Bank R.A.,Harbin Medical University | De Boer R.A.,University of Michigan | De Boer R.A.,University of Groningen
Circulation: Heart Failure | Year: 2013

Background-Galectin-3 has been implicated in the development of organ fibrosis. It is unknown whether it is a relevant therapeutic target in cardiac remodeling and heart failure. Methods and Results-Galectin-3 knock-out and wild-type mice were subjected to angiotensin II infusion (2.5 μg/kg for 14 days) or transverse aortic constriction for 28 days to provoke cardiac remodeling. The efficacy of the galectin-3 inhibitor N-acetyllactosamine was evaluated in TGR(mREN2)27 (REN2) rats and in wild-type mice with the aim of reversing established cardiac remodeling after transverse aortic constriction. In wild-type mice, angiotensin II and transverse aortic constriction perturbations caused left-ventricular (LV) hypertrophy, decreased fractional shortening, and increased LV end-diastolic pressure and fibrosis (P<0.05 versus control wild type). Galectin-3 knock-out mice also developed LV hypertrophy but without LV dysfunction and fibrosis (P=NS). In REN2 rats, pharmacological inhibition of galectin-3 attenuated LV dysfunction and fibrosis. To elucidate the beneficial effects of galectin-3 inhibition on myocardial fibrogenesis, cultured fibroblasts were treated with galectin-3 in the absence or presence of galectin-3 inhibitor. Inhibition of galectin-3 was associated with a downregulation in collagen production (collagen I and III), collagen processing, cleavage, cross-linking, and deposition. Similar results were observed in REN2 rats. Inhibition of galectin-3 also attenuated the progression of cardiac remodeling in a long-term transverse aortic constriction mouse model. Conclusions-Genetic disruption and pharmacological inhibition of galectin-3 attenuates cardiac fibrosis, LV dysfunction, and subsequent heart failure development. Drugs binding to galectin-3 may be potential therapeutic candidates for the prevention or reversal of heart failure with extensive fibrosis. © 2013 American Heart Association, Inc.


Objective To assess the degree to which the Chinese people are protected from catastrophic household expenditure and impoverishment from medical expenses and to explore the health system and structural factors influencing the first of these outcomes. Methods Data were derived from the Fourth National Health Service Survey. An analysis of catastrophic health expenditure and impoverishment from medical expenses was undertaken with a sample of 55 556 households of different characteristics and located in rural and urban settings in different parts of the country. Logistic regression was used to identify the determinants of catastrophic health expenditure. Findings The rate of catastrophic health expenditure was 13.0%; that of impoverishment was 7.5%. Rates of catastrophic health expenditure were higher among households having members who were hospitalized, elderly, or chronically ill, as well as in households in rural or poorer regions. A combination of adverse factors increased the risk of catastrophic health expenditure. Families enrolled in the urban employee or resident insurance schemes had lower rates of catastrophic health expenditure than those enrolled in the new rural corporative scheme. The need for and use of health care, demographics, type of benefit package and type of provider payment method were the determinants of catastrophic health expenditure. Conclusion Although China has greatly expanded health insurance coverage, financial protection remains insufficient. Policy-makers should focus on designing improved insurance plans by expanding the benefit package, redesigning cost sharing arrangements and provider payment methods and developing more effective expenditure control strategies.


Li C.,Harbin Medical University | Cai J.,Harbin Medical University | Geng J.,Harbin Medical University | Li Y.,Harbin Medical University | And 2 more authors.
International Journal of Biological Macromolecules | Year: 2012

In this study, we purified a homogeneous polysaccharide (PGPW1) from the root of Panax ginseng. Its molecular weight was estimated to be 3.5×105Da by high performance liquid chromatography (HPLC) and Gas chromatography (GC) analysis identified that PGPW1 contained Glc, Gal, Man and Ara in the molar ratio of 3.3:1.2:0.5:1.1. Furthermore the antitumor potential of PGPW1 on human bladder T24 cells was evaluated in vitro by MTT, lactate dehydrogenase (LDH), wound scratch and transwell motility assays. PGPW1 dose-dependently displayed potent anti-proliferation and anti-metastatic activities. Moreover the modulating effect of PGPW1 on the binding of 3H-NMS to M3 muscarinic receptors on the surface of T24 cells was evaluated. In muscarinic receptor binding assay, the attenuated expression of M3 muscarinic receptor on the surface of T24 cells by PGPW1 would contribute to its antitumor functions. All the data indicated the potential of its clinical application for the prevention and treatment of bladder cancer metastasis. © 2012 Elsevier B.V.


Feng P.,University of Sichuan | Zhou X.-H.,Harbin Medical University | Zhou X.-H.,University of Washington | Zhou X.-H.,Peking University | And 3 more authors.
Statistics in Medicine | Year: 2012

The propensity score method is widely used in clinical studies to estimate the effect of a treatment with two levels on patient's outcomes. However, due to the complexity of many diseases, an effective treatment often involves multiple components. For example, in the practice of Traditional Chinese Medicine (TCM), an effective treatment may include multiple components, e.g. Chinese herbs, acupuncture, and massage therapy. In clinical trials involving TCM, patients could be randomly assigned to either the treatment or control group, but they or their doctors may make different choices about which treatment component to use. As a result, treatment components are not randomly assigned. Rosenbaum and Rubin proposed the propensity score method for binary treatments, and Imbens extended their work to multiple treatments. These authors defined the generalized propensity score as the conditional probability of receiving a particular level of the treatment given the pre-treatment variables. In the present work, we adopted this approach and developed a statistical methodology based on the generalized propensity score in order to estimate treatment effects in the case of multiple treatments. Two methods were discussed and compared: propensity score regression adjustment and propensity score weighting. We used these methods to assess the relative effectiveness of individual treatments in the multiple-treatment IMPACT clinical trial. The results reveal that both methods perform well when the sample size is moderate or large. © 2011 John Wiley & Sons, Ltd.


Wu Y.-L.,Guangdong General Hospital and Guandong Academy of Medical science | Zhou C.,Shanghai Pulmonary Hospital | Cheng Y.,Jilin Tumor Hospital | Lu S.,Shanghai JiaoTong University | And 7 more authors.
Annals of Oncology | Year: 2013

Background: This phase II, open-label study evaluated the efficacy and safety of erlotinib as second-line therapy in non-small-cell lung cancer (NSCLC) patients with brain metastases (BM). Patients and methods: Forty-eight patients aged 18-75 years with Eastern Cooperative Oncology Group performance status 0-2, confirmed adenocarcinoma or activating epidermal growth factor receptor (EGFR) mutationpositive NSCLC, and asymptomatic BM without extracranial progressive disease after first-line platinum-doublet chemotherapy were recruited. Treatment comprised erlotinib 150mg/day. The primary end point was progression-free survival (PFS) determined by RECIST. Results: The median PFS was 10.1 months [95% confidence interval (CI) 7.1-12.3] for intracranial progression and 9.7 months (95% CI 2.5-17.8) for intracranial and systemic progression. Patients with EGFR mutation-positive disease had significantly longer median PFS versus EGFR wild-type disease [15.2 months (95% CI 8.3-22.2) versus 4.4 months (95% CI 0.0-11.6); P = 0.02]. The median overall survival was 18.9 months (95% CI 14.4-23.4); 6-month and 1-year survival rates were 85% and 73%, respectively. Overall response rate was 58.3%. Most common adverse events were rash (77.1%), paronychia (20.8%), hyperbilirubinemia (16.7%), and diarrhea (14.6%); these were predominantly of grade 1/2. Conclusions: Single-agent erlotinib was active and well tolerated in NSCLC patients with BM. Further studies are warranted. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Hurvitz S.A.,University of California at Los Angeles | Andre F.,University Paris - Sud | Jiang Z.,Beijing 307 Hospital of PLA | Shao Z.,Fudan University | And 16 more authors.
The Lancet Oncology | Year: 2015

Background: mTOR inhibition reverses trastuzumab resistance via the hyperactivated PIK/AKT/mTOR pathway due to PTEN loss, by sensitising PTEN-deficient tumours to trastuzumab. The BOLERO-1 study assessed the efficacy and safety of adding everolimus to trastuzumab and paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer. Methods: In this phase 3, randomised, double-blind trial, patients were enrolled across 141 sites in 28 countries. Eligible patients were aged 18 years or older, with locally assessed HER2-positive advanced breast cancer, with Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, who had not received previous trastuzumab or chemotherapy for advanced breast cancer within 12 months of randomisation, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) or bone lesions in the absence of measurable disease, without previous systemic treatment for advanced disease except endocrine therapy. Patients were randomly assigned (2:1) with an interactive voice and web response system to receive either 10 mg everolimus once a day orally or placebo plus weekly trastuzumab intravenously at 4 mg/kg loading dose on day 1 with subsequent weekly doses of 2 mg/kg of each 4 week cycle plus paclitaxel intravenously at a dose of 80 mg/m2 on days 1, 8, and 15 of each 4 week cycle. Randomisation was stratified according to previous use of trastuzumab and visceral metastasis. Patients and investigators were masked to the assigned treatments. Identity of experimental treatments was concealed by use of everolimus and placebo that were identical in packaging, labelling, appearance, and administration schedule. The two primary objectives were investigator-assessed progression-free survival in the full study population and in the subset of patients with hormone receptor-negative breast cancer at baseline; the latter was added during the course of the study, before unmasking based on new clinical and biological findings from other studies. All efficacy analyses were based on the intention-to-treat population. Enrolment for this trial is closed and results of the final progression-free survival analyses are presented here. This trial is registered with ClinicalTrials.gov, number NCT00876395. Findings: Between Sept 10, 2009, and Dec 16, 2012, 719 patients were randomly assigned to receive everolimus (n=480) or placebo (n=239). Median follow-up was 41·3 months (IQR 35·4-46·6). In the full population, median progression-free survival was 14·95 months (95% CI 14·55-17·91) with everolimus versus 14·49 months (12·29-17·08) with placebo (hazard ratio 0·89, 95% CI 0·73-1·08; p=0·1166). In the HR-negative subpopulation (n=311), median progression-free survival with everolimus was 20·27 months (95% CI 14·95-24·08) versus 13·08 months (10·05-16·56) with placebo (hazard ratio 0·66, 95% CI 0·48-0·91; p=0·0049); however, the protocol-specified significance threshold (p=0·0044) was not crossed. The most common adverse events with everolimus were stomatitis (314 [67%] of 472 patients in the everolimus group vs 77 [32%] of 238 patients in the placebo group), diarrhoea (267 [57%] vs 111 [47%] patients), and alopecia (221 [47%] vs 125 [53%]). The most frequently reported grade 3 or 4 adverse events in the everolimus group versus the placebo group were neutropenia (117 [25%] vs 35 [15%]), stomatitis (59 [13%] vs three [1%]), anaemia (46 [10%] vs six [3%]) and diarrhoea (43 [9%] vs 10 [4%]) On-treatment adverse event-related deaths were reported in 17 (4%) patients in the everolimus group and none in the placebo group. Interpretation: Although progression-free survival was not significantly different between groups in the full analysis population, the 7·2 months prolongation we noted with the addition of everolimus in the HR-negative, HER2-positive population warrants further investigation, even if it did not meet prespecified criteria for significance. The safety profile was generally consistent with what was previously reported in BOLERO-3. Proactive monitoring and early management of adverse events in patients given everolimus and chemotherapy is crucial. Funding: Novartis Pharmaceuticals. © 2015 Elsevier Ltd.


Hu D.,Peking University | Liu L.,Chinese Academy of Sciences | Li W.,Harbin Medical University
Advances in Therapy | Year: 2014

Introduction: Single-pill combination (SPC) therapy of two drugs is recommended by international guidelines, including the Chinese guidelines (2010), for the treatment of hypertension in high-risk patients who require marked blood pressure (BP) reductions. Real-world data on the efficacy and safety of valsartan/amlodipine (Val/Aml) SPC are scarce. The present study is the first observational study in China to evaluate the efficacy (primary endpoint) and safety of Val/Aml (80/5 mg) SPC in Chinese patients with hypertension whose BP was not adequately controlled by monotherapy in a real-world setting. Methods: This prospective, multicenter, open-label, post-marketing observational study included 11,422 Chinese adults (≥18 years) with essential hypertension from 238 sites of 29 provinces who were prescribed once-daily Val/Aml (80/5 mg) SPC. Patients were treated for 8 weeks. The primary efficacy variable of the study included changes in mean sitting systolic BP (MSSBP) and mean diastolic BP (MSDBP) from baseline to week 8 (end point). The secondary efficacy variable of the study included BP control rate and response rate at week 4 and 8. Safety assessments included recording and measurement of all adverse events (AEs) and vital signs in the safety population. Results: A significant reduction of 27.1 mmHg in MSSBP (159.6 vs. 132.5 mmHg; P < 0.0001) and 15.2 mmHg in MSDBP (95.6 vs. 80.4 mmHg; P < 0.0001) from baseline was observed at week 8. The BP-lowering efficacy of Val/Aml SPC was independent of age and comorbidities. BP control of <140/90 mmHg was achieved in 76.8% (n = 8,692) of the patients. The most frequently reported AEs were dizziness (0.2%), headache (0.2%), upper respiratory tract infection (0.2%), and edema (0.2%). Only three serious AEs were reported and they were not drug-related. Conclusion: This is the first evidence-based real-world data in Chinese hypertensive patients which demonstrate the efficacy and safety of Val/Aml (80/5 mg) SPC. © 2014 The Author(s).


Wang T.,Harbin Medical University | Wang G.,Harbin Medical University | Hao D.,University of Macau | Liu X.,Inner Mongolia Peoples Hospital | And 3 more authors.
Molecular Cancer | Year: 2015

RNA binding proteins (RBPs) and microRNAs (miRNAs) are two of the most important post-transcriptional regulators of gene expression, and their aberrant expression contributes to the development of human malignancies. Let-7, one of the most well-known tumor suppressors, is frequently down-regulated in a variety of human cancers. The RBP LIN28A/LIN28B, a direct target of the let-7 family of miRNAs, is an inhibitor of let-7 biogenesis and is frequently up-regulated in cancers. Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors is reportedly involved in cancer development, contributing to cellular proliferation, cell death resistance, angiogenesis, metastasis, metabolism reprogramming, tumor-associated inflammation, genome instability, acquiring immortality and evading immune destruction. In this review, we summarized the mechanisms of LIN28A/LIN28B and let-7 loop aberrant regulation in human cancer and discussed the roles and potential mechanisms of the LIN28A/LIN28B and let-7 loop in regulating the hallmarks of cancer. The crosstalk between LIN28A/LIN28B and let-7 loop and certain oncogenes (such as MYC, RAS, PI3K/AKT, NF-κB and β-catenin) in regulating hallmarks of cancer has also been discussed. © 2015 Wang et al.


Liu W.,Peking University | Lu M.,Peking University | Liu B.,Harbin Medical University | Huang Y.,Peking University | Wang K.,Peking University
Cancer Letters | Year: 2012

The etiology of prostatic adenocarcinoma remains unclear. Prostate cancer cells of varying metastatic potential and apoptotic resistance show altered expression of plasma membrane ion channels and unbalanced Ca2+ homeostasis. Ca2+-activated Cl- channels (CaCCs) are robustly expressed in epithelial cells and function to regulate epithelial secretion and cell volume for maintenance of ion and tissue homeostasis in proliferation, differentiation and apoptosis. ANO1/TMEM16A was recently identified as a CaCC, and it is of interest to determine whether ANO1 plays a role in development and metastasis of prostate carcinoma. Here we show that ANO1 mRNA and protein are highly expressed in human metastatic prostate cancer LNCaP and PC-3 cells by quantitative analysis of real-time PCR and Western blot. These findings were confirmed by whole-cell patch clamp recording of LNCaP and PC-3 cells with increased current density of ANO1 channels. Immunohistochemistry staining further revealed overexpression of ANO1 in human prostate cancer tissues, which correlated with the clinical TNM stage and Gleason score. Experiments with small hairpin RNAs (shRNAs) targeting human ANO1 resulted in a significant reduction of proliferation, metastasis and invasion of PC-3 cells using WST-8, colony formation, wound-healing and transwell assays. Moreover, intratumoral injection of ANO1 shRNA completely inhibited established tumor growth and survival in orthotopic nude mice implanted with PC-3 cells. Our findings provide compelling evidence that upregulation of CaCC ANO1 is involved in the proliferation, progression and pathogenesis of metastatic prostate cancer. Membrane ANO1 protein may therefore serve as a biomarker, and inhibition of overexpressed ANO1 has potential for use in prostate cancer therapy. © 2012 Elsevier Ireland Ltd.


Li J.,Fudan University | Qin S.,Chinese People's Liberation Army | Xu R.,Sun Yat Sen University | Yau T.C.C.,University of Hong Kong | And 16 more authors.
The Lancet Oncology | Year: 2015

Background: In the international randomised phase 3 CORRECT trial (. NCT01103323), regorafenib significantly improved overall survival versus placebo in patients with treatment-refractory metastatic colorectal cancer. Of the 760 patients in CORRECT, 111 were Asian (mostly Japanese). This phase 3 trial was done to assess regorafenib in a broader population of Asian patients with refractory metastatic colorectal cancer than was studied in CORRECT. Methods: In this randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done in 25 hospitals in mainland China, Hong Kong, South Korea, Taiwan, and Vietnam, we recruited Asian patients aged 18 years or older with progressive metastatic colorectal cancer who had received at least two previous treatment lines or were unable to tolerate standard treatments. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and adequate bone marrow, liver, and renal function, without other uncontrolled medical disorders. We randomly allocated patients (2:1; with a computer-generated unicentric randomisation list [prepared by the study funder] and interactive voice response system; block size of six; stratified by metastatic site [single vs multiple organs] and time from diagnosis of metastatic disease [<18 months vs ≥18 months]) to receive oral regorafenib 160 mg once daily or placebo on days 1-21 of each 28 day cycle; patients in both groups were also to receive best supportive care. Participants, investigators, and the study funder were masked to treatment assignment. The primary endpoint was overall survival, and we analysed data on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01584830. Findings: Between April 29, 2012, and Feb 6, 2013, we screened 243 patients and randomly assigned 204 patients to receive either regorafenib (136 [67%]) or placebo (68 [33%]). After a median follow-up of 7·4 months (IQR 4·3-12·2), overall survival was significantly better with regorafenib than it was with placebo (hazard ratio 0·55, 95% CI 0·40-0·77, one-sided p=0·00016; median overall survival 8·8 months [95% CI 7·3-9·8] in the regorafenib group vs 6·3 months [4·8-7·6] in the placebo group). Drug-related adverse events occurred in 132 (97%) of 136 regorafenib recipients and 31 (46%) of 68 placebo recipients. The most frequent grade 3 or higher regorafenib-related adverse events were hand-foot skin reaction (22 [16%] of 136 patients in the regorafenib group vs none in the placebo group), hypertension (15 [11%] vs two [3%] of 68 patients in the placebo group), hyperbilirubinaemia (nine [7%] vs one [1%]), hypophosphataemia (nine [7%] vs none), alanine aminotransferase concentration increases (nine [7%] vs none), aspartate aminotransferase concentration increases (eight [6%] vs none), lipase concentration increases (six [4%] vs one [1%]), and maculopapular rash (six [4%] vs none). Drug-related serious adverse events occurred in 12 (9%) patients in the regorafenib group and three (4%) in the placebo group. Interpretation: This phase 3 trial is the second to show an overall survival benefit with regorafenib compared with placebo in patients with treatment-refractory metastatic colorectal cancer, substantiating the role of regorafenib as an important treatment option for patients whose disease has progressed after standard treatments. In this trial, preceding standard treatments did not necessarily include targeted treatments. Adverse events were generally consistent with the known safety profile of regorafenib in this setting. Funding: Bayer HealthCare Pharmaceuticals. © 2015 Elsevier Ltd.


Wu H.,Johns Hopkins University | Wu H.,Harbin Medical University | Wu T.,Johns Hopkins University | Wu T.,Shanghai University | And 2 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2011

Intracerebral hemorrhage (ICH) is a devastating form of stroke. In this study, we examined the efficacy of deferoxamine (DFX), an iron chelator, after collagenase-induced ICH in 12-month-old mice. Intracerebral hemorrhage was induced by intrastriatal injection of collagenase. Deferoxamine (200 mg/kg, intraperitoneal) or vehicle was administrated 6 hours after ICH and then every 12 hours for up to 3 days. Neurologic deficits were examined on days 1 and 3 after ICH. Mice were killed after 1 or 3 days of DFX treatment for examination of iron deposition, neuronal death, oxidative stress, microglia/astrocyte activation, neutrophil infiltration, brain injury volume, and brain edema and swelling. Collagenase-induced ICH resulted in iron overload in the perihematomal region on day 3. Systemic administration of DFX decreased iron accumulation and neuronal death, attenuated production of reactive oxygen species, and reduced microglial activation and neutrophil infiltration without affecting astrocytes. Although DFX did not reduce brain injury volume, edema, or swelling, it improved neurologic function. Results of our study indicate that iron toxicity contributes to collagenase-induced hemorrhagic brain injury and that reducing iron accumulation can reduce neuronal death and modestly improve functional outcome after ICH in mice. © 2011 ISCBFM All rights reserved.


Zhang C.,Rutgers University | Liu J.,Rutgers University | Liang Y.,Rutgers University | Liang Y.,Harbin Medical University | And 10 more authors.
Nature Communications | Year: 2013

Tumour cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect. Its mechanism is not well understood. The tumour suppressor gene p53 is frequently mutated in tumours. Many tumour-associated mutant p53 (mutp53) proteins not only lose tumour suppressive function but also gain new oncogenic functions that are independent of wild-type p53, defined as mutp53 gain of function (GOF). Here we show that tumour-associated mutp53 stimulates the Warburg effect in cultured cells and mutp53 knockin mice as a new mutp53 GOF. Mutp53 stimulates the Warburg effect through promoting GLUT1 translocation to the plasma membrane, which is mediated by activated RhoA and its downstream effector ROCK. Inhibition of RhoA/ROCK/GLUT1 signalling largely abolishes mutp53 GOF in stimulating the Warburg effect. Furthermore, inhibition of glycolysis in tumour cells greatly compromises mutp53 GOF in promoting tumorigenesis. Thus, our results reveal a new mutp53 GOF and a mechanism for controlling the Warburg effect. © 2013 Macmillan Publishers Limited.


Pan S.,Peking University | Pan S.,Harbin Medical University | Dong Q.,Peking University | Sun L.-S.,Peking University | Li T.-J.,Peking University
Clinical Cancer Research | Year: 2010

Purpose: PTCH1 has been identified as the gene responsible for nevoid basal cell carcinoma syndrome (NBCCS). Keratocystic odontogenic tumors (KCOT) are aggressive jaw lesions that may occur in isolation or in association with NBCCS. The aim of this study was to investigate the genetic and/or epigenetic mechanisms of inactivation of the PTCH1 gene in patients with NBCCS and related sporadic KCOTs. Experimental Design: Loss of heterozygosity was analyzed in 44 patients (15 NBCCS-related and 29 sporadic KCOTs), all of whom were previously analyzed for PTCH1 mutations. Allelic location was established in tumors carrying two coincident mutations. PTCH1 mRNA expression and promoter methylation status were analyzed in a panel of KCOTs to define the possible role of epigenetic effects on PTCH1 inactivation. Results: Although mutations and loss of heterozygosity of PTCH1 were frequently detected in both syndromic and nonsyndromic cases, hypermethylation of the PTCH1 promoter was not identified in the present series. Of all the 44 cases examined, 13 were identified to fit the two-hit model, 14 to conform to a one-hit model, and the remaining 17 cases showing no alteration in PTCH1. The distribution of twohit, one-hit, and non-hit cases was significantly different between syndrome and nonsyndrome patients (P < 0.02). Conclusions: This study indicates that PTCH1 gene alternation may play a significant role in the pathogenesis of NBCCS and the related sporadic tumors. Not only the standard two-hit model, but also haploinsufficiency or dominant-negative isoforms may be implicated in the inactivation of the PTCH1 gene. ©2010 AACR.


Wang R.-T.,Harbin Medical University | Zhang J.-R.,Harbin Medical University | Li Y.,Harbin Medical University | Yu K.-J.,Harbin Medical University
Journal of Diabetes and its Complications | Year: 2015

Aims Diabetic retinopathy (DR) is the most common complication of type 2 diabetes mellitus (T2DM). Inflammation plays a considerable role in the pathogenesis of T2DM and DR. Emerging evidence revealed that the neutrophil-lymphocyte ratio (NLR) may be a useful marker of cardiovascular disease. The brachial-ankle pulse wave velocity (baPWV) is an indicator for early atherosclerotic changes. Therefore, this study aimed to investigate the association of NLR with baPWV in patients with DR. Methods In this cross-sectional study, we investigated the relationship between NLR and baPWV in 402 participants. Participants were divided into the following three groups: 133 control subjects without T2DM; 138 diabetic subjects without DR; and 131 patients with DR. Results NLR and baPWV were elevated both in T2DM and in DR. Moreover, compared to T2DM, NLR and baPWV were higher in DR. There was a positive correlation between NLR and baPWV in patients with T2DM and DR after adjusting confounding factors. Multiple linear regression analysis further revealed that NLR was an independent and significant determinant for elevated baPWV (for T2DM, β = 0.170; p = 0.041; for DR, β = 0.188; p = 0.022, respectively). Conclusions The findings showed that NLR and baPWV are elevated both in T2DM and in DR. In addition, NLR is independently associated with baPWV. Early detection of abnormal NLR levels may be helpful for the search of subclinical atherosclerosis in patients with T2DM and DR. © 2015 Elsevier Inc. All rights reserved.


Han X.,The Forsyth Institute | Lin X.,The Forsyth Institute | Lin X.,Liaoning Medical University | Yu X.,The Forsyth Institute | And 6 more authors.
Infection and Immunity | Year: 2013

Porphyromonas gingivalis is one of the oral microorganisms associated with human chronic periodontitis. The purpose of this study is to determine the role of the receptor activator of nuclear factor-κB ligand (RANKL) in P. gingivalis infection-associated periodontal bone resorption. Inbred female Rowett rats were infected orally on four consecutive days (days 0 to 3) with 1×109 P. gingivalis bacteria (strain ATCC 33277). Separate groups of rats also received an injection of anti-RANKL antibody, osteoprotegerin fusion protein (OPG-Fc), or a control fusion protein (L6-Fc) into gingival papillae in addition to P. gingivalis infection. Robust serum IgG and salivary IgA antibody (P<0.01) and T cell proliferation (P<0.05) responses to P. gingivalis were detected at day 7 and peaked at day 28 in P. gingivalis-infected rats. Both the concentration of soluble RANKL (sRANKL) in rat gingival tissues (P<0.01) and periodontal bone resorption (P<0.05) were significantly elevated at day 28 in the P. gingivalisinfected group compared to levels in the uninfected group. Correspondingly, RANKL-expressing T and B cells in rat gingival tissues were significantly increased at day 28 in the P. gingivalis-infected group compared to the levels in the uninfected group (P<0.01). Injection of anti-RANKL antibody (P<0.05) or OPG-Fc (P<0.01), but not L6-Fc, into rat gingival papillae after P. gingivalis infection resulted in significantly reduced periodontal bone resorption. This study suggests that P. gingivalis infection- associated periodontal bone resorption is RANKL dependent and is accompanied by increased local infiltration of RANKLexpressing T and B cells. © 2013, American Society for Microbiology.


Meng X.,Harbin Medical University | Liu Y.,Harbin Medical University | Liu B.,Peoples Liberation Army No202 Hospital
Diagnostic Pathology | Year: 2014

Background: Glutathione S-transferases (GSTs) have proved to be involved in the detoxifying several carcinogens and may play an important role in carcinogenesis of cancer. Previous studies on the association between Glutathione S-transferase M1 (GSTM1) polymorphism and gastric cancer (GC) risk reported inconclusive results. To get a precise result, we conducted this present meta-analysis through pooling all eligible studies.Methods: A comprehensive databases of Pubmed, Embase, Web of Science, and the Chinese Biomedical Database (CBM) were searched for case-control studies investigating the association between GSTM1 null genotype and GC risk. Odds ratios (OR) and 95% confidence intervals (95% CI) were used to assess this possible association. A χ2-based Q-test was used to examine the heterogeneity assumption. Begg's and Egger's test were used to examine the potential publication bias. The leave-one-out sensitivity analysis was conducted to determine whether our assumptions or decisions have a major effect on the results of present work. Statistical analyses were performed with the software program STATA 12.0.Results: A total of 47 eligible case-control studies were identified, including 6,678 cases and 12,912 controls. Our analyses suggested that GSTM1 null genotype was significantly associated with increased risk of GC (OR = 1.186, 95% CI = 1.057-1.329, Pheterogenetiy = 0.000, P = 0.004). Significant association was also found in Asians (OR = 1.269, 95% CI = 1.106-1.455, Pheterogenetiy = 0.002, P = 0.001). However, GSTM1 null genotype was not contributed to GC risk in Caucasians (OR = 1.115, 95% CI = 0.937-1.326, Pheterogenetiy = 0.000, P = 0.222). In the subgroup analysis stratified by sources of controls, significant association was detected in hospital-based studies (OR = 1.355, 95% CI = 1.179-1.557, Pheterogenetiy = 0.001, P = 0.000), while there was no significant association detected in population-based studies (OR = 1.017, 95% CI = 0.862-1.200, Pheterogenetiy = 0.000, P = 0.840).Conclusion: This meta-analysis showed the evidence that GSTM1 null genotype contributed to the development of GC.Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1644180505119533. © 2014 Meng et al.; licensee BioMed Central Ltd.


News Article | November 21, 2016
Site: www.eurekalert.org

A cellular component known as the Golgi apparatus may play a role in how lung cancer metastasizes, according to researchers at The University of Texas MD Anderson Cancer Center whose findings were reported in the Nov. 21 online issue of the Journal of Clinical Investigation. The Golgi apparatus, often referred to as a cellular "post office" for its ability to package proteins into vesicles for transportation to other sites within or outside the cell, may offer a new therapeutic approach for preventing metastasis. Think of vesicles as miniature mail trucks composed of a fatty shell filled with secretory liquids that travel from the Golgi to destinations within the cell where their contents are put to use. The Golgi can appear as a compacted membranous "stack" near the cell's nucleus or as a dispersed system of interconnected membranes. Vesicles can "bud" from the Golgi in either form. "Our findings show that certain proteins in the Golgi that control Golgi compaction may actually promote vesicle budding and transport and enhance the tumor cell's ability to metastasize" said Jonathan Kurie, M.D., professor of Thoracic Head and Neck Medical Oncology. "These findings highlight the potential utility of targeting certain cellular processes in the Golgi." According to Kurie, tumor cells gain their metastatic ability through a Golgi-related process driving the budding and transport of secretory vesicles. Unknown before this study was whether Golgi compaction was responsible for vesicular trafficking leading to metastasis. This study shows that Golgi compaction is associated with EMT or epithelial-to-mesenchymal transition, a process that allows a cell to detach and move away from its neighbors during wound healing and other normal processes and is thought to play a role in cancer cell migration. Using lung adenocarcinoma cell lines isolated from mice and patients, Kurie's team found that EMT depends on a Golgi protein called PAQR11 for successful tumor cell migration and metastasis in lung cancers. "We concluded that, through PAQR11, tumor cells can hijack a normal Golgi compaction process in order to gain metastatic ability," said Kurie. MD Anderson study team participants included Xiaochao Tan, Ph.D.; Priyam Banerjee; Ph.D., Hou-Fu Guo, Ph.D.; Daniela Pankova, Ph.D.; Xin Liu, Ph.D.;Yongming Xue, Jonathon Roybal and Don Gibbons, M.D., all of Thoracic Head and Neck Medical Oncology; Tomasz Zal, Ph.D., Immunology; and Chad Creighton, Ph.D., Bioinformatics and Computational Biology. Other participating institutions include the University of Michigan, Ann Arbor, Mich.; Ewha Woman's University School of Medicine, Seoul, South Korea; University of York, York, U.K.; Harbin Medical University Cancer Hospital, Harbin, China; University of Houston and Baylor College of Medicine, Houston. The study was funded by the National Institutes of Health (R01CA181184, R01CA125123, GM087364, GM105920, GM112786P30, EY007551, K08CA151661, NRF-2010-0027945, CA015672, 1S10OD012304-01, and 1S10RR09552-01), the American Cancer Society (RGS-09-278-01-CSM), the Cancer Prevention Research Institute of Texas (RP120713), and MCubed and the Fastforward Protein Folding Disease Initiative at the University of Michigan.


Li H.,Shanghai JiaoTong University | Li S.,Harbin Medical University | Yu B.,Harbin Medical University | Liu S.,Shanghai JiaoTong University
Molecular Medicine Reports | Year: 2012

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. The most significant histological property of AF is atrial fibrosis, but the underlying mechanism is not clear. In this study we investigated the expression of miR-133 and miR-30, anti-fibrotic microRNAs (miRNAs), in chronic AF in canines. A total amount of 42 mongrel canines of either gender, weighing between 20 and 28 kg, were randomly assigned to the sham-operated and AF groups. All canines were subjected to weekly physical examinations and electrocardiogram. Alterations in tissue structure were assessed in atrial tissue samples by using hematoxylin and eosin and Masson's trichrome. The expression of miR-133 and miR-30 was determined by TaqMan real-time polymerase chain reaction (RT-PCR) and northern blot analyses of atrial tissue. The data were analyzed using the program SPSS 11.5 for Windows. At follow-up, rapid pacing from the left superior pulmonary vein induced sustained AF in the AF group. In the left atrium, increased interstitial fibrosis and chronic inflammation were observed. RT-PCR and northern blot analyses showed that miR-133 and miR-30 expression was downregulated in the AF group. Our results show that both miR-133 and miR-30 play an important role in controling structural changes in chronic AF.


Kong L.,Heilongjiang University | Ren Z.,Heilongjiang University | Zheng N.,Harbin Medical University | Du S.,Heilongjiang University | And 3 more authors.
Nano Research | Year: 2015

Enzymeless hydrogen peroxide (H2O2) detection with high sensitivity and excellent selectivity is desirable for clinical diagnosis. Herein, one-dimensional Co3O4 nanowires have been successfully constructed on reduced graphene oxide (rGO) via a simple hydrothermal procedure and subsequent thermal treatment. These Co3O4 nanowires, assembled by small nanoparticles, are interlaced with one another and make a spider web-like structure on rGO. The formation of Co3O4-rGO hybrids is attributed to the structure-directing and anchoring roles of DDA and GO, respectively. The resulting structure possesses abundant active sites, the oriented transmission of electrons, and unimpeded pathways for matter diffusion, which endows the Co3O4-rGO hybrids with excellent electrocatalytic performance. As a result, the obtained Co3O4-rGO hybrids can serve as an efficient electrochemical catalyst for H2O2 oxidation and high sensitivity detection. Under physiological conditions, the oxidation current of H2O2 varies linearly with respect to its concentration from 0.015 to 0.675 mM with a sensitivity of 1.14 mA·mM−1·cm−2 and a low detection limit of 2.4 μM. Furthermore, the low potential (−0.19 V) and the good selectivity make Co3O4-rGO hybrids suitable for monitoring H2O2 generated by liver cancer HepG2 cells. Therefore, it is promising as a non-enzymatic sensor to achieve real-time quantitative detection of H2O2 in biological applications. © 2014, Tsinghua University Press and Springer-Verlag Berlin Heidelberg.


Zhao H.,Harbin Medical University | Guo L.,Harbin Medical University | Zhao J.,Harbin Medical University | Weng H.,Shanghai JiaoTong University | Zhao B.,Harbin Medical University
Oncotarget | Year: 2015

C-X-C chemokine receptor 4 (CXCR4) is frequently over-expressed in various types of cancer; many agents against CXCR4 are in clinical development currently despite variable data for the prognostic impact of CXCR4 expression. Here eighty-five studies with a total of 11,032 subjects were included to explore the association between CXCR4 and progression-free survival (PFS) or overall survival (OS) in subjects with cancer. Pooled analysis shows that CXCR4 over-expression is significantly associated with poorer PFS (HR 2.04; 95% CI, 1.72-2.42) and OS (HR=1.94; 95% CI, 1.71- 2.20) irrespective of cancer types. Subgroup analysis indicates significant association between CXCR4 and shorter PFS in hematological malignancy, breast cancer, colorectal cancer, esophageal cancer, renal cancer, gynecologic cancer, pancreatic cancer and liver cancer; the prognostic effects remained consistent across age, risk of bias, levels of adjustment, median follow-up period, geographical area, detection methods, publication year and size of studies. CXCR4 over-expression predicts unfavorable OS in hematological malignancy, breast cancer, colorectal cancer, esophageal cancer, head and neck cancer, renal cancer, lung cancer, gynecologic cancer, liver cancer, prostate cancer and gallbladder cancer; these effects were independence of age, levels of adjustment, publication year, detection methods and follow-up period. In conclusion, CXCR4 over-expression is associated with poor prognosis in cancer.


Li G.,Shanghai JiaoTong University | Li G.,Harbin Medical University | Liu J.,Shanghai JiaoTong University | Pang Y.,Shanghai JiaoTong University | And 5 more authors.
Biomacromolecules | Year: 2011

The hydrophobic block of polymeric micelles formed by amphiphilic copolymers has no direct therapeutical effect, and the metabolites of these hydrophobic segments might lead to some unexpected side effects. Here the hydrophobic core of polymeric micelles is replaced by highly water-insoluble drugs themselves, forming a new micellar drug delivery system. By grafting hydrophobic drugs of paclitaxel (PTX) onto the surface of hydrophilic hyperbranched poly(ether-ester) (HPEE), we constructed an amphiphilic copolymer (HPEE-PTX). HPEE-PTX could self-assemble into micellar nanoparticles in aqueous solution with tunable drug contents from 4.1 to 10.7%. Moreover, the hydrolysis of HPEE-PTX in serum resulted in the cumulative release of PTX. In vivo evaluation indicated that the dosage toleration of PTX in mice had been improved greatly and HPEE-PTX micellar nanoparticles could be used as an efficient prodrug with satisfactory therapeutical effect. We believe that most of the lipophilic drugs could improve their characters through this strategy. © 2011 American Chemical Society.


Guo S.,Shanghai JiaoTong University | Li X.,Shanghai JiaoTong University | Gao M.,Harbin Medical University | Li Y.,Shanghai JiaoTong University | And 2 more authors.
PLoS ONE | Year: 2013

Background: The prevalence of lung cancer in China will be the world's highest if allowed to proceed uncurbed. To unravel its genetic underpinnings, we sought to investigate the association of three well-characterized nonsynonymous polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) and XRCC3 (Thr241Met) genes with lung cancer risk in northeastern Chinese. Methodology/Principal Findings: This study was hospital-based in design, encompassing 684 patients with lung cancer and 604 cancer-free controls. Genotyping was performed using the PCR-LDR (ligase detection reactions) method. Data were analyzed by R language and multifactor dimensionality reduction (MDR) software. Single-locus analysis identified significance in genotype distributions of polymorphism Arg194Trp (P = 0.002) and Arg399Gln (P = 0.017), and in allele distributions of Thr241Met (P = 0.005). Carriers of 399Gln/Gln genotype conferred a 147% increased risk relative to the non-carriers (odds ratio (OR): 2.47; 95% confidence interval (95% CI): 1.48-4.13; P<0.001). For Thr241Met, significance persisted under allelic (OR = 1.63; 95% CI: 1.14-2.33; P = 0.005), additive (OR = 1.64; 95% CI: 1.16-2.32; P = 0.005) and dominant (OR = 1.67; 95% CI: 1.17-2.38; P = 0.004) models. However, common allele combinations were comparable in frequency between patients and controls. In interaction analysis, the overall best MDR model included Arg399Gln and Thr241Met polymorphisms, with a maximal testing accuracy of 63.18% and a maximal cross-validation consistency of 10 out of 10 (P = 0.0175). Conclusions: Our study significantly demonstrated an independent and synergistic contribution of XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms to lung cancer susceptibility in northeastern Chinese. © 2013 Guo et al.


Zhang R.,Tongji University | Dai L.-Z.,Tongji University | Xie W.-P.,Nanjing Medical University | Yu Z.-X.,Central South University | And 7 more authors.
Chest | Year: 2011

Background: In a previous study of Chinese patients with idiopathic pulmonary arterial hypertension (IPAH) in the nontargeted therapy era (defined as the time before 2006 when new pulmonary arterial hypertension-specific drugs were not available in China), we reported 1- and 3-year survival estimates of only 68% and 39%, respectively. However, it is not yet known whether the survival of patients with pulmonary arterial hypertension is improved in the modern treatment era (defined in China as after 2006). Methods: A retrospective cohort study was undertaken in 276 consecutive patients with newly diagnosed incident IPAH and connective tissue disease-related pulmonary arterial hypertension (CTDPAH) who were referred between 2007 and 2009. Baseline characteristics and survival rates in the two groups were compared. Results: The 1- and 3-year survival estimates were 92.1% and 75.1%, respectively, in patients with IPAH, and 85.4% and 53.6%, respectively, in patients with CTDPAH. Patients with CTDPAH had a significantly lower mean pulmonary artery pressure, more pericardial effusion, and more severe impairment of the diffusion capacity of the lung for carbon monoxide than patients with IPAH. A diagnosis of CTDPAH, World Health Organization functional class III or IV, single-breath diffusion capacity of the lung for carbon monoxide, < 80% predicted, and the presence of pericardial effusion were independent predictors of mortality. The 1- and 3-year survival rates of male patients were 93.5% and 77.5%, respectively, in those with IPAH, and 71.1% and 47.4%, respectively, in those with CTDPAH. Conclusions: The survival rates of patients with pulmonary arterial hypertension have improved in China in the modern treatment era, despite the high costs of treatment and financial constraints. However, the survival rates of patients with CTDPAH are inferior to those of patients with IPAH. Our study also indicates poorer survival rates in male patients with CTDPAH. © 2011 American College of Chest Physicians.


Zhang W.,Harbin Medical University | Wang R.,Henan Agricultural University | Yang F.,Harbin Medical University | Zhang L.,Henan Agricultural University | And 5 more authors.
PLoS ONE | Year: 2013

Background: Cryptosporidium spp. are common parasites of humans and animals. Farm animals, especially pre-weaned calves, are considered to be one of main animal reservoir hosts of Cryptosporidium in the transmission of human cryptosporidiosis. The aim of this study was to determine the distribution and genotypes of Cryptosporidium spp. in pre-weaned calves using molecular tools and to assess zoonotic transmission and elucidate the public health significance in northeastern China. Methodology/Principal Findings: A total of 151 fecal specimens from pre-weaned calves were collected in Heilongjiang Province and were screened for Cryptosporidium by PCR. The average prevalence of Cryptosporidium was 47.68% (72/151). Cryptosporidium spp. were characterized by DNA sequencing of the small subunit (SSU) rRNA gene and the 60-kDa glycoprotein (gp60) gene. Based on the SSU rRNA gene, five Cryptosporidium spp. were identified, including C. bovis (n = 34), C. andersoni (n = 26), C. ryanae (n = 5), C. meleagridis (n = 5) and C. parvum (n = 2). The SSU rRNA nucleotide sequences were identical to each other, respectively, within C. ryanae, C. parvum, C. meleagridis and C. andersoni. Four types of C. bovis were found in the SSU rRNA gene, with two novel types. The gp60 gene was successfully sequenced in one C. parvum isolate and three C. meleagridis isolates, with IIdA19G1 for C. parvum and IIIeA22G2R1 for C. meleagridis. Conclusion/Significance: Molecular analysis indicates that Cryptosporidium spp. are endemic in pre-weaned calves in Heilongjiang Province. The findings of C. parvum and C. meleagridis suggested the possibility of zoonotic transmission and public health significance. The transmission dynamics of C. parvum and C. meleagridis needed to be clarified by further molecular epidemiologic studies from humans and animals. Whether calves could act as the natural reservoirs of C. meleagridis needed to be confirmed by more systematic experimental infection studies. © 2013 Zhang et al.


Zhao W.,Harbin Medical University | Zhang W.,Harbin Medical University | Yang F.,Harbin Medical University | Cao J.,National Institute of Parasitic Diseases | And 4 more authors.
Applied and Environmental Microbiology | Year: 2014

Enterocytozoon bieneusi is an emerging and clinically significant enteric parasite infecting humans and animals and can cause life-threatening diarrhea in immunocompromised people. Pigs are considered to be one of the main reservoir hosts of E. bieneusi based on their high prevalence rates and zoonotic genotypes in pigs. As an opportunistic pathogen, E. bieneusi infection of pigs can be inapparent, which leads to neglect in detecting this parasite in pigs and assessing the epidemiological role of pigs in the transmission of human microsporidiosis. In the present study, 95 healthy pigs aged 2 or 3 months were randomly selected from three areas in Heilongjiang Province, China. E. bieneusi isolates were identified and genotyped based on the small-subunit (SSU) rRNA and internal transcribed spacer (ITS) regions of the rRNA gene by PCR and sequencing. A high prevalence of E. bieneusi was observed, 83.2% (79/95) at the SSU rRNA locus versus 89.5% (85/95) at the ITS locus. Ten ITS genotypes were obtained, comprising six known genotypes-EbpA (n = 30), D (n = 19), H (n = 18), O (n = 11), CS-1 (n = 1), and LW1 (n = 1)- and four novel genotypes named HLJ-I to HLJ-IV; 70.6% (60/85) of E. bieneusi genotypes were zoonotic (genotypes EbpA, D, and O). The findings of a high prevalence of E. bieneusi in pigs and a large percentage of zoonotic genotypes indicate that pigs may play a role in the transmission of E. bieneusi to humans and may become an important source of water contamination in our investigated areas. © 2014, American Society for Microbiology.


Zhang Z.-Y.,Heilongjiang University | Zhang Z.-Y.,Harbin Medical University | Deng Z.-P.,Heilongjiang University | Huo L.-H.,Heilongjiang University | And 2 more authors.
Inorganic Chemistry | Year: 2013

In this Article, self-assembly of AgX (X = NO3 - and ClO4 -) salts and four flexible unsymmetrical bis(pyridyl) ligands, namely, N-(pyridin-2-ylmethyl)pyridin-3-amine (L1), N-(pyridin-3-ylmethyl)pyridin-2-amine (L2), N-(pyridin-4-ylmethyl)pyridin-2- amine (L3), and N-(pyridin-4-ylmethyl)pyridin-3-amine (L4), results in the formation of eight helical silver(I) coordination polymers, [Ag(L)(NO 3)]n [L = L1 (1), L2 (2), L3 (3), L4 (4)] and [Ag(L)(ClO4)]n [L = L1 (5), L2 (6), L3 (7), L4 (8)], which have been characterized by elemental analysis, IR, TG, PL, and powder and single-crystal X-ray diffraction. The alternating one-dimensional (1-D) left- and right-handed helical chains are included in achiral complexes 1-3 and 5-8. By contrast, the ligand L4 only alternately bridges Ag(I) cation to form the 1-D right-handed helical chain in complex 4. The pitches of these helical chains locate in the range 5.694(5)-17.016(6) Å. Meanwhile, the present four unsymmetrical bis(pyridyl) ligands in the eight complexes present diverse cis-trans and trans-trans conformation and facilitate the construction of helical structures. Moreover, the solid-state luminescent emission intensities of the perchlorate-containing complexes are stronger than those of nitrate-containing complexes at room temperature. © 2013 American Chemical Society.


Yao L.,Heilongjiang University | Yao L.,Harbin Medical University | Dong W.,Heilongjiang University | Lu F.,Heilongjiang University | Liu S.,Heilongjiang University
American Journal of Chinese Medicine | Year: 2012

Rhizoma Dioscoreae Nipponicae (RDN) is an herbal medicine. In the theories of Traditional Chinese Medicine (TCM), the function of RDN is to expel wind and remove dampness. Inflammatory mechanisms play an important role in the pathological process and prognosis of acute gouty arthritis (AGA). The aim of this study was to determine the specially expressed proteins through testing the proteins of the synovium in rats with AGA. The animal model of AGA was set up by Monosodium urate crystal (MSU) combined with hypoxanthine (HX), which was ameliorated in our previous experiment. Blood samples for measurement of serum uric acid were collected prior to sacrifice. Outcomes were assessed (two days after injection) by histological stain and protein quantitation. Three chips of RayBio® Human Label-based Antibody Array I were applied to detect 90 proteins in the synovium tissue of AGA rats. 14 differently expressed proteins were found in the synovium of AGA rats, and nine of them were first found in this model. There were seven up-regulated and seven down-regulated proteins, both TRAIL and Neuropilin-2 could be identified as key contributors to the pathomechanism of AGA. © 2012 World Scientific Publishing Company & Institute for Advanced Research in Asian Science and Medicine.


Zhen Y.,Kansai Medical University | Zhen Y.,Harbin Medical University | Zhao S.,Harbin Medical University | Li Q.,Kansai Medical University | And 3 more authors.
Cancer Letters | Year: 2010

Cancer stem-like cells (CSLCs) are potential targets for treatment of glioblastoma multiforme (GBM) due to their role in tumorigenesis and recurrence. In this study, we investigated the inhibitory effect of arsenic trioxide (As2O3) on CSLCs of GBM in human glioma cell lines (U87MG, U251MG and U373MG) in vivo and in vitro. Immunofluorescence staining and flow cytometry revealed that the percentage of Nestin-positive cells in the aforementioned cell lines was diminished by 12%, 14% and 7%, respectively, after treatment with 2μM As2O3. Furthermore, we used soft-agar in U87MG and tumor xenografts in nude mice to demonstrate the ability of As2O3 to inhibit the formation of tumor in the three cell lines. These results indicate the negative regulation of CSLCs by As2O3. In addition, a Western blot analysis revealed decreased levels of Notch1 and Hes1 proteins due to As2O3 treatment. We conclude that As2O3 has a remarkable inhibitory effect on CSLCs in glioma cell lines in vivo and in vitro; in addition, we determined that the mechanism of CSLC inhibition involves the deregulation of Notch activation. © 2009 Elsevier Ireland Ltd.


Guo L.Z.,Harbin Medical University | Kim T.-H.,Soonchunhyang University | Han S.,Dong - A University | Kim S.-W.,Harbin Medical University | Kim S.-W.,Catholic Kwandong University
Circulation Journal | Year: 2016

Background: Although stem cells have been regarded as a promising therapeutic option, the marginal therapeutic effects of stem cells are limitations that must be overcome for the development of effective cell therapy. This study sought to identify the angio-vasculogenic properties of endothelial differentiated mesenchymal stem cells (MSCs) and to determine whether these cells are effective for vascular repair. Methods and Results: Adipose MSCs were cultured for 10 days under endothelial cell (EC) culture conditions. These endothelial cell differentiated adipose MSCs (EA) and undifferentiated adipose MSCs (UA) were characterized via angiogenesis and adhesion assays. These cells were transplanted into a hindlimb ischemia (HLI) model to determine therapeutic effects and their underlying mechanisms. EA displayed low adhesion and angiogenic properties in vitro compared with UA. When implanted into mouse HLI models, EA exhibited the decreased recovery of blood perfusion in limb ischemia than uncultured UA. Histology data showed that injected EA exhibited lower retention, angiogenic cytokine levels, and neovascularization in vivo than did UA. Short-term differentiated EA display less cell engraftment and angio-vasculogenic potential, and are less effective for peripheral vascular repair than UA. Conclusions: EC differentiation of MSCs may not present an effective strategy for the promotion of therapeutic neovascularization. © 2016, Japanese Circulation Society. All rights reserved.


Zuo Y.-C.,Inner Mongolia University | Peng Y.,Inner Mongolia University of Technology | Liu L.,Inner Mongolia University of Technology | Chen W.,Hebei United University | And 2 more authors.
Analytical Biochemistry | Year: 2014

Peroxidases as universal enzymes are essential for the regulation of reactive oxygen species levels and play major roles in both disease prevention and human pathologies. Automated prediction of functional protein localization is rarely reported and also is important for designing new drugs and drug targets. In this study, we first propose a support vector machine (SVM)-based method to predict peroxidase subcellular localization. Various Chou' pseudo amino acid descriptors and gene ontology (GO)-homology patterns were selected as input features to multiclass SVM. Prediction results showed that the smoothed PSSM encoding pattern performed better than the other approaches. The best overall prediction accuracy was 87.0% in a jackknife test using a PSSM profile of pattern with width = 5. We also demonstrate that the present GO annotation is far from complete or deep enough for annotating proteins with a specific function. © 2014 Elsevier Inc. All rights reserved.


Wu J.,Shanghai JiaoTong University | Zhang Y.-C.,Shanghai JiaoTong University | Suo W.-H.,Shanghai JiaoTong University | Liu X.-B.,Harbin Medical University | And 3 more authors.
Oncogene | Year: 2010

Anion exchanger-1 (AE1), an erythroid-specific membrane protein, mediates the Cl /HCO 3 exchange across the plasma membrane and regulates intracellular pH. We have found that AE1 was unexpectedly expressed in gastric cancer cells and participated in the tumorigenesis of the cancer. Here, we focus on the induction of AE1 expression and its role in gastric carcinogenesis as well as in the differentiation of K562 cells. The results show that expression of AE1 is not related to genetic mutation or the mRNA level, but rather, that it is modulated by miR-24. miR-24 decreases the expression of AE1 through binding to the 3′UTR of AE1 mRNA. Transfection of an miR-24 into gastric cancer cells reduced the elevation of the AE1 protein, which resulted in return of AE1-sequestrated p16 to the nucleus, thereby inhibiting proliferation of the cells. Furthermore, the miR-24 inhibitor cooperated with hemin to induce the expression of AE1 in K562 cells and differentiation of the cells, which is consistent with results obtained from the cells cultured at pH 7.6 or from forced stable expression of AE1. These findings establish a novel regulation of miR-24-related AE1 expression in gastric carcinogenesis and erythropoiesis. © 2010 Macmillan Publishers Limited All rights reserved.


Zhao Y.,Harbin Medical University | Xu H.,Heilongjiang Provincial Hospital | Yu W.,Heilongjiang University | Xie B.-D.,Harbin Medical University
Molecular Medicine Reports | Year: 2014

Interactions between complement anaphylatoxins have been investigated in numerous fields; however, their functions during arterial remodeling following injury have not been studied. The inhibitory effect of complement anaphylatoxin C4a on neointima formation induced by C5a following arterial injury was investigated. Mice were subjected to wire-induced endothelial denudation of the femoral artery and treated with C5a alone or C5a + C4a for two weeks. C4a significantly inhibited C5a-induced neointima formation and the expression of CD68, F4/80, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1). In vitro, although C4a did not directly inhibit the migration, proliferation or the expression of vascular cell adhesion molecule-1 (VCAM-1) of C5a-induced vascular smooth muscle cells (VSMCs), C5a-pretreated conditioned medium-induced migration, proliferation and VCAM-1 expression of VSMCs were suppressed when VSMCs were exposed to conditioned medium from C4a-pretreated macrophages. In addition, C5a-induced TNF-α, IL-6 and MCP-1 expression, Ca2+ influx and extracellular signal-regulated kinase (ERK) activation in macrophages were suppressed by C4a. C4a inhibits C5a-induced neointima formation, not by acting directly on VSMCs, but via a macrophage-mediated reaction by inhibiting the Ca2+- dependent ERK pathway in macrophages.


Song D.,Shanghai JiaoTong University | Li Z.,Shanghai JiaoTong University | Zhao J.,Shanghai JiaoTong University | Zhang N.,Shanghai JiaoTong University | And 2 more authors.
OncoTargets and Therapy | Year: 2014

Purpose: The study reported here examined the effect of hematoporphyrin monomethyl ether (HMME)-mediated sonodynamic therapy (SDT) on C6 gliomas implanted in rat brains.Methods: Two weeks after inoculation, glioma development was evaluated by measuring tumor volume using a 1.5 T magnetic resonance imager. Rats that had a well-developed C6 glioma (usually when the tumor diameter reached 3–5 mm) were used to test SDT, ultrasound-alone, and HMME-alone treatments. Rats both administered and not administered intravenous HMME 10 µg/mL were insonated by a 1 MHz ultrasound at a dose of 0.5 W/cm2.Results: SDT treatment could effectively inhibit the expansion of intracranial gliomas in vivo. The treatment with ultrasound alone could inhibit glioma growth within 1 week; however, 1 week later, the tumor started growing again. In contrast, the effect of SDT could last at least 2 weeks. Injection of HMME alone had no effects on inhibiting glioma growth, suggesting the sonosensitizer HMME has no antitumor effect. Both SDT and ultrasound-alone treatment could extend the survival of rats implanted with a C6 glioma. Pathological and electron microscopic examinations suggested SDT and ultrasound-alone treatment could induce glioma necrosis by way of triggering glioma-cell apoptosis, which was confirmed by immunohistological examination with cytochrome-c and caspase-3 antibodies. Most importantly, we found that the sonosensitizer HMME could enhance the ultrasound-induced antitumor effect by selectively assisting ultrasound targeting of glioma angiogenesis inhibition.Conclusion: This study with a rat C6 glioma experimental model showed that SDT can potentially be useful in the treatment of deep-seated malignant gliomas. © 2014 Song et al.


Wang D.,Shanghai JiaoTong University | Chen H.,Harbin Medical University | Su Y.,Shanghai JiaoTong University | Qiu F.,Shanghai JiaoTong University | And 6 more authors.
Polymer Chemistry | Year: 2013

Novel supramolecular amphiphilic multiarm hyperbranched copolymers were successfully constructed through the molecular recognition of nucleobases. First, adenine-terminated H40-star-poly(ε-caprolactone)-adenine (H40-star-PCL-A) and uracil-terminated poly(ethylene glycol) (PEG-U) were successfully prepared. Due to the molecular recognition between A and U moieties, supramolecular multiarm hyperbranched copolymers were obtained by simply mixing the hydrophobic H40-star-PCL-A core and hydrophilic PEG-U shell. They not only had similar properties to conventional covalent-linked multiarm hyperbranched copolymers, but also possessed a dynamic and tunable nature. These supramolecular hyperbranched copolymers were found to self-assemble into pH-responsive micelles with low critical micelle concentration (CMC) because of non-covalent connection and hyperbranched architecture. The size of the self-assembled micelles could be easily tailored by changing the ratio of hydrophobic H40-star-PCL-A core and hydrophilic PEG-U arm. Moreover, encapsulation and controlled drug release were demonstrated with the chemotherapeutic drug doxorubicin (DOX). These supramolecular hyperbranched copolymer systems represent an evolution over conventional stimuli-responsive covalent-bonded hyperbranched copolymer systems and display a significant reduction in the viability of HeLa cells upon triggered release of DOX from the supramolecular micelles. © 2013 The Royal Society of Chemistry.


Yaoxian W.,Harbin Medical University | Yaoxian W.,Heilongjiang University | Hui Y.,Harbin Medical University | Yunyan Z.,Harbin Medical University | And 3 more authors.
Cancer Cell International | Year: 2013

Background: Emodin is a natural anthraquinone derivative isolated from the Rheum palmatum L. Aim: The aim of the present study was to investigate the effect of emodin on the apoptosis of the human cervical cancer line HeLa and to identify the mechanisms involved.Methods: Relative cell viability was assessed by MTT assay after treatment with emodin. Cell apoptosis was detected with TUNEL, Hoechst 33342 staining and quantified with flow cytometry using annexin FITC-PI staining.Results: The percentage of apoptotic cells was 0.8, 8.2, 22.1, and 43.7%, respectively. The mRNA levels of Caspase-9, -8 and -3 detected by Real-time PCR after treatment with emodin were significantly increased. Emodin increased the protein levels of Cytochome c, Apaf-1, Fas, FasL, and FADD but decreased the protein levels of Pro-caspase-9, Pro-caspase-8 and Pro-caspase-3.Conclusion: We conclude that the emodin inhibited HeLa proliferation by inducing apoptosis through the intrinsic mitochondrial and extrinsic death receptor pathways. © 2013 Yaoxian et al.; licensee BioMed Central Ltd.


Wang X.,Huazhong University of Science and Technology | Li Z.,Huazhong University of Science and Technology | Xu Z.,Harbin Medical University | Wang Z.,Anhui Provincial Hospital | Feng J.,Huazhong University of Science and Technology
International Journal of Colorectal Disease | Year: 2014

Background Enterocolitis (EC) is the most common and serious postoperative complication of Hirschsprung's disease (HD). Probiotics potentially play a protective role in maintaining intestinal mucosal integrity. Based on the beneficial effects of probiotics, we hypothesized that oral probiotics could decrease the incidence and severity of Hirschsprung's disease-associated enterocolitis (HAEC). Methods We conducted a prospective, multicenter, randomized, and controlled trial to assess whether oral probiotics could decrease the incidence and severity of HAEC. HD patients were randomly assigned into the control group and probiotic-treated group. All children in probiotic-treated group were fed with probiotics per day for 4 weeks. In next 3 months, the incidence and severity of HAEC were analyzed. The peripheral blood T lymphocyte subsets and cytokines, including TNF-α, IFN-γ, IL-6, and IL-10, were analyzed by flow cytometry and enzyme immunoassay (EIA). Results Compared with the control group, the incidence of HAEC in the probiotic-treated group was significantly diminished. The severity of EC was also remarkably decreased. Furthermore, probiotics balanced T lymphocyte subsets. Moreover, pro-inflammatory cytokines TNF-α, IFN-γ, and IL-6 were significantly decreased and anti-inflammatory cytokine IL-10 was notably increased in probiotic-treated group. Conclusions Probiotics not only significantly diminished the incidence but also decreased the severity of HAEC. Moreover, our study revealed that probiotics decreased pro-inflammatory cytokine and increased ant i - inflammatory cytokine and furthermore balanced T lymphocytes (registered with ClinicalTrials.gov, NCT number: NCT01934959). © 2014, Springer-Verlag Berlin Heidelberg.


Ding Y.,Harvard University | Ding Y.,Harbin Medical University | Kim J.K.,Harvard University | Kim J.K.,Soonchunhyang University | And 5 more authors.
Journal of Biological Chemistry | Year: 2010

Autophagy can lead to cell death in response to stress, but it can also act as a protective mechanism for cell survival. We show that TGF-β1 induces autophagy and protects glomerular mesangial cells from undergoing apoptosis during serum deprivation. Serum withdrawal rapidly induced autophagy within 1 h in mouse mesangial cells (MMC) as determined by increased microtubule-associated protein 1 light chain 3 (LC3) levels and punctate distribution of the autophagic vesicle-associated-form LC3-II. We demonstrate that after 1 h there was a time-dependent decrease in LC3 levels that was accompanied by induction of apoptosis, evidenced by increases in cleaved caspase 3. However, treatment with TGF-β1 resulted in induction of the autophagy protein LC3 while suppressing caspase 3 activation. TGF-β1 failed to rescue MMC from serum deprivation-induced apoptosis upon knockdown of LC3 by siRNA and in MMC from LC3 null (LC3-/-) mice. We show that TGF-β1 induced autophagy through TAK1 and Akt activation, and inhibition of PI3K-Akt pathway by LY294002 or dominant-negative Akt suppressed LC3 levels and enhanced caspase 3 activation. TGF-β1 also up-regulated cyclin D1 and E protein levels while down-regulating p27, thus stimulating cell cycle progression. Bafilomycin A1, but not MG132, blocked TGF-β1 down-regulation of p27, suggesting that p27 levels were regulated through autophagy. Taken together, our data indicate that TGF-β1 rescues MMC from serum deprivation induced apoptosis via induction of autophagy through activation of the Akt pathway. The autophagic process may constitute an adaptive mechanism to glomerular injury by inhibiting apoptosis and promoting mesangial cell survival. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Zhao W.,Harbin Medical University | Zhang W.,Harbin Medical University | Yang F.,Harbin Medical University | Zhang L.,Henan Agricultural University | And 4 more authors.
Journal of Eukaryotic Microbiology | Year: 2015

Enterocytozoon bieneusi is the most frequently diagnosed microsporidian species in humans. It has been found in a wide range of animals and is considered an important zoonotic pathogen. To date, little information is available on the role that cattle play in the epidemiology of human microsporidiosis caused by E. bieneusi in China. In this study, 133 fecal specimens from dairy cattle were collected in Heilongjiang Province, China. Enterocytozoon bieneusi was identified and genotyped by nested PCR analysis of the internal transcribed spacer (ITS) region of the rRNA gene, with 30.1% positive. Nine ITS genotypes were identified: six known genotypes - O (n = 26), EbpA (n = 2), I (n = 2), J (n = 2), D (n = 1) and BEB4 (n = 1) - and three novel genotypes named as CC-I to CC-III (two each). Genotype O was identified in cattle for the first time. The observation of all the six known genotypes here reported previously in humans, and also the fact of all the three novel genotypes (CHN-DC1 to CHN-DC3) falling into zoonotic group 1, indicate the possibility of cattle in the transmission of E. bieneusi to humans. © 2015 The Author(s) Journal of Eukaryotic Microbiology © 2015 International Society of Protistologists.


Yu L.,Harbin Medical University | Ding G.-F.,Binzhou Medical University | He C.,Harbin Medical University | Sun L.,Harbin Medical University | And 2 more authors.
PLoS ONE | Year: 2014

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. MicroRNAs (miRNAs) are important regulators of multiple cellular processes, and the aberrant miRNAs expressions have been observed in different types of cancer including HCC. Their pathysiologic role and their relevance to tumorigenesis are still largely unknown. In this study, we demonstrated the down-regulation of miR-424 in HCC cell lines and tissues by quantitative RT-PCR analyses. Overexpression of miR-424 reduced the HCC cell prolifetation, migration, and invasion. Conversely, inhibiton of miR-424 expression significantly accelerated the cell proliferation, migration, and invasion. In addition, we further identified c-Myb as a functional downstream target of miR-424 by directly targeting the 3′UTR of c-Myb. Furthermore, overexpression of c-Myb impaired miR-424-induced inhibition of proliferation and invasion in HCC cells. Our results demonstrated that miR-424 was involved in tumorigenesis of HCC at least in part by suppression of c-Myb. © 2014 Zhu et al.


News Article | December 12, 2016
Site: www.eurekalert.org

The increased risk of hyperglycemia associated with prenatal exposure to famine is also passed down to the next generation, according to a new study of hundreds of families affected by widespread starvation in mid-20th Century China. Hyperglycemia is a high blood glucose level and a common sign of diabetes. The new study in the American Journal of Clinical Nutrition reports that hundreds of people who were gestated during a horrific famine that afflicted China between 1959 and 1961 had significantly elevated odds of both hyperglycemia and type 2 diabetes. Even more striking, however, was that their children also had significantly higher odds of hyperglycemia, even though the famine had long since passed when they were born. Public health researchers at Brown University and Harbin Medical University in China were able to make the findings by studying more than 3,000 local residents and their children. Some of the subjects were gestated during famine and some were gestated just afterward. Some of the studied offspring were born to two, one or no parents who had been famine-exposed. This study population allowed the scientists, who interviewed and took blood samples from the participants in 2012, to make well-controlled, multigenerational comparisons of the effects of in utero famine exposure that would never be ethical to intentionally create. "These were unique 'experiments,' so to speak, that were unfortunately done to those populations at a time when the society was under revolutionary, social and political upheavals.," said Dr. Simin Liu, the study's co-corresponding author and a professor of epidemiology and of medicine at Brown. "By studying these families we could determine multiple-generational exposure to nutritional factors and genetic interactions that occur due to famine." Among 983 people gestated during the famine years, 31.2 percent had hyperglycemia and 11.2 percent had type 2 diabetes. By comparison, among 1,085 people gestated just after the famine ended, the prevalence of hyperglycemia was 16.9 percent, and the prevalence of type 2 diabetes as 5.6 percent. Controlling for factors such as gender, smoking, physical activity, calorie consumption and body-mass index, the researchers calculated that in utero famine exposure was associated with 1.93-times higher odds of hyperglycemia and a 1.75 times greater chance of type 2 diabetes. The next generation sustained the significant risk of hyperglycemia when both parents had been famine-exposed. Overall in the second generation, hyperglycemia prevalence were 5.7 percent for 332 people with no famine-exposed parents, 10.0 percent for 251 people with famine-exposed fathers, 10.6 percent for 263 people with famine-exposed mothers, and 11.3 percent for the 337 people for whom both parents had famine exposure. Adjusting for all the same lifestyle factors, the offspring of two famine-exposed parents had 2.02 times the odds of hyperglycemia of people with no famine-exposed parents. The odds of hyperglycemia from one-parent exposure were also substantially elevated but not quite statistically significant. The odds of type 2 diabetes were not statistically significant after adjustment for multiple comparisons among the second generation, but co-corresponding author Dr. Sun Changhao, professor of nutrition and dean of the School of Public Health at Harbin, noted that these people were only in their 20s and 30s and could still be at increased risk as they age and that the research team will continue to follow up on these participants. How is this possible? Because the study only shows an association between metabolic changes and in utero famine exposure, it can't prove causality or the biological mechanism underlying a cause. But prior research on the effects of famine in humans and in laboratory animals suggest that famine does indeed cause such health risks, the study authors said. "It is indeed a remarkable finding that is consistent what with what one would have expected from prior findings from animal experiments," said lead author Jie Li, a Brown postdoctoral fellow. A prior team's study in mice showed a multigenerational effect on metabolism, and other studies of famine exposure in people have produced evidence of changes in the endocrine systems and in prenatal gene expression in reproductive systems. Liu said he hopes to continue working with colleagues and participants in China to further investigate how gene and environmental interaction may affect health outcomes across generations. Findings of such work would have implications not only for improving biological understanding of mechanisms but also for clinical and public health interventions. "Genetic, epigenetic reprogramming, and subsequent gene-diet interaction are all possible explanations," he said. "By establishing this Chinese famine cohort of families, we hope to conduct a much more comprehensive and in-depth assessment of the whole genome and epigenome along with metabolic biomarkers of these participants moving forward." The paper's other corresponding author is Ying Li. Other co-authors are Songtao Li, Rennan Feng, Lixin Na, Xia Chu, Xiaoyan Wu, Yucun Niu, Zongxiang Sun, Tianshu Han, Haoyuan Deng, Xing Meng, Huan Xu, Zhe Zhang, Qiannuo Qu and Qiao Zhang, all of Harbin. Several government and academic sources in China provided funding for the study.


Tian J.,Harbin Medical University | Che H.,China Agricultural University | Ha D.,Harbin Medical University | Wei Y.,Harbin Medical University | Zheng S.,Harbin Medical University
Carbohydrate Polymers | Year: 2012

A water-soluble polysaccharide (LJP-1), with a molecular weight of 1.8 × 105 Da, was isolated from the flower buds of Lonicera japonica. Gas chromatography (GC) analysis showed that the LJP-1 was mainly composed of d-glucose and a small amount of d-arabinose. On the basis of methylation analysis, LJP-1 had the backbone chain mainly consisting of 1,6-linked Glc and 1,3,6-linked Glc, which was terminated with 1-linked Ara residues at the O-3 position of 1,3,6-linked Glc in a relative molar ratio of 2.9:1:0.9. The anti-allergic effect of LJP-1 was evaluated on allergic contact dermatitis (ACD) induced by picryl chloride (PC) in mouse ear. Similar to prednisolone, orally administrated LJP-1 (20, 40 and 80 mg/kg) potently inhibited the PC-induced ACD, leading to substantial reductions in ear thickness, serum level of IgE and histamine, as well as tissue TNF-α. These results demonstrate that treatment with LJP-1 may be effective for preventing the development of PC-induced ACD. © 2012 Elsevier Ltd. All rights reserved.


Kubo T.,Wakayama Medical University | Akasaka T.,Wakayama Medical University | Shite J.,Kobe University | Suzuki T.,Toyohashi Heart Center | And 10 more authors.
JACC: Cardiovascular Imaging | Year: 2013

Objectives The aim of this study was to investigate the reliability of frequency domain optical coherence tomography (FD-OCT) for coronary measurements compared with quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS). Background Accurate luminal measurement is expected in FD-OCT because this technology offers high resolution and excellent contrast between lumen and vessel wall. Methods In 5 medical centers, 100 patients with coronary artery disease were prospectively studied by using angiography, FD-OCT, and IVUS. In addition, 5 phantom models of known lumen dimensions (lumen diameter 3.08 mm; lumen area 7.45 mm2) were examined using FD-OCT and IVUS. Quantitative image analyses of the coronary arteries and phantom models were performed by an independent core laboratory. Results In the clinical study, the mean minimum lumen diameter measured by QCA was significantly smaller than that measured by FD-OCT (1.81 ± 0.72 mm vs. 1.91 ± 0.69 mm; p < 0.001) and the minimum lumen diameter measured by IVUS was significantly greater than that measured by FD-OCT (2.09 ± 0.60 mm vs. 1.91 ± 0.69 mm; p < 0.001). The minimum lumen area measured by IVUS was significantly greater than that by FD-OCT (3.68 ± 2.06 mm2 vs. 3.27 ± 2.22 mm2; p < 0.001), although a significant correlation was observed between the 2 imaging techniques (r = 0.95, p < 0.001; mean difference 0.41 mm2). Both FD-OCT and IVUS exhibited good interobserver reproducibility, but the root-mean-squared deviation between measurements was approximately twice as high for the IVUS measurements compared with the FD-OCT measurements (0.32 mm2 vs. 0.16 mm2). In a phantom model, the mean lumen area according to FD-OCT was equal to the actual lumen area of the phantom model, with low SD; IVUS overestimated the lumen area and was less reproducible than FD-OCT (8.03 ± 0.58 mm2 vs. 7.45 ± 0.17 mm2; p < 0.001). Conclusions The results of this prospective multicenter study demonstrate that FD-OCT provides accurate and reproducible quantitative measurements of coronary dimensions in the clinical setting. © 2013 by the American College of Cardiology Foundation.


Li J.,Harbin Medical University | An R.,Harbin Medical University | Zhang Y.,Cangzhou Peoples Hospital | Li X.,Heilongjiang University of Chinese Medicine | Wang S.,Harbin Medical University
American Journal of Clinical Nutrition | Year: 2012

Background: Body energy homeostasis is largely regulated by the interactions between appetite-related brain regions and gut hormones. Objective: We hypothesized that the sensitivity of appetite-related brain regions [eg, hypothalamus, insula, thalamus, parahippocampal/hippocampal cortex, caudate, putamen, amygdala, and orbitofrontal cortex (OFC)] varies for each macronutrient, and the differential sensitivity is associated with gut hormone concentrations in humans. Design: Brain activation responses to ingested fat, glucose, protein, and water in the above-mentioned 8 brain regions of 14 healthy men were investigated by using functional magnetic resonance imaging. Fasting and postprandial plasma glucose, insulin, ghrelin, cholecystokinin (CCK), and glucagon-like peptide 1 (GLP-1) concentrations were measured. The relation of the blood oxygen level-dependent (BOLD) signal with plasma glucose and hormone concentrations was assessed by using Pearson's correlation analysis. Results: Ingested macronutrients similarly reduced the BOLD signal in the middle insula, thalamus, parahippocampal cortex, caudate, and lateral OFC. Protein ingestion reduced the BOLD signal in the amygdala more effectively than did fat and glucose ingestion. BOLD signal changes were positively correlated with circulating ghrelin concentrations and were negatively correlated with circulating insulin, CCK, and GLP-1 concentrations. The findings indicate variations in the correlation between brain activation and plasma hormone concentrations after ingestion of different macronutrients. Conclusions: The middle insula, thalamus, parahippocampal cortex, caudate, and lateral OFC, but not the amygdala, have similar sensitivities to isocaloric and isovolumetric macronutrient solutions. Differential correlations exist between BOLD signal changes in activated brain regions and postprandial changes in plasma concentrations of different gut hormones in response to the ingestion of different macronutrients. This trial was registered at chictr.org as ChiCTR-TRC-12001945. © 2012 American Society for Nutrition.


Tian J.,Key Laboratories of Education Ministry for Myocardial Ischemia | Gu X.,Key Laboratories of Education Ministry for Myocardial Ischemia | Sun Y.,Key Laboratories of Education Ministry for Myocardial Ischemia | Ban X.,Harbin Medical University | And 3 more authors.
BMC Cardiovascular Disorders | Year: 2012

Background: An increasing number of authors employing intravascular ultrasound (IVUS) and virtual histology (VH-IVUS) have investigated the effect of statin use on plaque volume (PV) and plaque composition. However, inconsistent results have been reported. Therefore, we conducted a meta-analysis to determine the appropriate regimen of statins to effectively stabilize vulnerable coronary plaques.Methods: Online electronic databases were carefully searched for all relevant studies. We compared mean values of PV and plaque composition between baseline and follow-up in patients receiving statin therapy. We pooled treatment effects and calculated mean differences (MD) with the 95% confidence interval (CI) using a random-effects model. By stratified analyses, we explored the influence of clinical presentation, dose and duration of statin treatment, and low-density lipoprotein-cholesterol (LDL-C) levels on the effects of statins.Results: Seventeen studies involving 2,171 patients were analyzed. Statin therapy significantly decreased PV (-5.3 mm3; 95% CI: -3.3 mm3 to -7.2 mm3; P < 0.001), without heterogeneity. When considering the dose and duration of statins used, only subgroups employing a high dose and long duration demonstrated a significant reduction in PV (p < 0.001). A significant decrease in PV was noted if achieved LDL-C levels were <100 mg/dL (p < 0.001). Statin treatment could induce a twofold decrease in PV in patients with acute coronary syndrome (ACS) compared with that observed in patients with stable angina pectoris (SAP). A regressive trend was seen for necrotic core volume (MD: -2.1 mm3; 95% CI: -4.7 mm3 to 0.5 mm3, P = 0.11). However, statin use did not induce a significant change for fibrotic, fibro-fatty, or dense calcium compositions.Conclusions: Our meta-analysis demonstrated that statin therapy (especially that involving a high dose and long duration and achieving <100 mg/dL LDL-C levels) can significantly decrease PV in patients with SAP or ACS. These data suggested that statins can be used to reduce the atheroma burden for secondary prevention by appropriately selecting the statin regimen. No significant change in plaque composition was seen after statin therapy. © 2012 Tian et al.; licensee BioMed Central Ltd.


Li Q.,Tianjin University of Science and Technology | Yu N.,General Hospital of Jinan Military Command | Wang Y.,Tianjin University of Science and Technology | Sun Y.,Heilongjiang University of Chinese Medicine | And 2 more authors.
Carbohydrate Polymers | Year: 2013

Box-Behnken design including independent variables such as extraction temperature (60-80 C), extraction time (20-40 min) and ratio of water to raw material (30-50 mL/g) was used to optimize the extraction process of Bruguiera gymnorrhiza polysaccharides (BGPs). The experimental data were fitted to a second-order polynomial equation using multiple regression analysis. The optimum conditions were predicted as follows: extraction temperature 71 C, extracting time 31.4 min, and ratio of water to raw material 42. Under these conditions, the yield of BGPs obtained was (16.43 ± 0.08)%, which was in good agreement with the predicted value 16.47%. Additionally, characterization of BGPs was obtained by FT-IR analysis. The antioxidant activities of BGPs were evaluated in vitro. BGPs demonstrated appreciable antioxidant potential on superoxide anion radical, ABTS radical, and hydroxyl radical scavenging. These may provide theoretical basis for further system research and rational development and utilization of mangrove resources. © 2013 Elsevier Ltd. All rights reserved.


Yang L.,New York Medical College | Yang L.,Harbin Medical University | Edvinsson J.,New York Medical College | Palmer L.G.,New York Medical College
Journal of General Physiology | Year: 2012

We investigated the effects of changing extracellular K+ concentrations on block of the weak inward-rectifier K+ channel Kir1.1b (ROMK2) by the three intracellular cations Mg2+, Na+, and TEA+. Single-channel currents were monitored in inside-out patches made from Xenopus laevis oocytes expressing the channels. With 110 mM K+ in the inside (cytoplasmic) solution and 11 mM K+ in the outside (extracellular) solution, these three cations blocked K+ currents with a range of apparent affinities (Ki (0) = 1.6 mM for Mg2+, 160 mM for Na+, and 1.8 mM for TEA+) but with similar voltage dependence (zδ = 0.58 for Mg2+, 0.71 for Na+, and 0.61 for TEA+) despite having different valences. When external K+ was increased to 110 mM, the apparent affinity of all three blockers was decreased approximately threefold with no significant change in the voltage dependence of block. The possibility that the transmembrane cavity is the site of block was explored by making mutations at the N152 residue, a position previously shown to affect rectification in Kir channels. N152D increased the affinity for block by Mg2+ but not for Na+ or TEA+. In contrast, the N152Y mutation increased the affinity for block by TEA+ but not for Na+ or Mg2+. Replacing the C terminus of the channel with that of the strong inward-rectifier Kir2.1 increased the affinity of block by Mg2+ but had a small effect on that by Na+. TEA+ block was enhanced and had a larger voltage dependence. We used an eight-state kinetic model to simulate these results. The effects of voltage and external K+ could be explained by a model in which the blockers occupy a site, presumably in the transmembrane cavity, at a position that is largely unaffected by changes in the electric field. The effects of voltage and extracellular K+ are explained by shifts in the occupancy of sites within the selectivity filter by K+ ions. © 2012 Yang et al.


Wu P.,Harbin Medical University | Wang M.,Harbin Medical University | Luan H.,Harbin Medical University | Li L.,Harbin Medical University | And 4 more authors.
Hypertension | Year: 2013

Chloride channels in the basolateral membrane play a key role in Cl absorption in the thick ascending limb (TAL). The patch-clamp experiments were performed to test whether angiotensin II (AngII) increases Cl absorption in the TAL by stimulating the basolateral 10-pS Cl channels. AngII (1-100 nmol/L) stimulated the 10-pS Cl channel in the TAL, an effect that was blocked by losartan (angiotension AT1 receptor [AT1R] antagonist) but not by PD123319 (angiotension AT2 receptor [AT2R] antagonist). Inhibition of phospholipase C or protein kinase C also abolished the stimulatory effect of AngII on Cl channels. Moreover, stimulation of protein kinase C with phorbol-12-myristate-13-acetate mimicked the effect of AngII and increased Cl channel activity. However, the stimulatory effect of AngII on Cl channels was absent in the TAL pretreated with diphenyleneiodonium sulfate, an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Moreover, treatment of the TAL with diphenyleneiodonium sulfate also blocked the effect of phorbol-12-myristate-13-acetate on the 10-pS Cl channel. Western blotting demonstrated that incubation of isolated TAL with AngII increased phosphorylation of p47 at Ser, suggesting that AngII stimulates the basolateral Cl channels by increasing NADPH oxidase-dependent superoxide generation. This notion was also supported by the observation that H2O2 significantly increased 10-pS Cl channel activity in the TAL. We conclude that stimulation of AT 1R increased the basolateral Cl channels by activating the protein kinase C-dependent NADPH oxidase pathway. The stimulatory effect of AngII on the basolateral Cl channel may contribute to AngII-induced increases in NaCl reabsorption in the TAL and AngII-infuse-induced hypertension. © 2013 American Heart Association, Inc.


Wang K.,Harbin Medical University | Wang K.,U.S. Center for Disease Control and Prevention | Yan H.,U.S. Center for Disease Control and Prevention | Liu Y.,U.S. Center for Disease Control and Prevention | And 3 more authors.
International Journal of Epidemiology | Year: 2012

Background: To monitor the prevalence of HIV and syphilis as well as behaviours, a sentinel site for men who have sex with men was established in Harbin in 2002. With additional funding, the sentinel surveillance evolved into annual cross-sectional surveys since 2006. Methods: Behavioural and serological data collected in five consecutive cross-sectional surveys were analysed. SPSS 13.0 was applied to compare prevalence of HIV and syphilis as well as behavioural variables over time by demographic variables, bivariate and multivariate analysis. Results: The prevalence of HIV and syphilis increased from 1.0% in 2006 to 7.5% in 2010 and from 9.2% in 2006 to 22.4% in 2009, respectively, whereas the rate of unprotected anal intercourse decreased from 61.3% in 2006 to 47.1% in 2010. Syphilis positivity and HIV infection are independently associated with each other across years. The rate of unprotected anal sex remains high although it has decreased over the years. Conclusion: Findings support an increasing prevalence of HIV and syphilis among men who have sex with men in Harbin. Targeted behavioural intervention and syphilis treatment are urgently needed to prevent the epidemic from growing. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2011; all rights reserved.


Wang Z.,Harbin Institute of Technology | Wu L.,Harbin Medical University | Zhou J.,Canadian Light Source Incorporated | Cai W.,Harbin Institute of Technology | And 2 more authors.
Journal of Physical Chemistry C | Year: 2013

The understanding of the interaction between the building blocks in the hybrids can advance our comprehension of design principles in high-performance microwave absorbing materials. Here, we report a hybrid material consisting of magnetite (Fe3O4) nanocrystals grown on multiwalled carbon nanotube (MWCNT) as a high-performance microwave absorber in the 2-18 GHz band, although Fe3O4 nanocrystals or MWCNTs alone or their physical mixture show little microwave absorption. The hybrid is characterized by transmission electron microscopy, X-ray diffraction, and vector network analysis, X-ray absorption near-edge structures at the C K-edge and Fe L 3,2-edge, and electron spin resonance analysis. Microstructural analysis reveals that Fe3O4 nanocrystals are immobilized on the MWCNT surface by a strong interaction. Charges in the MWCNT/Fe 3O4 hybrids transfer from the conduction band in Fe 3O4 to C 2p-derived states in the MWCNT substrate. Dipole interaction between the magnetic nanocrystals is increased. The synergetic interactions leads to much improved microwave absorption. © 2013 American Chemical Society.


Wang Y.,Okayama University of Science | Wang Y.,Harbin Medical University | Masuyama H.,Okayama University of Science | Nobumoto E.,Okayama University of Science | And 2 more authors.
Biochemical Pharmacology | Year: 2014

Background Ovarian cancer is commonly treated with anticancer agents; however, many tumors become resistant. Resistance is regulated, in part, by P-glycoprotein, which is encoded by the gene multiple drug resistance 1 (MDR1) and functions as a transmembrane efflux pump for the elimination of anticancer agents. Constitutive androstane receptor (CAR) is a nuclear receptor that regulates drug metabolism through control of MDR1 and other genes. Purpose We examined whether the inhibition of CAR-mediated pathway could influence the cytotoxicity of three anticancer drugs, cisplatin, paclitaxel, and arsenic trioxide, in ovarian cancer cells. Results We observed that the cell proliferation of several ovarian cell lines expressing CAR significantly increased when CITCO was combined with anticancer agents compared with any anticancer agent alone. The up-regulation of MDR1 and UGT1A1 by anticancer agents was further enhanced in the presence of CITCO. We confirmed that combining CITCO with anticancer agents induced significantly lower levels of apoptosis than those achieved with any single anticancer drug. CAR down-regulation by RNA interference caused a significant increase in cell growth inhibition and enhancement of apoptosis in the presence of anticancer agents. Combination of CITCO with any anticancer agents significantly enhanced CAR-mediated transcription compared with any anticancer agents alone and CAR down-regulation completely inhibited the transcription in the presence of CITCO and/or anticancer agents. Conclusion Inhibition of CAR pathway could be a novel therapeutic approach for the augmentation of sensitivity to anticancer agents, or to overcome resistance, in the treatment of ovarian cancer. © 2014 Elsevier Inc.


Lin D.-H.,Harbin Medical University | Lin D.-H.,New York Medical College | Yue P.,Harbin Medical University | Pan C.,Harbin Medical University | And 2 more authors.
Journal of the American Society of Nephrology | Year: 2011

Dietary potassium stimulates the surface expression of ROMK channels in the aldosterone-sensitive distal nephron, but the mechanism by which this occurs is incompletely understood. Here, a highpotassium diet increased the transcription of microRNA (miR) 802 in the cortical collecting duct in mice. In addition, high-potassium intake decreased the expression of caveolin-1, whose 3′ untranslated region contains the seed sequence of miR-802. In vitro, expression of miR-802 suppressed the expression of caveolin-1, and conversely, downregulation of endogenous miR-802 increased the expression of caveolin-1. Sucrose-gradient centrifugation suggested that caveolin-1 closely associated with ROMK channels, and immunoprecipitation showed that caveolin-1 interacted with the N terminus of ROMK. Expression of caveolin-1 varied inversely with the expression of ROMK1 in the plasma membrane, and caveolin-1 inhibited ROMK1 channel activity. Removal of the clathrin-dependent endocytosis motif from ROMK1 failed to abolish the effect of caveolin-1 on ROMK1 channel activity. Last, expression of miR-802 increased ROMK1 channel activity, an effect blocked by coexpression of caveolin-1. Taken together, miR-802 mediates the stimulatory effect of a high-potassium diet on ROMK channel activity by suppressing caveolin-1 expression, which leads to increased surface expression of ROMK channels in the distal nephron. Copyright © 2011 by the American Society of Nephrology.


Kato K.,Massachusetts General Hospital | Yonetsu T.,Massachusetts General Hospital | Kim S.-J.,Kyung Hee University | Xing L.,Massachusetts General Hospital | And 9 more authors.
Circulation: Cardiovascular Imaging | Year: 2012

Background-Patients with acute coronary syndrome (ACS) have a higher incidence of recurrent ischemic events. The aim of this study was to compare the plaque characteristics of nonculprit lesions between ACS and non-ACS patients using optical coherence tomography (OCT) imaging. Methods and Results-Patients who had 3-vessel OCT imaging were selected from the Massachusetts General Hospital (MGH) OCT Registry. MGH registry is a multicenter registry of patients undergoing OCT. The prevalence and characteristics of nonculprit plaques were compared between ACS and non-ACS patients. A total of 248 nonculprit plaques were found in 104 patients: 45 plaques in 17 ACS patients and 203 plaques in 87 non-ACS patients. Compared with plaques of non-ACS patients, plaques of ACS patients had a wider lipid arc (147.3±29.5A versus 116.2±33.7a, P<0.001), a longer lipid length (10.7±5.9 mm versus 7.0±3.7 mm, P=0.002), a larger lipid volume index [averaged lipid arclipid length] (1605.5±1013.1 versus 853.4±570.8, P<0.001), and a thinner fibrous cap (70.2±20.2m versus 103.3±46.8m, P<0.001). Moreover, thin-cap fibroatheroma (64.7% versus 14.9%, P<0.001), macrophage (82.4% versus 37.9%, P=0.001), and thrombus (29.4% versus 1.1%, P<0.001) were more frequent in ACS patients. Although the prevalence of microchannel did not differ between the groups, the closest distance from the lumen to microchannel was shorter in ACS subjects than in non-ACS (104.6±67.0 ?m versus 198.3±133.0 ?m, P=0.027). Conclusions-Nonculprit lesions in patients with ACS have more vulnerable plaque characteristics compared with those with non-ACS. Neovascularization was more frequently located close to the lumen in patients with ACS. © 2012 American Heart Association, Inc.


Shao N.,Harbin Medical University | Kuang H.Y.,Harbin Medical University | Hao M.,Harbin Medical University | Gao X.Y.,Harbin Medical University | And 2 more authors.
Diabetes/Metabolism Research and Reviews | Year: 2014

Background: The purpose of this study was to evaluate the advantages of exenatide treatment on obesity and non-alcoholic fatty liver disease (NAFLD) with elevated liver enzymes in patients with type 2 diabetes (T2D). Methods: A total of 60 newly diagnosed patients with obesity, NAFLD with elevated liver enzymes and T2D were included in the study. The patients were randomly divided into two groups. The exenatide treatment group (n=30) were treated with exenatide and insulin glargine, and the intensive insulin therapy group (n=30) were treated with insulin aspart and insulin glargine for 12weeks. Selected clinical characteristics were determined, and ultrasonography was performed at both baseline and 12weeks following treatment. Results: At baseline, the clinical characteristics were matched between the two groups. After 12weeks, fasting blood glucose (FBG), postprandial blood glucose (PBG), glycosylated haemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG) and total bilirubin levels were significantly decreased in the two groups (p<0.001). Body weight and waist circumference were significantly decreased in the exenatide group but increased in the intensive insulin group (p<0.001). The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyl transpeptidase (γGGT) in the exenatide group were significantly lower than in the intensive insulin group (p<0.001). The mean body weight change correlated with the levels of ALT, AST and γGGT change (ALT, r=0.761; AST, r=0.733; γGGT, r=0.752; p<0.001). Moreover, the reversal rate of fatty liver was significantly higher in the exenatide group (93.3%) than the intensive insulin group (66.7%) (p<0.01). Conclusions: Exenatide has a better hepatic-protective effect than intensive insulin therapy and perhaps represents a unique option for adjunctive therapy for patients with obesity, non-alcoholic fatty liver disease with elevated liver enzymes and T2D. © 2014 John Wiley & Sons, Ltd.


Wang H.,Harbin Medical University | Zhang Y.,The First Hospital of Qiqihar | Li Z.,Harbin Medical University | Wang T.,Hospital of Mingshui County | Liu P.,Harbin Medical University
Clinical and Experimental Ophthalmology | Year: 2014

Background: The study aimed to assess the prevalence and causes of corneal blindness in a rural northern Chinese population. Design: Cross-sectional study. Participants or Samples: The cluster random sampling method was used to select the sample. Methods: This population-based study included 11787 participants of all ages in rural Heilongjiang Province, China. These participants underwent a detailed interview and eye examination that included the measurement of visual acuity, slit-lamp biomicroscopy and direct ophthalmoscopy. An eye was considered to have corneal blindness if the visual acuity was <9/18 because of corneal diseases. Main Outcome Measures: The main outcome measure was prevalence rates of corneal blindness and low vision. Results: Among the 10384 people enrolled in the study, the prevalence of corneal blindness is 0.3% (95% confidence interval 0.2-0.4%). The leading cause was keratitis in childhood (40.0%), followed by ocular trauma (33.3%) and keratitis in adulthood (20.0%). Age and illiteracy were found to be associated with an increased prevalence of corneal blindness. Conclusion: Blindness because of corneal diseases in rural areas of Northern China is a significant public health problem that needs to be given more attention. © 2014 Royal Australian and New Zealand College of Ophthalmologists.


Huang X.,Medical College of Wisconsin | Liang M.,Harbin Medical University | Dittmar R.,Medical College of Wisconsin | Wang L.,Medical College of Wisconsin
International Journal of Molecular Sciences | Year: 2013

Small noncoding RNAs that are 19-23 nucleotides long, known as microRNAs (miRNAs), are involved in almost all biological mechanisms during carcinogenesis. Recent studies show that miRNAs released from live cells are detectable in body fluids and may be taken up by other cells to confer cell-cell communication. These released miRNAs (here referred to as extracellular miRNAs) are often protected by RNA-binding proteins or embedded inside circulating microvesicles. Due to their relative stability, extracellular miRNAs are believed to be promising candidates as biomarkers for diagnosis and prognosis of disease, or even as therapeutic agents for targeted treatment. In this review, we first describe biogenesis and characteristics of these miRNAs. We then summarize recent publications involving extracellular miRNA profiling studies in three representative urologic cancers, including: prostate cancer, bladder cancer, and renal cell carcinoma. We focus on the diagnostic, prognostic, and therapeutic potential of these miRNAs in biological fluids, such as serum, plasma, and urine. Finally, we discuss advantages and challenges of these miRNAs in clinical applications. © 2013 by the authors; licensee MDPI, Basel, Switzerland.


Li Y.,Harbin Medical University | Zhang S.,Harbin Medical University | Geng J.-X.,Harbin Medical University | Hu X.-Y.,Heilongjiang University of Chinese Medicine
Asian Pacific Journal of Cancer Prevention | Year: 2013

We intended to study the mechanism of the inhibitory action of curcumin on human non-small cell lung cancer A549 cell. The cell growth was determined by CCK-8 assay, and the results indicated that curcumin inhibited the cell proliferation in a concentration dependent manner. And to further confirm the relative anti-cancer mechanism of curcumin, RT-PCR was carried out to analysis the expression of relative apoptotic proteins Bax, Bcl-2. We found that curcumin could up-regulate the expression of Bax but down-regulate the expression of Bcl-2 in A549 cells. In addition, curcumin affect the mitochondrial apoptosis pathway. These results suggested that curcumin inhibited cancer cell growth through the regulation of Bcl-2/Bax and affect the mitochondrial apoptosis pathway.


Yun J.,University of Virginia | Yun J.,Research Institute and Hospital | Li J.,University of Virginia | Li J.,Harbin Medical University | Zuo Z.,University of Virginia
Brain Research Bulletin | Year: 2014

Ischemic preconditioning-induced neuroprotection is a well-known phenomenon. We hypothesize that this form of neuroprotection is transferable among the same type of cells. To test this hypothesis, human neuroblastoma SH-SY5Y cells were induced to become neuron-like cells. Primary rat cortical neuronal cultures were also used. These cells were subjected to various lengths of short oxygen-glucose deprivation (OGD, an in vitro simulation of ischemia) and then 1-h OGD. Some cells that were not exposed to a short episode of ischemia were incubated with culture medium from the cells that had 3- or 5-min OGD. Those cells were subjected to OGD for 1. h at 1 or 24. h after they were exposed to the medium. Cell injury was evaluated at 24. h after the 1-h OGD by lactate dehydrogenase release assay. In another experiment, cells subjected to a 3-min OGD or exposed to the medium from cells that had a 3-min OGD were harvested at 30. min after the OGD or the medium exposure for Western blotting of Akt, a prosurvival protein. Our study showed that a prior episode of ischemia lasting from 3 to 10. min significantly reduced the 1-h OGD-induced cell injury. Medium from cells subjected to a 3-min OGD also induced acute and delayed phases of neuroprotection in OGD-naïve human neuron-like cells and primary rat cortical neuronal cultures. Cells subjected to a 3-min OGD or incubated with the medium from cells exposed to a 3-min OGD had increased phosphorylated/activated Akt. The increased phosphorylated Akt and neuroprotection induced by medium transferring were inhibited by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an adenosine A1 receptor inhibitor. The 3-min OGD-induced neuroprotection was inhibited by LY294002, an Akt activation inhibitor. These results suggest that ischemic preconditioning-induced neuroprotection is transferable among the cells. Small molecules, such as adenosine, may mediate this effect. © 2014 Elsevier Inc.


Yang L.,New York Medical College | Yang L.,Harbin Medical University | Palmer L.G.,New York Medical College
Journal of General Physiology | Year: 2014

The ability of acid-sensing ion channels (ASICs) to discriminate among cations was assessed based on changes in conductance and reversal potential with ion substitution. Human ASIC1a was expressed in Xenopus laevis oocytes, and acid-induced currents were measured using two-electrode voltage clamp. Replacement of extracellular Na+ with Li+, K+, Rb+, or Cs+ altered inward conductance and shifted the reversal potentials consistent with a selectivity sequence of Li ~ Na > K > Rb > Cs. Permeability decreased more rapidly than conductance as a function of atomic size, with PK/PNa = 0.1 and GK/GNa = 0.7 and PRb/PNa = 0.03 and GRb/GNa = 0.3. Stimulation of Cl- currents when Na+ was replaced with Ca2+, Sr2+, or Ba2+ indicated a finite permeability to divalent cations. Inward conductance increased with extracellular Na+ in a hyperbolic manner, consistent with an apparent affinity (Km) for Na+ conduction of 25 mM. Nitrogen-containing cations, including NH4 +, NH3OH+, and guanidinium, were also permeant. In addition to passing through the channels, guanidinium blocked Na+ currents, implying competition for a site within the pore. The role of negative charges in an external vestibule of the pore was evaluated using the point mutation D434N. The mutant channel had a decreased single-channel conductance, measured in excised outside-out patches, and a macroscopic slope conductance that increased with hyperpolarization. It had a weakened interaction with Na+ (Km = 72 mM) and a selectivity that was shifted toward larger atomic sizes. We conclude that the selectivity of ASIC1 is based at least in part on interactions with binding sites both within and internal to the outer vestibule. © 2014 Yang and Palmer.


Xiao M.,Peking Union Medical College | Wang H.,Peking Union Medical College | Lu J.,Harbin Medical University | Chen S.C.-A.,University of Sydney | And 3 more authors.
Journal of Clinical Microbiology | Year: 2014

We investigated three nosocomial Candida quercitrusa candidemia cases occurring within 2 months in a Chinese hospital. Isolates were identifiable only by DNA sequencing of the rRNA genes. Genetic (via random amplified polymorphic DNA [RAPD]) and protein mass spectral (via matrix-assisted laser desorption ionization-time of flight mass spectrometry [MALDI-TOF MS]) analyses yielded identical profiles suggesting an outbreak. The fluconazole MICs of all the strains were 16 to 32 μg/ml. Copyright © 2014, American Society for Microbiology. All Rights Reserved.


Wang L.,Harbin Medical University | Wang L.,New York Medical College | Zhang C.,New York Medical College | Zhang C.,Xuzhou Medical College | And 3 more authors.
Journal of the American Society of Nephrology | Year: 2015

Kcnj10 encodes the inwardly rectifying K+ channel Kir4.1 in the basolateral membrane of the distal convoluted tubule (DCT) and is activated by c-Src. However, the regulation and function of this K+ channel are incompletely characterized. Here, patch-clamp experiments in Kcnj10-transfected HEK293 cells demonstrated that c-Src-induced stimulation of Kcnj10 requires coexpression of caveolin-1 (cav-1), and immunostainingshowed expression of cav-1 in the basolateralmembrane of parvalbumin-positive DCT. Patch-clamp experiments detected a 40-pS inwardly rectifying K+ channel, a heterotetramer of Kir4.1/Kir5.1, in the basolateral membrane of the early DCT (DCT1) in both wild-type (WT) and cav-1- knockout (KO) mice. However, the activity of this basolateral 40-pS K+ channel was lower in KO mice than inWTmice.Moreover, the K+ reversal potential (an indication ofmembrane potential) was less negative in the DCT1 of KO mice than in the DCT1 of WT mice. Western blot analysis demonstrated that cav-1 deficiency decreased the expression of the Na+/Cl- cotransporter and Ste20-proline-alanine-rich kinase (SPAK) but increased the expression of epithelial Na+ channel-α. Furthermore, the urinary excretion of Mg2+ and K+ was significantly higher in KO mice than in WT mice, and KO mice developed hypomagnesemia, hypocalcemia, and hypokalemia. We conclude that disruption of cav-1 decreases basolateral K+ channel activity and depolarizes the cell membrane potential in the DCT1 at least in part by suppressing the stimulatory effect of c-Src on Kcnj10. Furthermore, the decrease in Kcnj10 and Na+/Cl- cotransporter expression induced by cav-1 deficiency may underlie the compromised renal transport of Mg2+, Ca2+, and K+. Copyright © 2015 by the American Society of Nephrology.


Zhao J.,Peking Union Medical College | Ellwein L.B.,U.S. National Institutes of Health | Cui H.,Harbin Medical University | Ge J.,Sun Yat Sen University | And 7 more authors.
Ophthalmology | Year: 2010

Purpose: Describe the prevalence of visual impairment/blindness among older adults in rural populations in China. Design: Population-based, cross-sectional study. Participants: We evaluated 45 747 adults ≥50 years of age. Methods: Geographically defined cluster sampling was used in randomly selecting a cross-section of residents from a representative rural county within each of 9 provinces in mainland China. Participants were enumerated through village registers followed by door-to-door household visits. Eligible persons were invited to local examination sites for visual acuity (VA) testing and eye examination. Main Outcome Measures: Presenting and best-corrected distance VA. Results: Of 50 395 enumerated eligible persons, 45 747 (90.8%) were examined and tested for VA. The prevalence of presenting visual impairment <20/63 to ≥20/400 in the better eye was 10.8% and blindness (<20/400) was 2.29%. Across the 9 provinces, presenting visual impairment ranged from 6.89% to 15.8%, and blindness from 1.27% to 5.40%. With best-corrected VA, the prevalence of visual impairment was 5.30%, and 1.93% for blindness. The ranges across the 9 provinces were 3.13% to 9.51% for visual impairment and 0.74% to 4.95% for blindness. Visual impairment and blindness were associated with older age, female gender, lack of education, and geographic area (province) with both presenting and best-corrected VA. Conclusions: Visual impairment and blindness are important public health problems in rural China, with significant regional variations in prevalence. Blindness prevention programs targeting the rural elderly should be expanded, particularly in areas with limited access and affordability of eye care services. Special emphasis should be given to reaching women and those without education. Greater attention should also be given to correction of refractive error. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. © 2010 American Academy of Ophthalmology.


Li Y.,Harbin Medical University | Guo L.,Dong - A University | Ahn H.S.,Ilsin Christian Hospital | Kim M.H.,Dong - A University | And 2 more authors.
Journal of Cellular and Molecular Medicine | Year: 2014

Recently, we reported that human amniotic membrane-derived mesenchymal stem cells (AMMs) possess great angiogenic potential. In this study, we determined whether local injection of AMMs ameliorates peripheral neuropathy. AMMs were transplanted into injured sciatic nerves. AMM injection promoted significant recovery of motor nerve conduction velocity and voltage amplitude compared to human adipose-derived mesenchymal stem cells. AMM implantation also augmented blood perfusion and increased intraneural vascularity. Whole-mount fluorescent imaging analysis demonstrated that AMMs exhibited higher engraftment and endothelial incorporation abilities in the sciatic nerve. In addition, the higher expression of pro-angiogenic factors was detected in AMMs injected into the peripheral nerve. Therefore, these data provide novel therapeutic and mechanistic insights into stem cell biology, and AMM transplantation may represent an alternative therapeutic option for treating peripheral neuropathy. © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.


Chen G.,Peking Union Medical College | Pan S.-Q.,Harbin Medical University | Shen C.,Peking Union Medical College | Pan S.-F.,Capital Medical University | And 2 more authors.
Acta Pharmacologica Sinica | Year: 2014

Aim: To investigate the effects of puerarin (Pue), an isoflavone derived from Kudzu roots, on angiotensin II (Ang II)-induced hypertrophy of cardiomyocytes in vivo and in vitro.Methods:C57BL/6J mice were infused with Ang II and treated with Pue (100 mg·kg -1·d -1, po) for 15 d. After the treatment, systolic blood pressure (SBP) and left ventricular wall thickness were assessed. The ratios of heart weight to body weight (HW/BW) and left ventricular weight to body weight (LVW/BW) were determined, and heart morphometry was assessed. Expression of fetal-type genes (ANP, BNP and β-MHC) in left ventricles was measured using semi-quantitative RT-PCR. Mouse primary cardiomyocytes were treated with Pue (50, 100, 200 μmol/L), then exposed to Ang II (1 μmol/L). ROS level was examined with flow cytometry, the binding activity of NF-κB was determined using EMSA. Western blot was used to measure the levels of ERK1/2, p38 and NF-κB pathway proteins. [ 3 H]leucine incorporation was used to measure the rate of protein synthesis. Results: Oral administration of Pue significantly suppressed Ang II-induced increases in the myocyte surface area, HW/BW, LVW/BW, SBP and left ventricular wall thickness. Furthermore, Pue significantly suppressed Ang II-induced increases in ANP, BNP and β-MHC expression in the left ventricles in vivo. Treatment of cardiomyocytes with Pue (50-500 μmol/L) did not affect the viability of cardiomyocytes in vitro. Pretreatment of cardiomyocytes with Pue dose-dependently inhibited Ang II-induced increases in ROS production, NF-κB binding activity, protein synthesis and cell breadth. Furthermore, pretreatment with Pue significantly suppressed Ang II-induced activation of ERK1/2, p38 and the NF-κB pathway proteins and the expression of ANP and β-MHC in cardiomyocytes. The positive drug valsartan exerted similar effects on Ang II-induced cardiac hypertrophy in vivo and in vitro. Conclusion: Pue attenuates Ang II-induced cardiac hypertrophy by inhibiting activation of the redox-sensitive ERK1/2, p38 and the NF-κB pathways. © 2014 CPS and SIMM.


Luo Y.-P.,Harbin Medical University | Jiang L.,Harbin Medical University | Kang K.,Harbin Medical University | Fei D.-S.,Harbin Medical University | And 5 more authors.
International Immunopharmacology | Year: 2014

NLRP3 inflammasome activation contributes to acute lung injury (ALI), accelerating caspase-1 maturation, and resulting in IL-1β and IL-18 over-production. Heme oxygenase-1 (HO-1) plays a protective role in ALI. This study investigated the effect of hemin (a potent HO-1 inducer) on NLRP3 inflammasome in sepsis-induced ALI. The sepsis model of cecal ligation and puncture (CLP) was used in C57BL6 mice. In vivo induction and suppression of HO-1 were performed by pretreatment with hemin and zinc protoporphyrin IX (ZnPP, a HO-1 competitive inhibitor) respectively. CLP triggered significant pulmonary damage, neutrophil infiltration, increased levels of IL-1β and IL-18, and edema formation in the lung. Hemin pretreatment exerted inhibitory effect on lung injury and attenuated IL-1β and IL-18 secretion in serum and lung tissue. In lung tissues, hemin down-regulated mRNA and protein levels of NLRP3, ASC and caspase-1. Moreover, hemin reduced malondialdehyde and reactive oxygen species production, and inhibited NF-κB and NLRP3 inflammasome activity. Meanwhile, hemin significantly increased HO-1 mRNA and protein expression and HO-1 enzymatic activity. In contrast, no significant differences were observed between the CLP and ZnPP groups. Our study suggests that hemin-inhibited NLRP3 inflammasome activation involved HO-1, reducing IL-1β and IL-18 secretion and limiting the inflammatory response. © 2014 Elsevier B.V.


Li J.-F.,Harbin Medical University | Chen S.,Harbin Medical University | Feng J.-D.,Hospital of Heilongjiang Armed Police Corps | Zhang M.-Y.,Harbin Medical University | Liu X.-X.,Harbin Medical University
Experimental and Molecular Pathology | Year: 2014

Activation of Na+/H+ exchanger 1 (NHE1) by lipopolysaccharide (LPS) via Ca2+/calpain is responsible in vascular smooth muscle cell (VSMC) apoptosis and to the process of atherosclerosis. Probucol is a lipid-lowering drug which has an anti-atherosclerosis effect. The mechanism remains poorly understood. Here we hypothesized that probucol via inhibition of NHE1 in VSMCs attenuates LPS-accelerated atherosclerosis and promotes plaque stability. Our results revealed that treatment of VSMCs with LPS increased the NHE1 activity in a time-dependent manner, associated with the increased Ca2+ i. Probucol inhibited the LPS-induced increase of NHE1 activity in a dose-dependent manner in VSMCs for 24-hour co-incubation, as well as the change of Ca2+ i. In addition, LPS enhanced the calpain activity. Both probucol and calcium chelation of Ca2+ abolished the LPS-induced increase of calpain activity. Treatment of VSMCs with LPS reduced the expression of Bcl-2 without altering the mRNA level. Probucol inhibited the LPS-reduced expression of Bcl-2 protein in VSMCs. Animal studies indicated administration of probucol suppressed LPS-accelerated apoptosis, atherosclerosis and plaque instability in Apoe-/- mice. In conclusion, probucol via inhibition of NHE1 attenuates atherosclerosis lesion growth and promotes plaque stability. © 2014 Elsevier Inc.


Wang S.-J.,Harbin Medical University | Gao Y.,Sahlgrenska University Hospital | Chen H.,Harbin Medical University | Kong R.,Harbin Medical University | And 5 more authors.
Cancer Letters | Year: 2010

Gemcitabine is currently the best known chemotherapeutic option available for pancreatic cancer, but the tumor returns de novo with acquired resistance over time, which becomes a major issue for all gemcitabine-related chemotherapies. In this study, for the first time, we demonstrated that dihydroartemisinin (DHA) enhances gemcitabine-induced growth inhibition and apoptosis in both BxPC-3 and PANC-1 cell lines in vitro. The mechanism is at least partially due to DHA deactivates gemcitabine-induced NF-κB activation, so as to decrease tremendously the expression of its target gene products, such as c-myc, cyclin D1, Bcl-2, Bcl-xL. In our in vivo studies, gemcibabine also manifested remarkably enhanced anti-tumor effect when combined with DHA, as manifested by significantly increased apoptosis, as well as decreased Ki-67 index, NF-κB activity and its related gene products, and predictably, significantly reduced tumor volume. We concluded that inhibition of gemcitabine-induced NF-κB activation is one of the mechanisms that DHA dramatically promotes its anti-tumor effect on pancreatic cancer. © 2010 Elsevier Ireland Ltd.


Cong G.,Harbin Medical University | Cui L.,Harbin Medical University | Zang M.,Heilongjiang University of Chinese Medicine | Hao L.,Harbin Medical University
International Journal of Biological Macromolecules | Year: 2013

Renal ischemia-reperfusion (I/R) injury is a leading cause of acute renal failure and one of the major problems after I/R is the production of large amounts of reactive oxygen species (ROS). The present study was performed to evaluate the interference of a polysaccharide (WRDAP-1) from the roots of Dipsacus asperoides in I/R-induced renal injury in rats to determine whether it was mediated by the protective mechanism against oxidative stress to kidney. In vitro experiment, WRDAP-1 exhibited a potent scavenging ability on superoxide radical and hydroxyl radical. Renal protective effect of WRDAP-1 was evaluated in serum levels of blood urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), superoxide dismutase (SOD) and serum malonaldehyde (MDA), as well as some renal tissue antioxidant enzymes activities like SOD glutathion peroxidase (GSH-Px) and catalase (CAT). Pretreatment with WRDAP-1 produced reduction in serum levels of BUN, creatinine and LDH caused by I/R injury and significantly improved serum enzymatic activity of SOD and serum MDA level. Additionally, antioxidant enzymes activities of SOD, GSH-Px and CAT in renal tissue were also elevated by WRDAP-1. Collectively, administration with WRDAP-1 significantly improved renal function of I/R rats especially in the rats treated with higher dose of the polysaccharide. Therefore the findings of this study imply that the protective effect of WRDAP-1 against renal I/R injury in rat kidneys could be due to its antioxidant and free radical scavenging activities. WRDAP-1 seems to be a highly promising agent for protecting tissues from oxidative damage and preventing kidney damage due to renal I/R. © 2012 Elsevier B.V.


Li H.,Harbin Medical University | Sun M.,Harbin Medical University | Xu J.,Harbin Medical University | Zang M.,Heilongjiang University of Chinese Medicine | Cui Y.,Harbin Medical University
International Journal of Biological Macromolecules | Year: 2013

In this study, a polysaccharide (ACP-a1), with a molecular weight of 3.2×105Da, was successfully purified and identified from the roots of Aconitum coreanum (Lèvl.) Rapaics. Gas chromatography (GC) analysis indicated that ACP-a1 was mainly composed of β-d-mannose and β-d-glucose in a molar ratio of 1.2:3.5. The effects of ACP-a1 on the tumor growth and immune function were assessed in hepatoma H22 bearing mice. Results showed that ACP-a1 significantly inhibited the growth of hepatoma H22 transplanted in mice and prolonged the survival time of H22 tumor-bearing mice. Besides, the body weight, peripheral white blood cells (WBC), thymus index and spleen index of H22 tumor-bearing were also improved after ACP-a1 treatment. Furthermore, ACP-a1 could promote the secretion of serum cytokines in H22 tumor-bearing mice, such as IL-2, TNF-α and IFN-γ. Taken together, our results indicate that ACP-a1 inhibits tumor growth in vivo at least partly via improving immune responses of host organism, and seems to be safe and effective as a novel agent with immunomodulatory activity for the use of anti-tumor therapy. © 2013 Elsevier B.V.


Wang Z.-Y.,Harbin Medical University | Wang Z.-Y.,Heilongjiang University of Chinese Medicine | Sun Z.-R.,Heilongjiang University of Chinese Medicine | Zhang L.-M.,Harbin Medical University
Neurochemical Research | Year: 2014

Complement activation and inflammation have been suggested in the pathogenesis of stroke, mannose-binding lectin (MBL) were found to have roles during the process. The aim of this study was to investigate the relationship between acute ischemic stroke (AIS) and serum MBL levels in Chinese population. From January 1 to June 30 2013, all patients with first-ever AIS were recruited to participate in the study. Serum MBL levels and routine test were examined. The National Institutes of Health Stroke Scale (NIHSS) score was assessed on admission blinded to MBL levels. During the inclusion period, 148 patients with AIS were registered and completed study. The results indicated that the serum MBL levels were significantly (p < 0.0001) higher in acutely ischemic stroke patients as compared to normal controls [1,332; interquartile range (IQR) 996-2,134 μg/L and 897; IQR 678-1,100 μg/L, respectively]. There was a correlation between serum levels of MBL and NIHSS score [r (spearman) = 0.608, p < 0.0001). In multivariate analysis, serum MBL as a continuous variable was associated with an increased risk of AIS, after adjustment for above possible confounders (OR 1.002, 95 % CI 1.001-1.008; p < 0.0001). These results indicated that elevated MBL levels could be considered as an independent stroke risk factor in Chinese population, suggesting a role of MBL and the lectin pathway of complement activation in the pathogenesis of stroke. © 2013 Springer Science+Business Media New York.


Ma S.,Jilin University | Liu X.,Jilin University | Jiao B.,Jilin University | Yang Y.,Harbin Medical University | Liu X.,China Japan Union Hospital
International Journal of Radiation Biology | Year: 2010

Purpose:With the widespread use of ionising radiation, the risks of low-dose radiation have been increasingly highlighted for special attention. This review introduces the potential role of epigenetic elements in the regulation of the effects of low-dose radiation. Materials and methods:The related literature has been analysed according to the topics of DNA methylation, histone modifications, chromatin remodelling and non-coding RNA modulation in low-dose radiation responses. Results:DNA methylation and radiation can reciprocally regulate effects, especially in the low-dose radiation area. The relationship between histone methylation and radiation mainly exists in the high-dose radiation area; histone deacetylase inhibitors show a promising application to enhance radiation sensitivity, both in the low-dose and high-dose areas; phosphorylated histone 2 AX (H2AX) shows a low sensitivity with 115Gy irradiation as compared with lower dose radiation; and histone ubiquitination plays an important role in DNA damage repair mechanisms. Moreover, chromatin remodelling has an integral role in the repair of DNA double-strand breaks and the response of chromatin to ionising radiation. Finally, the effect of radiation on microRNA expression seems to vary according to cell type, radiation dose, and post-irradiation time point. Conclusion:Small advances have been made in the understanding of epigenetic regulation of low-dose radiation responses. Many questions and blind spots deserve to be investigated. Many new epigenetic elements will be identified in low-dose radiation responses, which may give new insights into the mechanisms of radiation response and their exploitation in radiotherapy. © 2010 Informa UK Ltd.


Gu Y.L.,Harbin Medical University | Zhang L.W.,Harbin Medical University | Ma N.,Harbin Medical University | Ye L.L.,Harbin Medical University | And 2 more authors.
Neuroscience Letters | Year: 2014

Though the evidence demonstrated that voluntary exercise programs could be implemented to enhance recovery of cognitive function induced by traumatic brain injury (TBI), the exact mechanisms were still not known. We proposed that the cognitive improvement induced by exercise in TBI mice is associated with cytochrome c oxidase (COX). To demonstrate this hypothesis, adult mice were housed with or without access to a running wheel (RW) for three weeks followed by TBI operation. Acquisition of spatial learning and memory retention was assessed by using the Morris Water Maze (MWM) on days 15 post TBI. The synaptic density was measured by Golji staining. Immunohistochemistry (IHC) for NeuN, GFAP and growth associated protein 43 (GAP43) were also performed. Using Western blot, the expressions of COX I, II, III, BDNF, synapsin I, synaptophysin (SYP) and GAP43 in hippocampus of TBI mice were determinated. Lastly, CcO activity and ATP amount were also detected. Results showed that voluntary exercise prior TBI: (i) counteracted the cognitive deficits and neuron and synaptic density loss associated with the injury; (ii) increased the levels of COX I, II, III, BDNF, synapsin I, SYP and GAP43; (iii) switched the mitochondrial CcO activity and ATP amounts. These studies demonstrated that the COX plays an important role in exercise's cognitive effects in TBI model and also provide evidence that RW training is a promise exercise for traumatically injured mice. © 2014 Elsevier Ireland Ltd.


Chen G.,Jilin University | Wang H.,Harbin Medical University | Xie S.,Jilin University | Ma J.,Jilin University | Wang G.,Jilin University
Oncology Reports | Year: 2013

Signal transducer and activator of transcription 1 (STAT1) regulates cell proliferation and survival. The present study aimed to investigate the role of STAT1 in the development and progression of human hepatocellular carcinoma (HCC). The levels of STAT1 expression in 36 HCC and 12 non-HCC liver tissues were examined by immunohistochemistry. The effect of STAT1 overexpression or silencing on the proliferation and apoptosis of HCC cells was determined by MTT and flow cytometric assays. The effect of STAT1 overexpression or silencing on the levels of p53 and cyclin E expression was determined by quantitative PCR and western blot assays. The level of STAT1 expression in the HCC tissues was significantly lower compared to the level in the non-HCC liver tissues and was negatively associated with the histological grade of HCC and serum HBsAg, anti-HCV and α-fetoprotein positivity in HCC patients. Induction of STAT1 overexpression significantly inhibited HepG2 cell proliferation and enhanced HCC cell apoptosis, accompanied by upregulation of p53 expression and STAT1 phosphorylation, but a reduction in cyclin E expression in HepG2 cells. In contrast, knockdown of STAT1 by introduction of STAT1-specific siRNA promoted HepG2 cell proliferation, but inhibited HCC cell apoptosis, accompanied by significant downregulation of p53 expression, but enhancement of cyclin E expression in vitro. Our data suggest that STAT1 may inhibit HCC growth by regulating p53-related cell cycling and apoptosis.


Cui X.-S.,Jilin University | Xu Y.-N.,Chungbuk National University | Shen X.-H.,Harbin Medical University | Zhang L.-Q.,Jilin University | And 2 more authors.
Cellular Reprogramming | Year: 2011

Low efficiency of somatic cell nuclear transfer (SCNT) is attributed to incomplete reprogramming of transferred nuclei into oocytes. Trichostatin A (TSA), a histone deacetylase inhibitor, has been used to enhance nuclear reprogramming following SCNT. However, the molecular mechanism of TSA for the improvement of the preimplantation embryo and fetal development following SCNT is not known. The present study investigates embryo viability and gene expression of cloned bovine preimplantation embryos in the presence and absence of TSA compared to embryos produced by in vitro fertilization or parthenogenetic activation. Our results indicated that TSA treatment significantly improved total and inner cell mass (ICM) cell number and ratio of ICM:trophectoderm (TE) and also decreased the apoptotic index including total, ICM, and ratio of ICM:TE. Four apoptotic-related genes, Bcl-xL, survivin, Bcl2-associated X protein (Bax), and caspase 3 (Casp3), and four pluripotency/differentiation related genes, Oct4, SRY (sex determining region Y)-box 2 (Sox2), Cdx2, and colony-stimulating factor 1 receptor (Csf1r), were measured by real-time RT-PCR. TSA treatment resulted in the high expression of antiapoptotic gene Bcl-xL and low expression of pro-apoptotic gene Bax compared to untreated NT embryos, fertilized embryos, or parthenotes. Furthermore, mRNA expression of Cdx2 was higher in NT-TSA embryos than in NT and in vitro fertilization (IVF) counterparts. Additionally, low expression of microRNA (mir)-21 in NT embryos was enhanced following TSA treatment. These results suggest that TSA positively regulates nuclear reprogramming, and TSA may increased resistance or reduced signal for induction of apoptosis. © 2011 Mary Ann Liebert, Inc.


Feng Y.,Harbin Medical University | Chen H.-L.,Chang Gung University | Chiu C.-H.,Chang Gung University
Genome Biology and Evolution | Year: 2013

Mutation and selection are both thought to impact significantly the nucleotide composition of bacterial genomes. Earlier studies have compared closely related strains to obtain mutation patterns based on the hypothesis that these bacterial strains had diverged so recently that selection will not have had enough time to play its role. In this study, we used a SOLiD autosequencer that was based on a dual-base encoding scheme to sequence the genome of Staphylococcus aureus with a mapping coverage of over 5,000x. Bydirectly counting the variation obtained from these ultradeep sequencing reads, we found that A→G was the predominant single-base substitution and 1 bp deletions were the major small indel. These patterns are completely different from those obtained by comparison of closely related S. aureus strains, where C→T accounted for a larger proportion of mutations and deletions were shown to occur at an almost equal frequency to insertion. These findings suggest that the genomic differences between closely related bacterial strains have already undergone selection and are therefore not representative of spontaneous mutation. © 2013 The Author(s).


Suo C.,Daqing General Hospital Group Oilfield General Hospital | Sun L.,Jilin University | Yang S.,Harbin Medical University
Experimental and Therapeutic Medicine | Year: 2013

Alpinetin is a natural flavonoid that protects cells against fatal injury in ischemia-reperfusion. δ receptor activation protects myocardial cells from trauma; however, the mechanism is unknown. The aim of this study was to explore the function of alpinetin in δ receptor-mediated myocardial apoptosis. The myocardial cells of newly born rats were cultivated and myocardial apoptosis was induced by serum deprivation. The MTT method was used to evaluate cell viability and Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining was used to analyze apoptosis. The expression levels of opioid receptor mRNA and protein were tested using reverse transcription-polymerase reaction (RT-PCR) and western blot assays. In addition, an opioid receptor antagonist, as well as protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) inhibitors, were used to determine the inferred signaling pathway. The results showed that that alpinetin reduced the myocardial apoptosis induced by serum deprivation in a concentration-dependent manner. However, the protection conferred to the myocardial cells by alpinetin was blocked by the δ opioid receptor antagonist naltrindole, as well as by PKC and ERK inhibitors (GF109203X and U0126, respectively). In addition, it was shown that alpinetin was able to maintain the stability of the mitochondrial membrane potential, lower the level of intracytoplasmic cytochrome c and reduce Bax displacement from the cytoplasm to the mitochondria. It was concluded that alpinetin was able to activate δ receptors to induce the endogenous protection of myocardial cells via the PKC/ERK signaling pathway.


Lin C.,Jilin University | Yu Y.,Xi'an Jiaotong University | Zhao H.-G.,Jilin University | Yang A.,Xi'an Jiaotong University | And 2 more authors.
Radiotherapy and Oncology | Year: 2012

Purpose: Quercetin (3, 3,′ 4′, 5, 7 - five-flavonoids) is one of the main components of flavonoids, with multifunctions on immune function, anti-oxidation, anti-viral, anti-inflammatory, and cardiovascular protection. We hypothesize that a combination of quercetin with radiation would increase tumor radiosensitivity. To test this hypothesis, we conducted in vitro and in vivo studies. Methods and materials: The in vitro radio-sensitization activity of quercetin was tested in DLD1, HeLa and MCF-7 tumor cell lines by colony formation assays. The in vivo activity was assessed in the DLD-1 human colorectal cancer xenograft model in nude mice. Mechanistic studies were conducted in several cell lines using Western blot analysis and immunofluorescence microscopy. Results: We found that quercetin can significantly increase tumor radiosensitivity both in vitro and in vivo. The in vitro Sensitizing Enhancement Ratios in DLD1, HeLa and MCF-7 cells were 1.87, 1.65, and 1.74, respectively. The mean doubling time of tumor xenografts was significantly increased in irradiated mice treated with quercetin. At the cellular level, exposure to quercetin resulted in prolonged DNA repair. The mechanistic studies demonstrated that quercetin induced radio-sensitization is through inhibiting the ATM kinase, one of the critical DNA damage response proteins. Conclusion: We demonstrate both in vitro and in vivo evidence that combination of quercetin with radiotherapy can enhance tumor radiosensitivity by targeting the ATM-mediated pathway in response to radiation. © 2012 Elsevier Ireland Ltd. All rights reserved.


Li Y.-B.,Harbin Medical University | Han J.-Y.,Sun Yat Sen University | Jiang W.,Harbin Medical University | Wang J.,Harbin Medical University
Molecular Biology Reports | Year: 2011

Selenium as a component of glutathione peroxidase may be beneficial in insulin resistance, hence potentially may modify the risk of diabetes and cardiovascular disease. The aim of our study was to evaluate whether selenium can also alter high glucose (HG), advanced glycation end products (AGE), high insulin (HI) and H2O2-induced expression of cyclooxygenase (COX)-2 and P-selectin. Human umbilical vein endothelial cells (HUVECs) were pretreated with selenium and stimulated by HG, AGE, HI and H2O 2. Selenium significantly inhibited HG, AGE, HI and H 2O2-induced expression of COX-2 and P-selectin. Moreover, selenium also inhibited HG, AGE, HI and H2O2-induced activation of p38 mitogenactivated protein kinase (p38 MAPK), which indicated that the preventive effects of selenium on COX-2 and P-selectin may be associated with p38. Our results indicated that selenium supplementation can reduce HG, AGE, HI and H2O2-induced expression of COX-2 and P-selectin by inhibition of the p38 pathway. © Springer Science+Business Media B.V. 2010.


Feng Y.,Harbin Medical University | Chien K.-Y.,Chang Gung University | Chen H.-L.,Chang Gung University | Chiu C.-H.,Chang Gung University
Journal of Proteome Research | Year: 2012

Recoding refers to the reprogramming of mRNA translation by nonstandard read-out rules. In this study, we used stable isotope labeling with amino acids in cell culture (SILAC) technology to investigate the proteome of host-adapted Salmonella serovars, which are characteristic of accumulation of pseudogenes. Interestingly, a few annotated pseudogenes were indeed able to express peptides downstream of the inactivation site, suggesting the occurrence of recoding. Two mechanisms of recoding, namely, programmed frameshifting and codon redefinition, were both found. We believe that the phenomena of recoding are not rare in bacteria. More studies are required for a better understanding of bacterial translation and the implication of pseudogene recoding in Salmonella serovars. © 2012 American Chemical Society.


Xue W.-Q.,Sun Yat Sen University | He Y.-Q.,Sun Yat Sen University | Zhu J.-H.,Harbin Medical University | Ma J.-Q.,Harbin Medical University | And 2 more authors.
Scientific Reports | Year: 2014

BRCA2 gene plays an important role in homologous recombination. Polymorphic variants in this gene has been suggested to confer cancer susceptibility. Numerous studies have investigated association between BRCA2 N372H polymorphism and risk of several cancers, especially breast cancer. However, the results were inconsistent. We performed a comprehensive meta-analysis to provide a more precise assessment of the association between N372H and cancer risk, following the latest meta-analysis guidelines (PRISMA). Forty six studies involving 36299 cases and 48483 controls were included in our meta-analysis. The crude ORs and the 95% CIs were used to evaluate the strength of the association. The results indicated that the BRCA2 N372H variant was significantly associated with an increased risk of overall cancer (dominant model: OR = 1.07, 95% CI = 1.01-1.13; recessive model: OR = 1.12, 95% CI = 1.02-1.23). Moreover, stratified analyses by the cancer type and source of control observed significantly increased risk associated with BRCA2 N372H in subgroups with ovarian cancer, non-Hodgkin lymphoma and population-based controls, but not breast cancer or hospital-based controls. We also found such association among Africans. Overall, the meta-analysis suggested that BRCA2 N372H may be a cancer susceptibility polymorphism. Well-designed and large-scale studies are needed to substantiate the association between BRCA2 N372H polymorphism and cancer risk.


Li Q.,Cornell University | Li Q.,Harbin Medical University | Bian S.,Cornell University | Hong J.,Cornell University | And 5 more authors.
PLoS ONE | Year: 2011

The adult hippocampus consists of the dentate gyrus (DG) and the CA1, CA2 and CA3 regions and is essential for learning and memory functions. During embryonic development, hippocampal neurons are derived from hippocampal neuroepithelial cells and dentate granular progenitors. The molecular mechanisms that control hippocampal progenitor proliferation and differentiation are not well understood. Here we show that noncoding microRNAs (miRNAs) are essential for early hippocampal development in mice. Conditionally ablating the RNAase III enzyme Dicer at different embryonic time points utilizing three Cre mouse lines causes abnormal hippocampal morphology and affects the number of hippocampal progenitors due to altered proliferation and increased apoptosis. Lack of miRNAs at earlier stages causes early differentiation of hippocampal neurons, in particular in the CA1 and DG regions. Lack of miRNAs at a later stage specifically affects neuronal production in the CA3 region. Our results reveal a timing requirement of miRNAs for the formation of specific hippocampal regions, with the CA1 and DG developmentally hindered by an early loss of miRNAs and the CA3 region to a late loss of miRNAs. Collectively, our studies indicate the importance of the Dicer-mediated miRNA pathway in hippocampal development and functions. © 2011 Li et al.


Zhong W.,Harbin Medical University | Gu B.,LSUHSC Shreveport | Gu Y.,LSUHSC Shreveport | Groome L.J.,LSUHSC Shreveport | And 2 more authors.
Journal of Steroid Biochemistry and Molecular Biology | Year: 2014

Endothelial dysfunction associated with vitamin D deficiency has been linked to many chronic vascular diseases. Vitamin D elicits its bioactive actions by binding to its receptor, vitamin D receptor (VDR), on target cells and organs. In the present study, we investigated the role of VDR in response to 1,25(OH)2D3 stimulation and oxidative stress challenge in endothelial cells. We found that 1,25(OH)2D3 not only induced a dose- and time-dependent increase in VDR expression, but also induced up-regulation of vascular endothelial growth factor (VEGF) and its receptors (Flt-1 and KDR), as well as antioxidant CuZn-superoxide dismutase (CuZn-SOD) expression in endothelial cells. We demonstrated that inhibition of VDR by VDR siRNA blocked 1,25(OH)2D3 induced increased VEGF and KDR expression and prevented 1,25(OH)2D3 induced endothelial proliferation/migration. Using CoCl2, a hypoxic mimicking agent, we found that hypoxia/oxidative stress not only reduced CuZn-SOD expression, but also down-regulated VDR expression in endothelial cells, which could be prevented by addition of 1,25(OH)2D3 in culture. These findings are important indicating that VDR expression is inducible in endothelial cells and oxidative stress down-regulates VDR expression in endothelial cells. We conclude that sufficient vitamin D levels and proper VDR expression are fundamental for angiogenic and oxidative defense function in endothelial cells. © 2013 Elsevier Ltd.


Kong F.,Bioleadorg Research Group | Zhu J.,Harbin Medical University | Wu J.,Bioleadorg Research Group | Peng J.,Bioleadorg Research Group | And 5 more authors.
Nucleic Acids Research | Year: 2011

Chromosomal rearrangement (CR) events result from abnormal breaking and rejoining of the DNA molecules, or from crossing-over between repetitive DNA sequences, and they are involved in many tumor and non-tumor diseases. Investigations of diseaseassociated CR events can not only lead to important discoveries about DNA breakage and repair mechanisms, but also offer important clues about the pathologic causes and the diagnostic/therapeutic targets of these diseases. We have developed a database of Chromosomal Rearrangements In Diseases (dbCRID, http://dbCRID.biolead.org), a comprehensive database of human CR events and their associated diseases. For each reported CR event, dbCRID documents the type of the event, the disease or symptoms associated, and-when possible-detailed information about the CR event including precise breakpoint positions, junction sequences, genes and gene regions disrupted and experimental techniques applied to discover/ analyze the CR event. With 2643 records ofdisease-associated CR events curated from 1172 original studies, dbCRID is a comprehensive and dynamic resource useful for studying DNA breakage and repair mechanisms, and for analyzing the genetic basis of human tumor and non-tumor diseases. © The Author(s) 2010.


Liu Y.,Harbin Medical University | Yu L.,Harbin Medical University | Wang Y.,Harbin Medical University | Zhang Y.,Harbin Medical University | And 2 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2012

Purpose: Angiogenesis, estimated by microvessel density (MVD), has been shown to predict poor progression-free survival in women with advanced epithelial ovarian cancer. Inhibitor of growth (ING) family proteins inhibit angiogenesis in a number of cancers. We evaluated the role of ING4 in regulation of angiogenesis in patients with epithelial ovarian cancer. Methods: Semi-quantitative RT-PCR was used to determine ING4 mRNA levels in 40 ovarian cancer patients and 40 normal controls. Also, we used immunohistochemistry to evaluate (1) ING4 protein expression levels and (2) the level of MVD by staining CD34, a microvessel marker, in these patients. Through statistical analysis, the possible correlation between the ING4 expression and angiogenesis was explored. Results: ING4 mRNA and protein were significantly downregulated in all ovarian cancer patients compared to normal controls (P<0.001). Endometrioid carcinoma tissue had significantly lower ING4 levels compared to serous or mucinous ovarian cancer. ING4 expression correlated negatively with stage and histological grade of ovarian cancers. MVD correlated negatively with ING4 protein and mRNA levels (ρ = -0.865; P<0.001 and ρ = -0.724; P<0.001, respectively). Conclusions: Loss of ING4 may promote microvessel formation and plays a role in facilitating the development of ovarian cancer. Although the specific mechanisms are not yet understood, our data suggest that ING4 may be a promising target for the treatment for ovarian cancer. © Springer-Verlag 2012.


Ma L.,Jilin University | Cai Y.-J.,Jilin University | Yu L.,Harbin Medical University | Feng J.-Y.,Jilin University | And 4 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013

Chronic infection with hepatitis B virus (HBV) is associated with impairment of T and NK cell immunity. This study was aimed at investigating the impact of treatment with telbivudine (LDT) on T and NK cell immunity in patients with chronic hepatitis B (CHB). A total of 54 CHB patients and 30 healthy controls (HC) were recruited. Individual patients were treated orally with 600 mg LDT daily for 13 months. The serum HBV DNA loads, the levels of the HBV-related biomarkers alanine aminotransferase (ALT) and aspartate transaminase (AST), and the numbers of different subsets of peripheral T and NK cells in subjects were measured before and longitudinally after LDT treatment. Following treatment with LDT, the serum HBV DNA loads and the percentages of HBsAg- or HBeAg-seropositive cases were gradually reduced, accompanied by decreased levels of serum ALT and AST. In comparison with the HC, fewer CD3- CD56+ and CD244+ NK cells and CD3+ CD8 + T cells, lower frequencies of cytokine + CD4+ T cells, and more CD3+ CD4+, CD4+ CD25 + Foxp3+, CD4+ CD25+ CD127 low, and CD8+ PD-1+ T cells were detected in CHB patients. Treatment with LDT increased the numbers of NK and CD8+ cells and the frequencies of cytokine+ CD4+ T cells but reduced the numbers of CD4+ CD25+ Foxp3+, CD4+ CD25+ CD127low, and CD8+ PD-1+ T cells in CHB patients. The frequencies of cytokine + CD4+ T cells were negatively associated with the levels of serum HBV DNA, ALT, and AST. Thus, treatment with LDT inhibits HBV replication, modulates T and NK cell immunity, and improves liver function in Chinese patients with CHB. Copyright © 2013, American Society for Microbiology.


Mao R.,Baylor College of Medicine | Mao R.,Harbin Medical University | Fan Y.,Baylor College of Medicine | Mou Y.,Sun Yat Sen University | And 3 more authors.
Cellular Signalling | Year: 2011

Lys63-linked TAK1 polyubiquitination plays an essential role in the regulation of TAK1 activation. TRAF6-mediated Lys63-linked polyubiquitylation of TAK1 has been shown to be required for TGF-β-induced TAK1 activation. However, it remains unclear which lysine residue on TAK1 is TRAF6-mediated TAK1 polyubiquitination acceptor site in TGF-β signaling pathway. Here we report that lysine 158 on TAK1 is required for TGF-β-induced TRAF6-mediated TAK1 polyubiquitination and TAK1-mediated IKK, JNK and p38 activation. Notably, in contrast to TAK1 wild-type and K34R mutant, TAK1 K158R mutant co-overexpression with TAB1 failed to induce Lys63-linked TAK1 polyubiquitination. TRAF6-induced K63-linked TAK1 polyubiquitination was blocked by TAK1 K158R mutation, but not by K34R mutation. Furthermore, TGF-β-induced TAK1 polyubiquitination was inhibited by TAK1 K158R mutation, but not by K34R mutation in HeLa cells. Reconstitution of TAK1-deficient mouse embryo fibroblast cells with TAK1 wild-type, K158R mutant, or K34R mutant reveals that TAK1 lysine 158 residue is required for TGF-β-induced IKK, p38 and JNK activation. © 2010 Elsevier Inc.


Li B.,Jilin University | Li B.,Harbin Medical University | Wang L.,Affiliated Hospital | Chi B.,Jilin University
Molecular Biology Reports | Year: 2013

Periostin is frequently upregulated in human cancers including gastric cancer and implicated in cancer cell proliferation, invasion, and epithelial-mesenchymal transition. This study was undertaken to investigate the effects of periostin overexpression on the chemosensitivity of gastric cancer cells. We constructed a stable cell line overexpressing periostin in SGC-7901 human gastric cancer cells. The 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide assay revealed that periostin had no influence on the proliferation of SGC-7901 cells. Compared to empty vector-transfected cells, overexpression of periostin rendered SGC-7901 cells more resistant to cisplatin or 5-fluorouracil (5-FU)-induced apoptosis, accompanying with less release of cytochrome c from mitochondria and diminished cleavage of caspase-3 and poly (ADP-ribose) polymerase. Periostin-overexpressing cells treated with cisplatin or 5-FU showed significantly (p < 0.05) decreased expression of Bax and p53 proteins and increased expression of Bcl-2 protein, when compared to drug-treated mock counterparts. Restoration of p53 expression by delivering wild-type p53 gene resulted in a marked increase in drug-induced apoptosis in periostin-overexpressing SGC-7901 cells. Periostin overexpression elevated the phosphorylation of Akt. Pretreatment of periostin-overexpressing cells with an Akt inhibitor, MK-2206, partially rescued periostin-mediated inhibition of p53 expression and drug resistance. Taken together, our data indicate that periostin confers protection against cisplatin or 5-FU-induced apoptosis in SGC-7901 cells, likely through modulating the Akt/p53 pathway, and thus represents a potential therapeutic target in gastric cancer. © 2012 Springer Science+Business Media Dordrecht.


Zhang Z.-R.,Harbin Medical University | Chou C.-F.,University of Alabama at Birmingham | Wang J.,University of Alabama at Birmingham | Liang Y.-Y.,University of Alabama at Birmingham | Ma H.-P.,University of Alabama at Birmingham
Pflugers Archiv European Journal of Physiology | Year: 2010

Anionic phospholipids (APs) present a variety of lipids in the cytoplasmic leaflet of the plasma membrane, including phosphatidylinositol (PI), PI-4-phosphate (PI(4) P), phosphatidylserine (PS), PI-4,5-bisphosphate (PI(4,5) P2), PI-3,4,5-trisphosphate (PI(3,4,5)P3), and phosphatidic acid (PA). We previously showed that PI(4,5)P2 and PI (3,4,5)P3 upregulate the renal epithelial sodium channel (ENaC). Further studies from others suggested that PI(4,5) P2and PI(3,4,5)P3 respectively target β- and γ-ENaC subunit. To determine whether PI(4,5)P2 and PI(3,4,5)P3 selectively bind to ß and y subunit, we performed lipidprotein overlay experiments. Surprisingly, the results reveal that most APs, including PI(4)P, PS, PI(4,5)P2, PI(3,4,5)P3, and PA, but not PI, non-selectively bind to not only β and γ but also a subunit. To determine how these APs regulate ENaC, we performed inside-out patch-clamp experiments and found that PS, but not PI or PI(4)P, maintained ENaC activity, that PI(4,5)P2 and PI(3,4,5)P3 stimulated ENaC, and that PA, however, inhibited ENaC. These data together suggest that APs differentially regulate ENaC by physically interacting with α-, β-, and γ-ENaC. Further, the data from cell-attached patch-clamp and confocal microscopy experiments indicate that PA, a product of phospholipase D, may provide one of the pathways for inhibition of ENaC by endothelin receptors.


Song W.,University of Alabama at Birmingham | Wei S.,Harbin Medical University | Matalon S.,University of Alabama at Birmingham
Annals of the New York Academy of Sciences | Year: 2010

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and children worldwide. Infection of mice with RSV decreased sodium (Na+) dependent alveolar fluid clearance (AFC), resulting in increased lung water content and hypoxemia. RSV infection resulted in higher levels of pyrimidines and purines in the alveolar space. Intratracheal administration of UTP or UDP also decreased AFC. The effects of RSV on AFC and oxygen saturation of Balb/c mice were reversed by intraalveolar administration of antagonists of P2Y nucleotide receptors, enzymes that enhance the breakdown of pyrimidines and systemic or intranasal administration of inhibitors of the de novo pathway of pyrimidine synthesis. RSV infection of H441 or mouse tracheal epithelial cells decreased the amiloride-sensitive Na + currents and pretreatment of H441 cells with A77 prevented this effect. These findings indicate that the harmful effects of RSV on lung epithelia are mediated at least in part via the production of UTP and its paracrine action on ENaC. © 2010 New York Academy of Sciences.


Dorsey-Oresto A.,Public Health Research Institute Center | Lu T.,Public Health Research Institute Center | Lu T.,Yunnan University | Mosel M.,Public Health Research Institute Center | And 6 more authors.
Cell Reports | Year: 2013

Stress-mediated programmed cell death (PCD) in bacteria has recently attracted attention, largely because it raises novel possibilities for controlling pathogens. How PCD in bacteria is regulated to avoid population extinction due to transient, moderate stress remains a central question. Here, we report that the YihE protein kinase is a key regulator that protects Escherichia coli from antimicrobial and environmental stressors by antagonizing the MazEF toxin-antitoxin module. YihE was linked to a reactive oxygen species (ROS) cascade, and a deficiency of yihE stimulated stress-induced PCD even after stress dissipated. YihE was partially regulated by the Cpx envelope stress-response system, which, along with MazF toxin and superoxide, has both protective and destructive roles that help bacteria make a live-or-die decision in response to stress. YihE probably acts early in the stress response to limit self-sustaining ROS production and PCD. Inhibition of YihE may provide a way of enhancing antimicrobial lethality and attenuating virulence.


Liu Y.,Heilongjiang Province Hospital | Zhou L.-Y.,Harbin Medical University | Meng X.-W.,Jilin University
Hepato-Gastroenterology | Year: 2012

Background/Aims: Alcohol abuse is becoming an increasingly severe problem among the Han, Mongol and Chaoxian nationalities in the northeast of China. The study aimed to investigate the relationship between alcoholic liver disease (ALD) and the genetic polymorphism of two enzymes, cytochrome P450IIE1 (CYPIIE1) and glutathione S-transferase P1 (GSTP1) in patients of three nationalities. Methodology: Peripheral blood was collected from 353 Chinese patients with ALD, 300 alcohol-dependent patients without liver disease (alcoholic) and 360 healthy controls. Each group included patients from the Han, Mongol and Chaoxian nationalities. PCR-restriction fragment length polymorphism (PCR-RFLP) was used in this research. Results: Regardless of nationality patients who carried the rare CYPIIE1 C2 and GSTP1 Val allele were at higher risk of ALD. The frequency of C2 and Val in patients with ALD was 50.00% and 26.98% in the Han, 31.36% and 22.87% in the Mongol and 45.87% and 22.02% in the Chaoxian, respectively. No significant differences were seen in the frequency of either the C2 or Val alleles in ALD, among the three nationalities. In each nationality, the frequency of both the C2 and Val alleles was significantly higher in ALD compared to alcoholic and healthy controls. Conclusions: In this group of Chinese patients, we found that regardless of nationality, patients with ALD tended to carry the C2 allele and the Val allele. This may indicate a causal relationship between these polymorphic alleles that lead to the development of ALD. © H.G.E. Update Medical Publishing S.A.


Bian S.,Cornell University | Hong J.,Cornell University | Li Q.,Cornell University | Li Q.,Harbin Medical University | And 5 more authors.
Cell Reports | Year: 2013

During development of the embryonic neocortex, tightly regulated expansion of neural stem cells (NSCs) and their transition to intermediate progenitors (IPs) are critical for normal cortical formation and function. Molecular mechanisms that regulate NSC expansion and transition remain unclear. Here, we demonstrate that the microRNA (miRNA) miR-17-92 cluster is required for maintaining proper populations of cortical radial glial cells (RGCs) and IPs through repression of Pten and Tbr2 protein. Knockout of miR-17-92 and its paralogs specifically in the developing neocortex restricts NSC proliferation, suppresses RGC expansion, and promotes transition of RGCs to IPs. Moreover, Pten and Tbr2 protectors specifically block silencing activities of endogenous miR-17-92 and control proper numbers of RGCs and IPs invivo. Our results demonstrate a critical role for miRNAs in promoting NSC proliferation and modulating the cell-fate decision of generating distinct neural progenitors in the developing neocortex.


He J.,Sun Yat Sen University | Liao X.-Y.,Sun Yat Sen University | Zhu J.-H.,Harbin Medical University | Xue W.-Q.,Sun Yat Sen University | And 4 more authors.
Scientific Reports | Year: 2014

Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism and DNA synthesis. A number of studies have examined the association of MTHFR C677T and A1298C polymorphisms with non-Hodgkin lymphoma (NHL) susceptibility; however, the conclusions were contradictory. We searched available publications assessing the polymorphisms of MTHFR and NHL susceptibility from MEDLINE, EMBASE and CBM. Genotype-based mRNA expression analysis was performed using data from 270 individuals with three different ethnicities. Ultimately, a total of 7448 cases and 11146 controls from 25 studies were included for the C677T polymorphism, 6173 cases and 9725 controls from 19 studies for the A1298C polymorphism. Pooled results indicated that neither C677T nor A1298C polymorphism was associated with NHL susceptibility. However, C677T polymorphism showed a statistically significantly increased risk for Caucasians, but a decreased risk for Asians in the subgroup analysis by ethnicity. The same variants may confer increased susceptibility to develop follicular lymphoma (FL). Moreover, A1298C polymorphism was associated with increased NHL risk for Asians. This meta-analysis indicated that C677T polymorphism was associated with altered NHL susceptibility for Caucasians, Asians and FL. Increased NHL risk was also shown for A1298C among Asians. These findings warrant validation in large and well-designed prospective studies.


Chen X.,Harbin Medical University | Li Y.,U.S. Center for Disease Control and Prevention | Lin Q.,University of Rhode Island | Wang Y.,U.S. Center for Disease Control and Prevention | And 5 more authors.
Scientific Reports | Year: 2014

To study the mechanism of tea polyphenols (TP)-induced apoptosis of breast cancer cells. Proliferation of MCF-7 and SK-BR-3 cells was evaluated by MTT assays. Cellular ultrastructure was examined by electron microscopy. Apoptosis was detected by TUNEL. PCNA, Cyclin D1, Cyclin E and Survivin expression was measured by Western blot. Cell proliferation was significantly inhibited by TP. Spindle and round cells were loosely distributed with increased particles after TP treatment. Increased cell size, frequent nuclear atypia and a collapse of apoptosis were observed. The nucleus was pushed towards one side, while the cytoplasm was rich in free ribosome. The membrane of mitochondria was thickening, and the cell apoptotic body was observed. TP treated cells experienced significantly enhanced apoptosis compared with 5-Fu treated or control groups. The expression of survivin was downregulated by TP. To conclude, TP can inhibit cell growth and induce apoptosis through downregulating the expression of survivin in breast cancer.


Wu C.,Harbin Medical University | Wen Z.,Harbin Medical University | Dai C.,Harbin Institute of Technology | Lu Y.,Harbin Institute of Technology | Yang F.,Harbin Institute of Technology
Surface and Coatings Technology | Year: 2010

Four calcium phosphate/chitosan composite films were fabricated on the surface of micro-arc oxidized (MAO)-AZ91D alloy through electrophoretic deposition (EDP) followed by a conversion process of the coatings in a phosphate buffer solution (PBS). In the EPD process, nano hydroxyapatite (n-HA, Ca10(PO4) 6(OH)2) and Ca(OH)2 in the layers were obtained from a n-HA/ethanol suspension and a n-HA/chitosan-acetic acid aqueous solution, respectively. After immersion into PBS, brushite (DCPD, CaHPO4·2H2O) and new HA were introduced into the deposited layers. The percentage of Ca(OH)2 in the deposited layers played an important role in developing the new phase in the conversion layers. When the percentages of Ca(OH)2 in the deposited layers were 32wt. % and 54wt. %, the main phase of the conversion layers was DCPD with a little HA. However, when the percentages of Ca(OH)2 were 64wt. % and 100wt. %, the main phase of the conversion layers became HA with a little DCPD. The calcium phosphate/chitosan coatings with more homogeneous bioactive layers and better adhesion strength on MAO-AZ91D alloy substrate were obtained from the electrolyte whose volume percentages of the n-HA/chitosan-acetic acid aqueous solution being 60% and 80%.So, EPD combined with a conversion process into PBS could be a promising method for the preparation of new calcium phosphate/chitosan coatings. © 2010 Elsevier B.V.


Liang C.,Harbin Institute of Technology | Liu C.,Harbin Institute of Technology | Wang H.,Harbin Institute of Technology | Wu L.,Harbin Medical University | And 4 more authors.
Journal of Materials Chemistry A | Year: 2014

Controllable dielectric-magnetic coaxial hybrid nanowires, having a core of SiC nanowires and a shell of Fe3O4 nanoparticles, have been synthesized using a straightforward polyol approach. The morphology, microstructure and magnetic properties of the SiC-Fe3O4 hybrid nanowires have been characterized by transmission electron microscope, powder X-ray diffractometer and vibrating sample magnetometer. The characterization confirms that monodisperse Fe3O4 nanoparticles of core size 10 nm have been successfully coated on the surface of SiC nanowires. The coverage density of the nanoparticles may be adjusted simply by changing the weight ratio of the precursors. Measurement of the electromagnetic (EM) parameters indicates that the Fe3O4 nanoparticles increase the magnetic loss and improve the impedance matching conditions compared to untreated SiC nanowires. When the coverage density of Fe3O4 is optimal, the reflection loss of an EM wave can be as low as -51 dB. By changing the loading density of Fe3O4, the best microwave absorption state was obtained in the 2-18 GHz band. These results suggest that SiC-Fe3O4 hybrid nanowires will be valuable in EM absorption applications. This journal is © the Partner Organisations 2014.


Lv J.,Harbin Institute of Technology | Liu H.,Harbin Institute of Technology | Huang Z.,Harbin Institute of Technology | Su J.,Harbin Medical University | And 4 more authors.
Nucleic Acids Research | Year: 2013

In silico prediction of genomic long non-coding RNAs (lncRNAs) is prerequisite to the construction and elucidation of non-coding regulatory network. Chromatin modifications marked by chromatin regulators are important epigenetic features, which can be captured by prevailing high-throughput approaches such as ChIP sequencing. We demonstrate that the accuracy of lncRNA predictions can be greatly improved when incorporating high-throughput chromatin modifications over mouse embryonic stem differentiation toward adult Cerebellum by logistic regression with LASSO regularization. The discriminating features include H3K9me3, H3K27ac, H3K4me1, open reading frames and several repeat elements. Importantly, chromatin information is suggested to be complementary to genomic sequence information, highlighting the importance of an integrated model. Applying integrated model, we obtain a list of putative lncRNAs based on uncharacterized fragments from transcriptome assembly. We demonstrate that the putative lncRNAs have regulatory roles in vicinity of known gene loci by expression and Gene Ontology enrichment analysis. We also show that the lncRNA expression specificity can be efficiently modeled by the chromatin data with same developmental stage. The study not only supports the biological hypothesis that chromatin can regulate expression of tissue-specific or developmental stage-specific lncRNAs but also reveals the discriminating features between lncRNA and coding genes, which would guide further lncRNA identifications and characterizations. © 2013 The Author(s).


Fan X.,Harbin Institute of Technology | Jiao G.,Harbin Institute of Technology | Gao L.,Harbin Medical University | Jin P.,Harbin Institute of Technology | Li X.,Harbin Institute of Technology
Journal of Materials Chemistry B | Year: 2013

We report a green and facile procedure of synthesizing a graphene nanosheet-carbon nanotube-iron oxide nanoparticle hybrid (GN-CNT-Fe 3O4) as a promising platform for the loading and delivery of anticancer drugs. The obtained GN-CNT-Fe3O4 hybrid exhibited superparamagnetic properties with the saturation magnetization of 19.824 emu g-1. This hybrid nanostructure possesses a superior capability of binding the anticancer drug 5-fluorouracil (5-FU) with a high loading capacity of up to 0.27 mg mg-1 with a 5-FU concentration of 0.5 mg mL-1, and also possesses a pH-activated release profile. Moreover, cellular uptake studies show that the resulting GN-CNT-Fe 3O4 hybrid can be internalized efficiently by HepG2 cells. In vitro cytotoxicity tests suggest that the obtained GN-CNT-Fe 3O4 hybrid is nontoxic for Chang liver cells, even at the high concentration of 80 μg mL-1, however, the 5-FU-loaded GN-CNT-Fe3O4 hybrid showed significant cytotoxic effects in HepG2 cells. The results show that this novel 3D hybrid is a promising candidate for anti-cancer drug delivery systems. © 2013 The Royal Society of Chemistry.


Liu B.,Harbin Institute of Technology | Cheng H.D.,Harbin Institute of Technology | Cheng H.D.,Utah State University | Huang J.,Harbin Institute of Technology | And 3 more authors.
Pattern Recognition | Year: 2010

Region of interest (ROI) is a region used to extract features. In breast ultrasound (BUS) image, the ROI is a breast tumor region. Because of poor image quality (low SNR (signal/noise ratio), low contrast, blurry boundaries, etc.), it is difficult to segment the BUS image accurately and produce a ROI which precisely covers the tumor region. Due to the requirement of accurate ROI for feature extraction, fully automatic classification of BUS images becomes a difficult task. In this paper, a novel fully automatic classification method for BUS images is proposed which can be divided into two steps: "ROI generation step" and "ROI classification step". The ROI generation step focuses on finding a credible ROI instead of finding the precise tumor location. The ROI classification step employs a novel feature extraction and classification strategy. First, some points in the ROI are selected as the "classification checkpoints" which are evenly distributed in the ROI, and the local texture features around each classification checkpoint are extracted. For each ROI, all the classification checkpoints are classified. Finally, the class of the BUS image is determined by analyzing every classification checkpoint in the corresponding ROI. Both steps were implemented by utilizing a supervised texture classification approach. The experiments demonstrate that the proposed method is very robust to the segmentation of BUS images, and very effective and useful for classifying breast tumors. © 2009 Elsevier Ltd. All rights reserved.


Liu B.,Harbin Institute of Technology | Cheng H.D.,Harbin Institute of Technology | Cheng H.D.,Utah State University | Huang J.,Harbin Institute of Technology | And 3 more authors.
Pattern Recognition | Year: 2010

Because of its low signal/noise ratio, low contrast and blurry boundaries, ultrasound (US) image segmentation is a difficult task. In this paper, a novel level set-based active contour model is proposed for breast ultrasound (BUS) image segmentation. At first, an energy function is formulated according to the differences between the actual and estimated probability densities of the intensities in different regions. The actual probability densities are calculated directly. For calculating the estimated probability densities, the probability density estimation method and background knowledge are utilized. The energy function is formulated with level set approach, and a partial differential equation is derived for finding the minimum of the energy function. For performing numerical computation, the derived partial differential equation is approximated by the central difference and non-re-initialization approach. The proposed method was operated on both the synthetic images and clinical BUS images for studying its characteristics and evaluating its performance. The experimental results demonstrate that the proposed method can model the BUS images well, be robust to noise, and segment the BUS images accurately and reliably. © 2010 Elsevier Ltd. All rights reserved.


Xia W.,Wenzhou University | Zhang F.,Harbin Medical University | Xie C.,Wenzhou University | Jiang M.,Harbin Medical University | Hou M.,Wenzhou University
Stem Cell Research and Therapy | Year: 2015

Introduction: Mesenchymal stem cells (MSCs)-based therapies have had positive outcomes in animal models of cardiovascular diseases. However, the number and function of MSCs decline with age, reducing their ability to contribute to endogenous injury repair. The potential of stem cells to restore damaged tissue in older individuals can be improved by specific pretreatment aimed at delaying senescence and improving their regenerative properties. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that modulates age-related signaling pathways, and hence is a good candidate for rejuvenative function. Methods: Bone marrow-derived mesenchymal stem cells (BM-MSCs) were isolated from young (6-month-old) or aged (24-month-old) male donor rats. Cell proliferation was measured using the CCK8 cell proliferation assay; secretion of VEGF, bFGF, HGF, and IGF was assessed by RT-qPCR and ELISA. Apoptosis was induced by hypoxia and serum deprivation (hypoxia/SD) for up to 6 hr, and examined by flow cytometry. Expression levels of AMP-activated protein kinase (AMPK) and forkhead box class O 3a (FOXO3a) were detected by Western blotting. CD74 expression was assayed using RT-qPCR, Western blotting, and immunofluorescence. Results: In this study, we found that MSCs isolated from the bone marrow of aged rats displayed reduced proliferative capacity, impaired ability to mediate paracrine signaling, and lower resistance to hypoxia/serum deprivation-induced apoptosis, when compared to younger MSCs. Interestingly, pretreatment of aged MSCs with MIF enhanced their growth, paracrine function and survival. We detected enhanced secretion of VEGF, bFGF, HGF, and IGF from MIF-treated MSCs using ELISA. Finally, we show that hypoxia/serum deprivation-induced apoptosis is inhibited in aged MSCs following MIF exposure. Next, we found that the mechanism underlying the rejuvenating function of MIF involves increased CD74-dependent phosphorylation of AMPK and FOXO3a. Furthermore, this effect was abolished when CD74, AMPK, or FOXO3a expression was silenced using small-interfering RNAs(siRNA). Conclusions: MIF can rejuvenate MSCs from a state of age-induced senescence by interacting with CD74 and subsequently activating AMPK-FOXO3a signaling pathways. Pretreatment of MSCs with MIF may have important therapeutic implications in restoration or rejuvenation of endogenous bone marrow-MSCs in aged individuals. © 2015 Xia et al.; licensee BioMed Central.


Harada M.,Montreal Heart Institute | Harada M.,Hamamatsu Medical Center | Luo X.,Montreal Heart Institute | Luo X.,Harbin Medical University | And 4 more authors.
Circulation Research | Year: 2014

MicroRNAs (miRNAs) are emerging as key control molecules in the regulation of gene expression, and their role in heart disease is becoming increasingly evident. Given the critical role of Ca handling and signaling proteins in the maintenance of cardiac function, the targeting of such proteins by miRNAs would be expected to have important consequences. miRNAs have indeed been shown to control the expression of genes encoding important Ca handling and signaling proteins, and are themselves regulated by Ca-dependent processes. Ca-related miRNAs have been found to be significant pathophysiological contributors in conditions like myocardial ischemic injury, cardiac hypertrophy, heart failure, ventricular arrhythmogenesis, and atrial fibrillation. This review is a comprehensive analysis of the present knowledge concerning miRNA regulation of Ca handling processes, the participation of Ca-regulating miRNAs in the evolution of heart disease, the mutual relationship between Ca signaling and miRNAs in the control of cardiac function, and the potential value of miRNA-control of Ca handling as a therapeutic target. © 2014 American Heart Association, Inc.


Jin A.,University of Toyama | Jin A.,Harbin Medical University | Ozawa T.,University of Toyama | Tajiri K.,University of Toyama | And 3 more authors.
Nature Protocols | Year: 2011

Here we report a new method for isolating antigen-specific antibody-secreting cells (ASCs) using a microwell array chip, which offers a rapid, efficient and high-throughput (up to 234,000 individual cells) system for the detection and retrieval of cells that secrete antibodies of interest on a single-cell basis. We arrayed a large population of lymphoid cells containing ASCs from human peripheral blood on microwell array chips and detected spots with secreted antibodies. This protocol can be completed in less than 7 h, including 3 h of cell culture. The method presented here not only has high sensitivity and specificity comparable with enzyme-linked immunospot (ELISPOT) but it also overcomes the limitations of ELISPOT in recovering ASCs that can be used to produce antigen-specific human monoclonal antibodies. This method can also be used to detect cells secreting molecules other than antibodies, such as cytokines, and it provides a tool for cell analysis and clinical diagnosis. © 2011 Nature America, Inc. All rights reserved.


Chen Y.,Dalian Medical University | Hu F.,Harbin Medical University | Zhou Y.,U.S. Center for Disease Control and Prevention | Chen W.,Harbin Medical University | And 2 more authors.
Archives of Medical Research | Year: 2013

Background and Aims: We undertook this study to comprehensively summarize the associations between MGMT promoter methylation and prognosis of glioblastoma (GBM). Methods: We searched PubMed, EMBASE and Cochrane databases (from January 2003 to November 1, 2011) and the references of the relevant articles in English with hazard ratios (HRs) and 95% confidence intervals (95% CIs). Two reviewers independently extracted data using a standardized form. Discrepancies were adjudicated by discussion. Results: Twenty four studies met the inclusion criteria. There were 22 studies reporting on the relationship between MGMT methylation and overall survival (OS) of GBM and 12 studies on the association between MGMT methylation and progression-free survival (PFS) of GBM. Patients with a methylated status of MGMT had significant OS and PFS advantage (HR= 0.48, 95% CI: 0.35-0.65; I2= 79.78 for OS; HR= 0.43, 95% CI: 0.32-0.56; I2= 50.38 for PFS). Pooled HRs remained significant in further subgroup analysis based on the year of publication and continents of studies. Conclusions: Patients with MGMT promoter methylation had significant OS and PFS advantage than those without methylated status. © 2013 IMSS.


Wang Z.,Harbin Institute of Technology | Wu L.,Harbin Medical University | Cai W.,Harbin Institute of Technology | Jiang Z.,Harbin Institute of Technology
Journal of Materials Chemistry | Year: 2012

The poor thermal stability of nanoparticle superlattices heavily inhibits their practical applications. In present research, using stable thiolate-capped Au 11(SCH 2CH 2COO -) 7([CH 3(CH 2) 7] 4N +) 7 nanoclusters as the building blocks, novel luminescent Au 11 nanocluster superlattices with high thermal stability have been fabricated by self-assembly. The nanocluster superlattices have a blade-like morphology and extend on a micrometre length scale with the largest over 50 μm. Under an excitation at 400 nm, the fabricated Au 11 nanocluster superlattices emit a blue luminescence with the emission peak of 473 nm. The native stability of thiolate-capped gold nanoclusters and the steric repulsion induced by the high-density ligands (SCH 2CH 2COO -) 7([CH 3(CH 2) 7] 4N +) 7 endows the fabricated superlattices with high thermal stability. The differential scanning calorimetry and thermogravimetric analysis indicates that the superlattices undergo irreversible endothermic transitions in the range of room temperature to 200 °C, which starts at 124 °C and reaches a peak at 160 °C. When processed with heat treatment below the transition temperature or stored for six months at room temperature, there is no obvious difference detected in the emission intensity of the fabricated Au 11 nanocluster superlattices. Such thermostability gives the fabricated nanocluster superlattices great potential for many applications, especially for optical devices. © 2012 The Royal Society of Chemistry.


Wang Z.,Harbin Institute of Technology | Wu L.,Harbin Medical University | Zhou J.,Canadian Light Source Inc. | Shen B.,Harbin Medical University | Jiang Z.,Harbin Institute of Technology
RSC Advances | Year: 2013

To enhance the microwave absorption of Fe3O4 nanocrystals, ZnO nanoshells with a thickness of 2 nm were grown on Fe 3O4 nanocrystals by heterogeneous nucleation. After being coated with ZnO nanoshells, the material possesses a far more improved ability for microwave absorption. A minimum reflection loss of -3.31 dB for Fe 3O4 nanocrystals alone was improved to a minimum reflection loss of -22.69 dB and with an effective absorption band (R L < -10 dB) covering a frequency range of 10.08-15.97 GHz. The reasons for the enhanced microwave absorption were studied by the use of X-ray absorption near-edge structures at O K-edge, electron spin resonance analysis and microwave electromagnetic parameters mapping. The results indicate that the decoration of the dielectric ZnO shell had varied the dielectric property as well as the oxidization environment and distribution of Fe ions on the surface of the Fe3O4. This well balances the permeability and the permittivity of the nanomaterials and decreases the difficulty of impedance matching the microwave absorber within the free space. This leads to the Fe 3O4@ZnO nanohybrids possessing vastly improved microwave absorption as compared to Fe3O4 nanocrystals alone. © 2013 The Royal Society of Chemistry.


Wang Z.,Harbin Institute of Technology | Wu L.,Harbin Medical University | Shen B.,Harbin Medical University | Jiang Z.,Harbin Institute of Technology
Talanta | Year: 2013

Fluorescent detection is an attractive method for the detection of toxic chemicals. However, most chemosensors that are currently utilized in fluorescent detection are based on organic dyes or quantum dots, which suffer from instability, high background noise and interference from organic impurities in solution, which can also be excited by UV radiation. In the present research, we developed a novel NaYF4:Yb,Ho/Au nanocomposite-based chemosensor with high sensitivity (10 ppb) and selectivity over competing analytes for the detection of the insecticide cartap. This nanosensor is excited with a 970-nm laser instead of UV radiation to give an emission peak at 541 nm. In the presence of cartap, the nanocomposites aggregate, resulting in enhanced luminescence resonance energy transfer between the NaYF4:Yb,Ho nanocrystals and the gold nanoparticles, which decreases the emission intensity at 541 nm. The relative luminescence intensity at 541 nm has a linear relationship with the concentration of cartap in the solution. Based on this behavior, the developed nanosensor successfully detected cartap in farm produce and water samples with satisfactory results. © 2013 Elsevier B.V.


Ding J.,Harbin Institute of Technology | Cheng H.,Harbin Institute of Technology | Cheng H.,Utah State University | Ning C.,Harbin Medical University | And 2 more authors.
Journal of Ultrasound in Medicine | Year: 2011

Objectives-The purpose of this study was to evaluate color thyroid elastograms quantitatively and objectively and select more effective features to differentiate benign from malignant thyroid nodules. Methods-The study was approved by the Ethics Committee of Harbin Medical University. A total of 125 cases (56 malignant and 69 benign) were analyzed in this retrospective study. The original color thyroid elastograms were transferred from the red-green-blue color space to the hue-saturation-value color space. The elasticity information was represented by the hue component of color elastograms. The lesion regions were delineated by radiologists, and statistical and textural features were extracted. Then the most effective and reliable features among them were selected by using a minimum redundancy-maximum relevance algorithm. The selected features were input to a support vector machine to differentiate benign from malignant thyroid nodules. Results-The classification accuracy was 93.6% when the hard area ratio and textural feature (energy) of the lesion region were used. The area under the receiver operating characteristic curve for the hard area ratio was higher than that for the strain ratio (0.97 versus 0.87; P< .01), and the area under the curve for the hard area ratio was also higher than that for the color score (0.97 versus 0.80; P < .001). The results also showed that the features were robust for lesion region delineation. Conclusions-The hard area ratio is an important and quantitative metric for elastograms. Quantitative analysis of elastograms using computer-aided diagnostic techniques can improve diagnostic accuracy. © 2011 by the American Institute of Ultrasound in Medicine.


Li Q.,Harbin Medical University | Wu D.,Harbin Veterinary Research Institute | Zhang L.,Harbin Medical University | Zhang Y.,Harbin Medical University
Experimental Gerontology | Year: 2010

Galantamine (Gal) is an acetylcholinesterase inhibitor and used to treat the symptoms of Alzheimer's disease (AD). Recent studies show that Gal may affect amyloid precursor protein (APP) metabolism and increase release of secretory APPα (sAPPα). However the effect of Gal on amyloid-Β peptide (AΒ) release and Β-site cleaving enzyme 1 (BACE1) expression is still unknown. Consequently, we investigated the effect of Gal on the level of AΒ and BACE1. In a differentiated human neuroblastoma cell line (SH-SY5Y), Gal (0.3 ΜM) was found to significantly decrease AΒ release and BACE1 expression following treatment for 6, 12, and 24. h. Increasing Gal to 0.9 ΜM or 10 ΜM had no further effect. The effect of Gal (0.3 ΜM for 18. h) was maximal on BACE1 expression but not on AΒ secretion. At higher concentration (0.9 ΜM and 10 ΜM), Gal had no effect on the level of full-length APP but could still stimulate further decrease in AΒ secretion and release of sAPPα. These observations suggested that 0.3 ΜM Gal exerts its effect on AΒ production by inhibiting BACE1 expression, while 0.9 μM or 10 ΜM Gal mainly reduces AΒ production by stimulating the non-amyloidogenic pathway to decrease the amount of APP substrate available for Β-secretase cleavage. In addition, α7 nicotinic acetylcholine receptor (α7nAChR) and multiple second messengers (including PKC, MEK, and p38MAPK) were found to be involved in the regulation of Gal-inhibited AΒ release and BACE1 expression. © 2010 Elsevier Inc.


Zhang Y.,Harbin Medical University | Liu H.,Harbin Medical University | Lv J.,Harbin Medical University | Xiao X.,Harbin Medical University | And 7 more authors.
Nucleic Acids Research | Year: 2011

DNA methylation plays critical roles in transcriptional regulation and chromatin remodeling. Differentially methylated regions (DMRs) have important implications for development, aging and diseases. Therefore, genome-wide mapping of DMRs across various temporal and spatial methylomes is important in revealing the impact of epigenetic modifications on heritable phenotypic variation. We present a quantitative approach, quantitative differentially methylated regions (QDMRs), to quantify methylation difference and identify DMRs from genome-wide methylation profiles by adapting Shannon entropy. QDMR was applied to synthetic methylation patterns and methylation profiles detected by methylated DNA immunoprecipitation microarray (MeDIP-chip) in human tissues/cells. This approach can give a reasonable quantitative measure of methylation difference across multiple samples. Then DMR threshold was determined from methylation probability model. Using this threshold, QDMR identified 10651 tissue DMRs which are related to the genes enriched for cell differentiation, including 4740 DMRs not identified by the method developed by Rakyan et al. QDMR can also measure the sample specificity of each DMR. Finally, the application to methylation profiles detected by reduced representation bisulphite sequencing (RRBS) in mouse showed the platform-free and species-free nature of QDMR. This approach provides an effective tool for the high-throughput identification of potential functional regions involved in epigenetic regulation. © 2011 The Author(s).


Xing J.,Harbin Medical University | Jia C.-R.,Harbin Medical University | Wang Y.,Harbin Medical University | Guo J.,Jian Hua Hospital | Cai Y.,Harbin Medical University
Journal of Cancer Research and Clinical Oncology | Year: 2012

Purpose: This study investigated the effect of shRNA targeting survivin on cultured ovarian cancer cells and on a murine ovarian cancer xenograft. Methods: An RNAi plasmid for survivin was transfected into SKOV3 cells, and the effect of shRNA targeting survivin on the expression of survivin was determined. Transmission electron microscopy (TEM), flow cytometry, and TUNEL staining were used to assess apoptosis. The MTT assay was used to measure cell growth and changes in cisplatin sensitivity. SKOV3 cells were injected into nude mice, and the effect of shRNA targeting the survivin gene on tumor growth was assessed. Results: SKOV3 cells transfected with an RNAi plasmid against survivin had increased apoptosis and slower growth. At the molecular level, these cells also had lower expression of survivin. Nude mice inoculated with SKOV3 cells developed cancers, and treatment with shRNA targeting survivin markedly inhibited the growth of these cancers with no obvious side effects. Conclusions: Our studies of SKOV3 cells and ovarian cancer xenografts in nude mice indicate that shRNA targeting survivin has potential for the treatment of ovarian cancer. © Springer-Verlag 2012.


Lv J.,Harbin Medical University | Lv J.,Harbin Institute of Technology | Liu H.,Harbin Medical University | Su J.,Harbin Medical University | And 6 more authors.
Nucleic Acids Research | Year: 2012

DNA methylation is an important epigenetic modification for genomic regulation in higher organisms that plays a crucial role in the initiation and progression of diseases. The integration and mining of DNA methylation data by methylation-specific PCR and genome-wide profiling technology could greatly assist the discovery of novel candidate disease biomarkers. However, this is difficult without a comprehensive DNA methylation repository of human diseases. Therefore, we have developed DiseaseMeth, a human disease methylation database (http://bioinfo.hrbmu.edu.cn/diseasemeth). Its focus is the efficient storage and statistical analysis of DNA methylation data sets from various diseases. Experimental information from over 14 000 entries and 175 high-throughput data sets from a wide number of sources have been collected and incorporated into DiseaseMeth. The latest release incorporates the gene-centric methylation data of 72 human diseases from a variety of technologies and platforms. To facilitate data extraction, DiseaseMeth supports multiple search options such as gene ID and disease name. DiseaseMeth provides integrated gene methylation data based on cross-data set analysis for disease and normal samples. These can be used for in-depth identification of differentially methylated genes and the investigation of gene-disease relationship. © The Author(s) 2011. Published by Oxford University Press.


Xia Y.,Harbin Medical University | Zhang B.,Shanxi Institute of Coal CAS Chemistry | Wang Y.,Harbin Institute of Technology | Qian M.,Harbin Institute of Technology | Geng L.,Harbin Institute of Technology
Materials Science and Engineering C | Year: 2012

In this paper, the in-vitro cytotoxicity and the in-vivo compatibility of Mg-4.0Zn-0.2Ca alloy are studied. The cytotoxicity of Mg-4.0Zn-0.2Ca alloy is examined by MTT method on osteoblast cells. The in-vivo behavior of Mg-4.0Zn-0.2Ca alloy is investigated on rabbits. It has been found that Mg-4.0Zn-0.2Ca alloy extract has no cytotoxicity on osteoblast cells. Three months after in-vivo experiment, about 35-38% magnesium alloy implant has been degraded and a degradation layer which is composed of Ca, P, O and Mg has been formed on the magnesium alloy implants. Histological analysis showed that new bone is observed around magnesium implant without inflammation reaction. In-vitro and in-vivo test indicated that the Mg-4.0Zn-0.2Ca alloy has good biocompatibility. © 2012 Elsevier B.V. All rights reserved.


Yue H.Y.,Sungkyunkwan University | Yue H.Y.,Harbin University of Science and Technology | Huang S.,Harbin Medical University | Chang J.,Sungkyunkwan University | And 12 more authors.
ACS Nano | Year: 2014

We report that vertically aligned ZnO nanowire arrays (ZnO NWAs) were fabricated on 3D graphene foam (GF) and used to selectively detect uric acid (UA), dopamine (DA), and ascorbic acid (AA) by a differential pulse voltammetry method. The optimized ZnO NWA/GF electrode provided a high surface area and high selectivity with a detection limit of 1 nM for UA and DA. The high selectivity in the oxidation potential was explained by the gap difference between the lowest unoccupied and highest occupied molecular orbitals of a biomolecule for a set of given electrodes. This method was further used to detect UA levels in the serum of patients with Parkinson's disease (PD). The UA level was 25% lower in PD patients than in healthy individuals. This finding strongly implies that UA can be used as a biomarker for PD. © 2014 American Chemical Society.


Sun Y.,Harbin Medical University | Zhang B.,Shanxi Institute of Coal CAS Chemistry | Wang Y.,Harbin Institute of Technology | Geng L.,Harbin Institute of Technology | Jiao X.,Harbin Medical University
Materials and Design | Year: 2012

In this paper, the mechanical properties, in vitro degrades and cytotoxicity of Mg-4.0Zn-0.2Ca alloy were studied. The extruded Mg-4.0Zn-0.2Ca alloy exhibited peak strength of 297. MPa, yield strength of 240. Mpa, elongation of 21.3% and elastic modulus of 45. GPa, respectively. After 30. days immersion in SBF solutions, the values of the yield strength, the ultimate tensile strength, the elongation and the elastic modulus of the alloy were degraded to 160. MPa, 220. MPa, 8.5% and 40. GPa respectively. It is still enough for bone fixed. The in vitro corrosion test in the simulated body fluid (SBF) revealed that the addition of Zn and Ca into Mg matrix could enhance the corrosion potential and reduced the degradation rate. In vitro cytotoxicity of the alloy was disclosed that Mg-4.0Zn-0.2Ca alloy has suitable biocompatibility. © 2011 Elsevier Ltd.


Wang Z.,Harbin Institute of Technology | Wu L.,Harbin Medical University | Zhou J.,Canadian Light Source Inc. | Jiang Z.,Harbin Institute of Technology | Shen B.,Harbin Medical University
Nanoscale | Year: 2014

A chemoselective route to induce Fe3O4@ZnO core-shell nanoparticles decorating carbon nanotubes to form MWCNT/Fe3O4@ZnO heterotrimers has been developed. Charges are redistributed in the heterotrimers through C-O-Zn, C-O-Fe and Fe-O-Zn bondings, giving rise to multiple electronic phases. The generated significant interfacial polarization and synergetic interaction between dielectric and magnetic absorbers result in the MWCNT/Fe3O4@ZnO heterotrimers with high-performance microwave absorption in an entire X band. © 2014 the Partner Organisations.


Shao B.,Harbin Medical University | Li Y.,U.S. Center for Disease Control and Prevention | Yu L.,U.S. Center for Disease Control and Prevention | Wang K.,U.S. Center for Disease Control and Prevention | And 3 more authors.
Journal of Infection | Year: 2014

Objective: To investigate the characteristics and trends of the HIV epidemic in Heilongjiang province of China between 1993 and 2012. Methods: Data from the provincial surveillance system for HIV infections and AIDS were reviewed. Local health staff reviewed medical records, including dates of HIV/AIDS diagnoses and deaths, exposure category, treatment, laboratory testing, and demographics. Results: By 31 October 2012, a total of 3062 HIV-infections were detected with 426 deaths and 206 who presently live outside Heilongjiang province, 38.1% of whom were diagnosed as AIDS. Since 2007, homosexual transmission has increased and become the dominant route of HIV transmission, accounting for 57.9% of cases during 2009-2010, and 69.0% during 2011-2012. Men who have sex with men (MSM) with HIV-infections had the following characteristics: 21-30 year age group (42.4%); unmarried (61.6%); urban residents (46.7%); and college or higher education (36.8%). In addition, the proportion of MSM ≤ 30 years of age and rural residents showed an uptrend across the study years. Conclusions: The HIV/AIDS epidemic has continued to increase in Heilongjiang province, and has shown an explosive growth since 2008, with MSM making a tremendous contribution to the HIV outbreak. Homosexual contact has become the dominant route of HIV transmission. Urgent intervention is needed to recognize this target population, especially those ≤30 years of age, unmarried, and urban residents. © 2013 The British Infection Association.


Guo X.M.,Harbin Institute of Technology | Guo B.,Harbin Institute of Technology | Zhang Q.,Harbin Medical University | Sun X.,Harbin Institute of Technology
Dalton Transactions | Year: 2011

In this paper, the structural and zeta potential properties of 10-hydroxycamptothecin (HCPT) were investigated by FT-IR and zeta potential analyzer under different pH. The anticancer drug HCPT as a model drug was used to prepare a high-performance and relatively easy-to-fabricate system on Fe 3O4 magnetite nanoparticles by using a polystyrene sulfonate (PSS) and HCPT interlayer self-assembly method. The results obtained from FT-IR and XRD confirmed that HCPT was molecularly dispersed into the nanoparticles. The method holds not only environment-friendly characteristics and the ability to mimic the self-organization process in biological systems but also greatly decreases adjuvant polymers. In addition, the system has an ideal drug payload for the delivery of insoluble HCPTs. © The Royal Society of Chemistry 2011.


Wang F.,Harbin Medical University | Shan Y.,Harbin Institute of Technology | Shan Y.,Harbin Medical University
Nutrition Research | Year: 2012

Sulforaphane (SFN), an isothiocyanate that exists exclusively in cruciferous vegetables, may be the most promising preventive agent for bladder cancer (BC) to date. We previously observed that SFN dramatically inhibits human BC T24 cells in vitro. Our hypothesis is that SFN may attenuate BC growth. To test our hypothesis, we investigated the effect of SFN on human BC UM-UC-3 cell xenografts implanted into athymic mice. Sulforaphane extract was routinely prepared in our laboratory, and its content was measured with high-performance liquid chromatography. Athymic mice were injected subcutaneously with a UM-UC-3 cell suspension (2.0×10 6 cells/200 μL per mouse) and randomly divided into 2 groups. The positive control group was orally gavaged with water, and the treatment group was orally administered SFN from broccoli sprout (12 mg/kg body weight) for 5 weeks. At the end of the experiment, tumor tissues were harvested and processed for hematoxylin and eosin staining and immunohistochemistry. The average tumor volume decreased from 4.1±1.67 cm 3 in the positive control mice to 1.5±0.72 cm 3 in the SFN-treated mice, evidencing an inhibitory rate of 63%. The SFN extract also reduced the appearance of tumors, including karyopyknosis and angiogenesis. Sulforaphane extract induced caspase 3 and cytochrome c expression but reduced the expression of survivin. Sulforaphane extract retards the growth of UM-UC-3 xenografts in vivo, confirming its future potential in BC therapy. © 2012 Elsevier Inc..


Xia W.,Wenzhou University | Zhang F.,Harbin Medical University | Xie C.,Wenzhou University | Jiang M.,Harbin Medical University | Hou M.,Wenzhou University
Stem Cell Research and Therapy | Year: 2015

Introduction: Mesenchymal stem cells (MSCs)-based therapies have had positive outcomes in animal models of cardiovascular diseases. However, the number and function of MSCs decline with age, reducing their ability to contribute to endogenous injury repair. The potential of stem cells to restore damaged tissue in older individuals can be improved by specific pretreatment aimed at delaying senescence and improving their regenerative properties. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that modulates age-related signaling pathways, and hence is a good candidate for rejuvenative function. Methods: Bone marrow-derived mesenchymal stem cells (BM-MSCs) were isolated from young (6-month-old) or aged (24-month-old) male donor rats. Cell proliferation was measured using the CCK8 cell proliferation assay; secretion of VEGF, bFGF, HGF, and IGF was assessed by RT-qPCR and ELISA. Apoptosis was induced by hypoxia and serum deprivation (hypoxia/SD) for up to 6 hr, and examined by flow cytometry. Expression levels of AMP-activated protein kinase (AMPK) and forkhead box class O 3a (FOXO3a) were detected by Western blotting. CD74 expression was assayed using RT-qPCR, Western blotting, and immunofluorescence. Results: In this study, we found that MSCs isolated from the bone marrow of aged rats displayed reduced proliferative capacity, impaired ability to mediate paracrine signaling, and lower resistance to hypoxia/serum deprivation-induced apoptosis, when compared to younger MSCs. Interestingly, pretreatment of aged MSCs with MIF enhanced their growth, paracrine function and survival. We detected enhanced secretion of VEGF, bFGF, HGF, and IGF from MIF-treated MSCs using ELISA. Finally, we show that hypoxia/serum deprivation-induced apoptosis is inhibited in aged MSCs following MIF exposure. Next, we found that the mechanism underlying the rejuvenating function of MIF involves increased CD74-dependent phosphorylation of AMPK and FOXO3a. Furthermore, this effect was abolished when CD74, AMPK, or FOXO3a expression was silenced using small-interfering RNAs(siRNA). Conclusions: MIF can rejuvenate MSCs from a state of age-induced senescence by interacting with CD74 and subsequently activating AMPK-FOXO3a signaling pathways. Pretreatment of MSCs with MIF may have important therapeutic implications in restoration or rejuvenation of endogenous bone marrow-MSCs in aged individuals. © 2015 Xia et al.; licensee BioMed Central.


Su J.,Harbin Medical University | Yan H.,Harbin Medical University | Wei Y.,Harbin Medical University | Liu H.,Harbin Medical University | And 4 more authors.
Nucleic Acids Research | Year: 2013

High-throughput bisulfite sequencing is widely used to measure cytosine methylation at single-base resolution in eukaryotes. It permits systems-level analysis of genomic methylation patterns associated with gene expression and chromatin structure. However, methods for large-scale identification of methylation patterns from bisulfite sequencing are lacking. We developed a comprehensive tool, CpG-MPs, for identification and analysis of the methylation patterns of genomic regions from bisulfite sequencing data. CpG-MPs first normalizes bisulfite sequencing reads into methylation level of CpGs. Then it identifies unmethylated and methylated regions using the methylation status of neighboring CpGs by hotspot extension algorithm without knowledge of pre-defined regions. Furthermore, the conservatively and differentially methylated regions across paired or multiple samples (cells or tissues) are identified by combining a combinatorial algorithm with Shannon entropy. CpG-MPs identified large amounts of genomic regions with different methylation patterns across five human bisulfite sequencing data during cellular differentiation. Different sequence features and significantly cell-specific methylation patterns were observed. These potentially functional regions form candidate regions for functional analysis of DNA methylation during cellular differentiation. CpG-MPs is the first user-friendly tool for identifying methylation patterns of genomic regions from bisulfite sequencing data, permitting further investigation of the biological functions of genome-scale methylation patterns. © 2012 The Author(s). Published by Oxford University Press.


Fan H.-X.,Harbin Medical University | Li H.-X.,Harbin Medical University | Chen D.,Harbin Medical University | Gao Z.-X.,Harbin Medical University | And 2 more authors.
Journal of Experimental and Clinical Cancer Research | Year: 2012

Background: Type IV collagen (ColIV) is the most important scaffold for the basement membrane (BM) proteins, and plays an important role in regulating and limiting tumour invasion and metastasis. Methods. Here, we observed the changes in morphology and distribution of type IV collagen (ColIV) in the basement membrane (BM) surrounding nests of carcinoma in 48 patients with oral tongue squamous cell (OTSCC). We examined the correlation between the expressions of ColIV, MMP-2 and MMP-9 and the prognosis of OTSCC patients. The intensity and patterns of expression were assessed immunohistochemically using anti-human mouse monoclonal MMP-2, MMP-9 and Col IV antibodies. Statistical analyses were performed to determine the prognostic correlations of ColIV, MMP-2, and MMP-9 levels. Results: MMP-2 and MMP-9 expressions in OTSCC were higher than those in normal oral mucosa and dysplastic oral mucosa group(MMP-2 iOD: 66.40 24.20, 134.69 37.08, and 357.79 116.78; MMP-9 iOD: 88.05 23.85, 307.13 93.22, and 791.31 260.52; in normal, dysplastic oral mucosa, and tumour tissues, respectively, P < 0.01); however, ColIV immunoreactivity was lower (ColIV iOD: 406.87 62.95, 247.83 42.30, and 151.92 38.17 in normal, dysplastic oral mucosa, and tumour tissues, respectively, P < 0.01). High tumour and stromal MMP-2 and MMP-9 expression was significantly associated with positive lymph node status. Col IV expression was associated with positive lymph node status (P < 0.05), and have negatively correlated with the expression of MMP-2 and MMP-9. Overall survival was significantly shorter in patients with high tumour and stromal MMP-2 and MMP-9 expression, and tended to be shorter in patients with low ColIV expression. Conclusions: Degradation of ColIV was closely related to increased MMP-2 and MMP-9 expression; MMP-9 have more important function than MMP-2 during the cancer development. Monitoring changes in the expression of ColIV, MMP-2, and MMP-9 may be a useful technique for assessing prognoses in OTSCC patients. © 2012 Fan et al.; licensee BioMed Central Ltd.


Jiang G.,Zhejiang University | Cui Y.,Harbin Medical University | Yu X.,Chinese Institute of Basic Medical Sciences | Wu Z.,Zhejiang University | And 2 more authors.
Oncotarget | Year: 2015

Dysregulation of microRNAs (miRs) is involved in carcinogenesis. Deregulation of miR-211 has recently been observed in many tumors, but its function in hepatocellular carcinoma (HCC) is still unknown. Here we found that miR-211 was decreased in HCC cancer tissues compared with adjacent normal tissues. We also found that overexpression of miR-211 repressed proliferation and invasion in HepG2 and SMMC7721 cells. Luciferase reporter assays and western blot indicated that special AT-rich sequence-binding protein-2 (SATB2), is a direct target of miR-211. The expression of SATB2 was upregulated in HCC cancer tissues and cell lines and miR-211 levels inversely correlated with SATB2 levels in HCC. Importantly, SATB2 rescued the miR-211-mediated inhibition of cell invasion and proliferation. Finally, reintroduction of miR-211 repressed tumor formation of HCC in xenograft mice. This study provides insights into molecular mechanisms that miR-211 contributed to HCC.


Zhu M.,Harbin Medical University | Gao W.,Harbin Institute of Technology | Wang X.,Harbin Medical University | Shi C.,New York University | Lin Z.,Harbin Medical University
Academic Radiology | Year: 2012

Rationale and Objectives: Magnetic resonance imaging (MRI) studies reveal that atrophy of the corpus callosum (CC) is involved in early Alzheimer's disease (AD). The aim of this study was to investigate when and how callosal changes occur in the early course of AD. Materials and Methods: The Open Access Series of Imaging Studies data sets were used in this study to investigate callosal change. High-resolution structural MRI was performed in 196 older patients. Subjects were characterized using the Clinical Dementia Rating (CDR); 98 healthy controls were not demented (CDR 0), and 98 patients had clinical diagnosis of AD in the very mild dementia stage (CDR 0.5; n = 70) and the mild dementia stage (CDR 1; n = 28). A semiautomatic segmentation method was used to extract the CC in the midsagittal plane. The total and regional areas of the CC were measured. Results: The results indicated that callosal atrophy occurred in when subjects' CDRs were 0.5. The area of the genu and rostral body of the CC in the healthy controls (CDR 0) was significantly different from that of the subjects with very mild dementia (CDR 0.5) (P < .05). A significant difference could also be found in the area of the rostral body and midbody of the CC between subjects with very mild dementia (CDR 0.5) and those with mild dementia (CDR 1) (P < .05). Conclusions: Callosal atrophy can be detected in subjects with CDRs of 0.5. The change in the CC in the early stage of AD indicates an anterior-to-posterior atrophic process as the degree of dementia assessed by the CDR (from 0 to 0.5 to 1) increases. © 2012 AUR.


Wu L.,Harbin Medical University | Wang Z.,Harbin Institute of Technology | Shen B.,Harbin Medical University
Nanoscale | Year: 2013

Large scale and well-ordered gold nanoparticle superlattices were fabricated by self-assembly as an active substrate for surface-enhanced Raman scattering (SERS) that can quantitatively detect carbaryl with a detection limit of 1 ppm. These fabricated superlattices with a dimension of several hundred micrometers exhibited high, reproducible SERS activity. © 2013 The Royal Society of Chemistry.


Xia Y.H.,Harbin Medical University | Zhang B.P.,Shanxi Institute of Coal CAS Chemistry | Lu C.X.,Shanxi Institute of Coal CAS Chemistry | Geng L.,Harbin Institute of Technology
Materials Science and Engineering C | Year: 2013

In this paper, corrosion resistance of the Mg-4.0Zn-0.2Ca alloy was modified by micro-arc oxidation (MAO) process. The microstructure and phase constituents of MAO layer were characterized by SEM, XRD and X-ray photoelectron spectroscopy (XPS). The corrosion resistance of MAO treated Mg-4.0Zn-0.2Ca alloy in the simulated body fluid were characterized by potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) techniques. The microstructure results indicated that a kind of ceramic film was composed byMgO and MgF2 was formed on the surface of Mg-4.0Zn-0.2Ca alloy after MAO treatment. The electrochemical test reveals that the corrosion resistance ofMAO treated samples increase 1 order of magnitude. Themechanical intensity test showed that the MAO treated samples has suitable mechanical properties. © 2013 Elsevier B.V. All rights reserved.


Liu Y.,Harbin Institute of Technology | Jin J.,Harbin Institute of Technology | Wang Q.,Harbin Institute of Technology | Shen Y.,Harbin Institute of Technology | Dong X.,Harbin Medical University
Signal Processing | Year: 2014

Region level based methods are popular in recent years for multifocus image fusion as they are the most direct fusion ways. However, the fusion result is not ideal due to the difficulty in focus region segmentation. In this paper, we propose a novel region level based multifocus image fusion method that can locate the boundary of the focus region accurately. As a novel tool of image analysis, phases in the quaternion wavelet transform (QWT) are capable of representing the texture information in the image. We use the local variance of the phases to detect the focus or defocus for every pixel initially. Then, we segment the focus detection result by the normalized cut to remove detection errors, thus initial fusion result is acquired through copying from source images according to the focus detection results. Next, we compare initial fusion result with spatial frequency weighted fusion result to accurately locate the boundary of the focus region by structural similarity. Finally, the fusion result is obtained using spatial frequency as fusion weight along the boundary of the focus region. Furthermore, we conduct several experiments to verify the feasibility of the fusion framework. The proposed algorithm is demonstrated superior to the reference methods.


Sun Y.,Harbin Medical University | Kong M.-X.,Harbin Institute of Technology | Jiao X.-H.,Harbin Medical University
Transactions of Nonferrous Metals Society of China (English Edition) | Year: 2011

The in-vitro degradation and in-vitro cytotoxicity of the as-extruded Mg-4.0Zn-0.2Ca alloy were investigated. The in-vitro corrosion tests indicate that Zn and Ca elements can dramatically increase the corrosion potential of the as-extruded Mg-4.0Zn-0.2Ca alloy in the simulated body fluid and reduce the degradation rate. The cytotoxicity of the as-extruded Mg-4.0Zn-0.2Ca alloy examined by MTT tests on L929 cells suggest that the alloy has eligible toxicity for implant applications. © 2011 The Nonferrous Metals Society of China.


He J.,Harbin Institute of Technology | Zhang W.,Harbin Institute of Technology | Zhou Q.,Harbin Institute of Technology | Zhao T.,Harbin Medical University | And 3 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2013

Glioma is the most common highly malignant primary brain tumor. The molecular pathways that result in the pathogenesis of glioma remain elusive. In this study, we found microRNA-107 (miR-107) was downregulated in glioma tissues and cell lines. Our results revealed miR-107 overexpression suppressed cell proliferation in glioma cells, whereas miR-107 knockdown promoted cell growth in MO59K. miR-107 expression induced apoptosis in glioma cells possibly through the increase in Fas (TNFRSF6)-associated via death domain (FADD) expression and activation of caspases-8 and -3/7. Moreover, the activity of caspase-8 in miR-107-overexpressing SHG44 cells was suppressed with FADD knockdown. The tumor growth in nude mice bearing miR-107-overexpressing SHG44 cells was blocked through apoptosis induction. Sal-like 4 (Drosophila) (SALL4) level was reduced upon miR-107 overexpression in glioma cells, and the inverse was observed upon miR-107 knockdown in MO59K. Using a luciferase reporter system, SALL4 3′-UTR-dependent luciferase activity was reduced by miR-107 mimics or increased by an inhibitor of miR-107. In SHG44, SALL4 downregulation triggered growth inhibition and activated FADD-mediated cell apoptosis pathway. The caspase-8 activity in miR-107-overexpressing SHG44 cells was suppressed with SALL4 upregulation. Furthermore, primary glioma tumors with low miR-107 expression show elevated SALL4 level. An obvious inverse correlation was observed between miR-107 expression and SALL4 level in clinical glioma samples. Therefore, our results demonstrate upregulation of miR-107 suppressed glioma cell growth through direct targeting of SALL4, leading to the activation of FADD/caspase-8/caspase-3/7 signaling pathway of cell apoptosis. These data suggest miR-107 is a potential therapeutic target against glioma. © 2013 Elsevier Ltd. All rights reserved.


Wang H.,Harbin Institute of Technology | Wu L.,Harbin Medical University | Jiao J.,China Aerospace Science and Technology Corporation | Zhou J.,Canadian Light Source Inc. | And 5 more authors.
Journal of Materials Chemistry A | Year: 2015

The interaction between components in hybrids is an indispensable factor in designing and fabricating composites with distinguished electromagnetic (EM) absorption performances. Herein, covalently bonded SiC/Co hybrid nanowires (NWs) have been fabricated, which present significantly enhanced EM absorption compared to a simple physical mixture of SiC and Co. The hybrids are characterized by transmission electron microscopy, X-ray diffraction, Raman spectroscopy, vector network analysis, and X-ray absorption near-edge spectroscopy at the Si K-edge, C K-edge, Co L3,2-edge and O K-edge. Microstructure analysis indicates the formation of Si-O-Co bonds between SiC NWs and magnetic Co nanocrystals. Charge transfer takes place in the covalently bonded SiC/Co hybrid NWs. The induced synergistic coupling interaction in SiC/Co leads to an effective EM absorption band (RL < -10 dB) covering the frequency range of 10-16.6 GHz when the Co content is 25.1 wt% in the hybrid. This journal is © The Royal Society of Chemistry 2015.


Liu C.,Harbin Institute of Technology | Xu Y.,Harbin Institute of Technology | Wu L.,Harbin Medical University | Jiang Z.,Harbin Institute of Technology | And 2 more authors.
Journal of Materials Chemistry A | Year: 2015

Core-multishell MWCNT/Fe3O4/polyaniline (PANI)/Au hybrid nanotubes are synthetized by a facile layer-by-layer technique which well integrates the dielectric components (MWCNT and PANI) and the magnetic absorber (Fe3O4) as well as the electromagnetic (EM) wave reflector (Au) into one unit. The hybrid nanotubes are characterized by transmission electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, Raman spectroscopy and vector network analysis. Microstructure analysis indicates that the coverage of the gold nanoparticles could be adjusted simply by varying the weight ratio of the precursors. When gold is introduced into the hybrid nanotubes, the EM absorption is sharply enhanced. The lowest reflection loss value reduces from -22 dB to -60 dB. This may be ascribed to the fact that the introduction of gold nanoparticles is beneficial for the multi-reflection of EM waves within the absorbers, balances the impedance matching between the absorbers and free space, and induces charge redistribution within the hybrid nanotubes generating significant interfacial polarization. © The Royal Society of Chemistry.2015.


Song W.,Harbin Institute of Technology | Cui H.,Harbin Medical University | Zhang R.,Harbin Institute of Technology | Zheng J.,Harbin Medical University | And 2 more authors.
Anticancer Research | Year: 2011

Background: 5-Aminolevulinic acid (ALA) has been used as a photodynamic sensitizer for cancer treatment using photodynamic therapy. However, the light has markedly limited penetration depth. It was found that ALA also responds to low energy ultrasound, which has the capability to penetrate deep into tissues. Therefore, sonodynamic therapy (SDT) is a promising method for noninvasive treatment of tumors embedded deep in the tissue. It is desirable to kill the cancer cells via apoptosis rather than necrosis, and therefore, it is necessary to gain a better understanding of the mechanisms of treating cancer using SDT. Materials and Methods: The apoptosis of SAS cells induced by pulsed 1.05MHz ultrasound in combination with ALA was investigated in vitro. Results: The cells exposed to SDT with 10 μg/ml ALA displayed significantly higher apoptosis than cells treated by ultrasound alone. There was notably increased reactive oxygen species (ROS) production in the cells treated by SDT with ALA than by ultrasound alone, resulting in higher lipid peroxidation (LPO) level and more cells losing their mitochondrial membrane potential (MMP). Conclusion: ALA-mediated SDT produced strong apoptotic effects on SAS cells, which were mainly related to the excessive intracellular ROS production followed by LPO increase and MMP decrease.


Zhou S.,Harvard University | Zhou S.,Harvard Stem Cell Institute | Geng S.,Harvard University | Geng S.,Harbin Medical University | Glowacki J.,Harvard University
Journal of Steroid Biochemistry and Molecular Biology | Year: 2013

Vitamin D metabolites are important effectors of bone and mineral homeostasis. Human bone marrow stromal cells (hMSCs) are targets of 1α,25-dihydroxyvitamin D [1α,25(OH)2D] action to promote their differentiation to osteoblasts. Osteoblastogenesis is also stimulated by 25-hydroxyvitamin D [25(OH)D], an effect that requires conversion to 1α,25(OH)2D3 by 25-hydroxyvitamin D3 1α-hydroxylase (CYP27B1). These findings support an autocrine/paracrine role of vitamin D metabolism in osteoblastogenesis of hMSCs. In this study, we assessed whether and by what mechanisms osteoblastogenesis could be rejuvenated with hMSCs from elders. First, knockdown studies with VDR-siRNA showed that both the prodifferentiation and anti-proliferative effects of 1α,25(OH) 2D3 required VDR. Second, 100 nM 25(OH)D3 (p < 0.01 vs. control, ANOVA) and 100 nM PTH1-34 (p < 0.05) significantly stimulated alkaline phosphatase (ALP) activity (a measure of osteoblastogenesis), with a synergistic effect when combined (p < 0.001). Scriptaid, an inhibitor of histone deacetylase, blocked the effect of 25(OH)D3 and PTH on osteoblastogenesis. Scriptaid alone downregulated VDR in hMSCs. These data demonstrate that histone deacetylation is required for the synergistic effect of 25(OH)D3 and PTH on osteoblastogenesis in hMSCs. Both VDR siRNA and Scriptaid dowregulated VDR mRNA and inhibited osteoblastogenesis. Thus, epigenetic regulation of the VDR may be central to rejuvenating osteoblastogenesis in hMSCs from elders. © 2012 Elsevier Ltd. All rights reserved.


Yang Y.,Harbin Medical University | Luo C.,Harbin Medical University | Luo C.,U.S. Center for Disease Control and Prevention | Feng R.,Harbin Medical University | Bi S.,Harbin Medical University
Journal of Cancer Research and Clinical Oncology | Year: 2011

Objective: TNF-α-308 G/A, TNF-α-238 G/A, IL-1B-31 T/C, IL-1B-511 C/T, and IL-10-1082 G/A polymorphisms have been reported to influence the risk for hepatocellular carcinoma (HCC) in many studies; however, the results still remains controversial and ambiguous. The aim of this study was to determine more precise estimations for the relationship between TNF-α, IL-1B, and IL-10 polymorphisms and the risk for HCC by meta-analysis. Methods: Electronic searches for all publications were conducted on associations between these variants and HCC in several databases through September 2010. Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated to estimate the strength of this association in a random-effect model. Twenty studies were identified, involving 2,763 HCC patients and 4,152 controls. Results: This meta-analysis showed significant association between TNF-α-308 polymorphism and HCC (AA + GA vs. GG: OR = 1.74, 95% CI = 1.12-2.72). In Caucasian and Asian subgroups, OR values (95% CI) were 1.49 (0.58-3.82) and 1.84 (1.06-3.20), respectively. While the ORs for TNF-α-238 G/A, IL-1B-31 T/C, -511 C/T and IL-10-1082 G/A polymorphisms and HCC were 1.37 (0.95-2.00), 1.24 (0.99-1.55), 1.12 (0.66-1.88) and 0.91 (0.74-1.12), respectively. The sensitivity analysis further strengthened the overall strong positive correlations. No publication bias was observed in this study. Conclusions: TNF-α-308 G/A polymorphism is assumed to confer a higher risk for HCC, especially in Asian population. TNF-α-238 G/A, IL-1B-31 T/C, -511 C/T, and IL-10-1082 G/A polymorphisms were not detected to be related to the risk for HCC. © 2010 Springer-Verlag.


Gu Y.,Harbin Institute of Technology | Cui Z.,Harbin Institute of Technology | Xiu C.,Harbin Medical University | Wang L.,Harbin Medical University
Neurocomputing | Year: 2014

Ultrasound imaging is one of the most important instruments of modern medical imaging modalities. However, the usefulness of ultrasound imaging is degraded due to the presence of a signal-dependent noise known as speckle. Recently, lots of algorithms have been proposed for despeckling. Unfortunately, few attentions have been paid on time series of ultrasound images like echocardiography. In this paper, we address this problem by developing a time series non-local means (NLM) filter algorithm. A distance measure relevant to a speckle model is firstly introduced to take place of the Gaussian-weighted Euclidian distance according to a Bayesian formulation. By taking the information along the temporal axis into account, we further extend the NLM filter from single frame to image time series. To lighten the computational burden, a blockwise approach and a pre-classification process are used to accelerate the algorithm. In order to evaluate our method, experiments are conducted on both synthetic and in vivo ultrasound images. Experiments show that the proposed method achieves satisfactory results in terms of removing the speckle and preserving the edges and image details, compared with the state-of-the-art methods. © 2013 Elsevier B.V.


Li B.,Harvard University | Li B.,Harbin Medical University | Cohen A.,Intra-Cellular Therapies, Inc. | Hudson T.E.,Harvard University | And 4 more authors.
Circulation | Year: 2010

BACKGROUND-: Understanding the mechanisms of repair and regeneration of the kidney after injury is of great interest because there are currently no therapies that promote repair, and kidneys frequently do not repair adequately. We studied the capacity of human CD34 hematopoietic stem/progenitor cells (HSPCs) to promote kidney repair and regeneration using an established ischemia/reperfusion injury model in mice, with particular focus on the microvasculature. METHODS AND RESULTS-: Human HSPCs administered systemically 24 hours after kidney injury were selectively recruited to injured kidneys of immunodeficient mice (Jackson Labs, Bar Harbor, Me) and localized prominently in and around vasculature. This recruitment was associated with enhanced repair of the kidney microvasculature, tubule epithelial cells, enhanced functional recovery, and increased survival. HSPCs recruited to kidney expressed markers consistent with circulating endothelial progenitors and synthesized high levels of proangiogenic cytokines, which promoted proliferation of both endothelial and epithelial cells. Although purified HSPCs acquired endothelial progenitor markers once recruited to the kidney, engraftment of human endothelial cells in the mouse capillary walls was an extremely rare event, indicating that human stem cell mediated renal repair is by paracrine mechanisms rather than replacement of vasculature. CONCLUSIONS-: These studies advance human HSPCs as a promising therapeutic strategy for promoting renal repair after injury. © 2010 American Heart Association, Inc.


Zhang B.,Shanxi Institute of Coal CAS Chemistry | Hou Y.,Harbin Medical University | Wang X.,Harbin Medical University | Wang Y.,Harbin Institute of Technology | Geng L.,Harbin Institute of Technology
Materials Science and Engineering C | Year: 2011

In this paper, ternary Mg-Zn-Ca magnesium alloys were investigated as degradable biomedical material. Tensile results showed that the mechanical properties of the alloys can be modulated by controlling Zn content. With increasing Zn contents, yield strength (YS), ultimate tensile strength (UTS) and ductility of the materials are increased at first and then decreased. In-vitro corrosion tests in Hank's simulated body fluid presented that the composition and microstructure of Mg-Zn-Ca alloys strongly affected their corrosion behavior. An increasing content of Zn element can lead to a high corrosion potential and bad corrosion resistance. The cytotoxicity evaluated by neutral red kits on L-929 cells revealed that Mg-1.0 Zn-1.0Ca, Mg-2.0 Zn-1.0 Ca, and Mg-3.0 Zn-1.0 Ca alloys did not induce toxicity in cells. © 2011 Elsevier B.V. All rights reserved.


Wu X.,Harbin Institute of Technology | Sun Y.,Harbin Institute of Technology | Xie W.,Harbin Medical University | Liu Y.,Harbin Institute of Technology | Song X.,Harbin Institute of Technology
Dental Materials | Year: 2010

Objectives: It has been the focus to develop low shrinkage dental composite resins in recent ten years. A major difficulty in developing low shrinkage dental materials is that their deficiency in mechanical properties cannot satisfy the clinical purpose. The aim of this study is to develop novel dental nanocomposites incorporated with polyhedral oligomeric silsesquioxane (POSS). It is especially interesting to evaluate the volumetric shrinkage and mechanical properties, improve the shrinkage, working performances and service life of dental composite resins. Methods: The effect of added POSS on the composites' mechanical properties has been evaluated. The weight percentages of added POSS are 0, 2, 5, 10 and 15 wt% respectively. Fourier-transform infra-red spectroscopy and X-ray diffraction were used to characterize their microstructures. Physico-mechanical properties that were investigated included volumetric shrinkage, flexural strength, flexural modulus, compressive strength, compressive modulus, Viker's hardness and fracture energy. Furthermore, the possible reinforced mechanism has been discussed. Results: The shrinkage of novel nanocomposites decreased from 3.53% to 2.18%. The nanocomposites incorporated with POSS showed greatly improved mechanical properties, for example, with only 2 wt% POSS added, the nanocompsite's flexural strength increased 15%, compressive strength increased 12%, hardness increased 15% and uncommonly, even the toughness of resins was obviously increased. With 5 wt% POSS polymerized, compressive strength increased from 192 MPa to 251 MPa and compressive modulus increased from 3.93 GPa to 6.62 GPa, but flexure strength began to decline from 87 MPa to 75 MPa. This finding indicated that the reinforcing mechanism of flexure state maybe different from that of compressive state. Conclusions: The mechanical properties and volumetric shrinkage of dental composite resins polymerized with POSS can be improved significantly. In current study, the nanocomposite with 2 wt% POSS incorporated is observed to achieve the best improved effects. © 2010 Academy of Dental Materials.


Wu J.,Harbin Medical University | Zhou J.,Harbin Institute of Technology | Lang Y.,Harbin Medical University | Yao L.,Harbin Medical University | And 3 more authors.
International Journal of Biological Macromolecules | Year: 2012

Armillaria mellea is a famous traditional Chinese medicinal and edible fungus. In this study, we purified a water-soluble polysaccharide (AMP) from the fruiting bodies of this fungus. AMP contained 94.8% carbohydrate, 2.3% uronic acid and 0.5% protein. Its molecular weight was determined as 4.6×105Da, as determined by high-performance gel-permeation chromatography (HPGPC). Gas chromatography (GC) analysis indicated that AMP was mainly composed of d-glucose. In vitro assay, AMP exhibited a potent tumor growth inhibitory effect on A549 cells, and induced cell cycle disruption in the G0/G1 phase, accompanied by an increment of apoptotic cells. Furthermore, AMP induced the disruption of mitochondrial membrane potential, thus leading to cytochrome c release from mitochondria and activation of caspase-3 and -9. Taken together, our results demonstrate that AMP possesses strong antitumor activities through the mitochondria dependent pathway and activation of caspase cascade through cytochrome c release. © 2012 Elsevier B.V.


Meng F.,Harbin Medical University | Luo C.,Harbin Medical University | Ma L.,Hulunbuir People Hospital | Hu Y.,Red Cross | Lou G.,Harbin Medical University
International Journal of Gynecological Pathology | Year: 2011

Summary: Astrocyte elevated gene-1 (AEG-1) plays an important role in tumor progression including transformation, evasion of apoptosis, invasion, metastasis, and chemoresistance. However, the expression of AEG-1 in ovarian carcinoma and its significance are still unclear. The aim of this study was to examine the expression of AEG-1 in ovarian carcinoma. Immunohistochemistry was performed to determine the expression of AEG-1 in 81 ovarian carcinoma specimens. The correlation of AEG-1 expression with clinicopathological parameters was assessed using χ analysis. Patient survival was analyzed using the Kaplan-Meier and log-rank tests. Cox regression was used for the multivariate analysis of prognostic factors. High expression of AEG-1 was detected in 66.67% of the ovarian carcinomas and was significantly associated with the International Federation of Gynecology and Obstetrics stage, histological grade, presence of residual tumor after primary surgery, and tumor recurrence. Patients with high AEG-1 expression had significantly poorer overall survival and disease-free survival (both P<0.001) when compared with patients with low expression of AEG-1. The multivariate Cox analysis showed that AEG-1 was an independent factor for both overall survival and disease-free survival (both P<0.001). These results showed that high AEG-1 expression was associated with progression and prognosis of ovarian carcinoma. © 2011 International Society of Gynecological Pathologists.


He Y.,Harbin Medical University | He Y.,National Research Council Canada | Li Y.,Harbin Medical University | Zhao T.,National Research Council Canada | And 4 more authors.
PLoS ONE | Year: 2013

Background:Ursolic acid (UA) is a triterpenoid compound with multiple biological functions. This compound has recently been reported to possess an anti-obesity effect; however, the mechanisms are less understood.Objective:As adipogenesis plays a critical role in obesity, the present study was conducted to investigate the effect of UA on adipogenesis and mechanisms of action in 3T3-L1 preadipocytes.Methods and Results:The 3T3-L1 preadipocytes were induced to differentiate in the presence or absence of UA for 6 days. The cells were determined for proliferation, differentiation, fat accumulation as well as the protein expressions of molecular targets that regulate or are involved in fatty acid synthesis and oxidation. The results demonstrated that ursolic acid at concentrations ranging from 2.5 μM to 10 μM dose-dependently attenuated adipogenesis, accompanied by reduced protein expression of CCAAT element binding protein β (C/EBPβ), peroxisome proliferator-activated receptor γ (PPARγ), CCAAT element binding protein α (C/EBPα) and sterol regulatory element binding protein 1c (SREBP-1c), respectively. Ursolic acid increased the phosphorylation of acetyl-CoA carboxylase (ACC) and protein expression of carnitine palmitoyltransferase 1 (CPT1), but decreased protein expression of fatty acid synthase (FAS) and fatty acid-binding protein 4 (FABP4). Ursolic acid increased the phosphorylation of AMP-activated protein kinase (AMPK) and protein expression of (silent mating type information regulation 2, homolog) 1 (Sirt1). Further studies demonstrated that the anti-adipogenic effect of UA was reversed by the AMPK siRNA, but not by the Sirt1 inhibitor nicotinamide. Liver kinase B1 (LKB1), the upstream kinase of AMPK, was upregulated by UA. When LKB1 was silenced with siRNA or the inhibitor radicicol, the effect of UA on AMPK activation was diminished.Conclusions:Ursolic acid inhibited 3T3-L1 preadipocyte differentiation and adipogenesis through the LKB1/AMPK pathway. There is potential to develop UA into a therapeutic agent for the prevention or treatment of obesity. © 2013 He et al.


Ma H.-P.,Jining No 1 Peoples Hospital | Li W.,Jining No 1 Peoples Hospital | Liu X.-M.,Harbin Medical University
Experimental and Therapeutic Medicine | Year: 2014

Previous studies have revealed the role of matrix metalloproteinase 9 (MMP9) in asthma and chronic obstructive pulmonary disease (COPD). However, its role in airway inflammation in cough variant asthma (CVA) remains unknown. In the present study, variations in the levels of MMP9 and interleukin (IL)-5 in the induced sputum of patients with CVA prior to and following therapy with inhaled corticosteroid and long-acting β2-agonist (ICS/LABA), were detected. The levels of IL-5 and percentage of eosinophils (EOS) in the induced sputum from patients with CVA were significantly higher than those in the control group of healthy individuals. The levels of MMP9 in the induced sputum from patients with CVA were also significantly higher than those in the control group. Following treatment with ICS/LABA for 6-9 months, the levels of MMP9 and IL-5, as well as the percentage of EOS, in the induced sputum from patients with CVA had significantly decreased. Thus, MMP9 may be an important biomarker in the airway inflammation of CVA.


Li Y.-H.,University of Electronic Science and Technology of China | Li Y.-H.,China National Institute of Biological Sciences | Dong M.-Q.,China National Institute of Biological Sciences | Guo Z.,University of Electronic Science and Technology of China | Guo Z.,Harbin Medical University
Mechanisms of Ageing and Development | Year: 2010

An important task of aging research is to find genes that regulate lifespan. However, identification of genes related to longevity (referred to as longevity genes hereafter) through web-lab experiments such as genetic screens is a tedious and labor-intensive activity. Developing an algorithm to predict longevity genes should facilitate aging research. In this paper, we systematically analyzed properties of longevity genes in Caenorhabditis elegans and found that, when compared to genes not yet known to be involved in longevity, known longevity genes display the following features: (i) longer genomic sequences and protein sequences, (ii) a stronger tendency to co-express with other genes during a transition from dauer state (an extremely long lifespan) to non-dauer state (a normal lifespan), (iii) significant enrichment in certain functions and RNAi phenotypes, (iv) higher sequence conservation, and (v) higher in several network topological features such as degrees in a functional interaction network. Based on these features, we developed an algorithm to predict longevity genes in C. elegans and obtained 243 novel longevity genes with a precision rate of 0.85. Some of the predicted genes have been validated by published articles or wet lab experiments. The contribution of each feature to the predicted results was also evaluated. © 2010 Elsevier Ireland Ltd.


Li B.,Harvard University | Li B.,Harbin Medical University | Castano A.P.,Harvard University | Hudson T.E.,Harvard University | And 5 more authors.
FASEB Journal | Year: 2010

Kidney damage due to injury rarely resolves completely, and there are currently no therapies capable of promoting repair. In addition to understanding mechanisms by which tissues are damaged, illuminating mechanisms of repair and regeneration is also of great importance. Here we show that the melanoma-associated, transmembrane glycoprotein, Gpnmb, is up-regulated 15-fold following ischemic damage in kidney tissue and by more than 10-fold in macrophages and 3-fold in surviving epithelial cells. Gpnmb-expressing macrophages and epithelial cells were found to contain apoptotic bodies at 3 times the rate of nonexpressing cells. Either mutation of Gpnmb or ablation of inflammatory macrophages prevents normal repair of the kidney. Significantly, the kidneys from postischemic Gpnmb mutant mice exhibited a 5-fold increase in apoptotic cellular debris compared to wild-type mice. These mice also experienced an 85% increase in mortality following bilateral ischemic kidney. Finally, we demonstrate that Gpnmb is a phagocytic protein that is necessary for recruitment of the autophagy protein LC3 to the phagosome where these proteins are colocalized and for lysosomal fusion with the phagosome and hence bulk degradation of their content. Therefore, Gpnmb is a novel prorepair gene that is necessary for crosstalk between the macroautophagic degradation pathway and phagocytosis. © FASEB.


Sun C.,Harbin Medical University | Sun C.,Skåne University Hospital | Ansari D.,Harbin Medical University | Ansari D.,Skåne University Hospital | And 3 more authors.
World Journal of Gastroenterology | Year: 2012

AIM: To assess whether gemcitabine-based combination therapy improves the prognosis of unresectable pancreatic cancer compared with gemcitabine treatment alone. METHODS: A quantitative up-to-date meta-analysis was undertaken to investigate the efficacy of gemcitabine- based combination treatment compared with gemcitabine monotherapy in locally advanced or metastatic pancreatic cancer. Inclusion was limited to highquality randomized clinical trials. RESULTS: Twenty-six studies were included in the present analysis, with a total of 8808 patients recruited. The studies were divided into four subgroups based on the different kinds of cytotoxic agents, including platinum, fluoropyrimidine, camptothecin and targeted agents. Patients treated with gemcitabine monotherapy had significantly lower objective response rate [risk ratio (RR), 0.72; 95% confidence interval (CI): 0.63-0.83; P < 0.001], and lower 1-year overall survival (RR, 0.90; 95%CI: 0.82-0.99; P = 0.04). Gemcitabine monotherapy caused fewer complications, including fewer grade 3-4 toxicities: including vomiting (RR, 0.75; 95%CI: 0.62-0.89; P = 0.001), diarrhea (RR, 0.66; 95%CI: 0.49-0.89; P = 0.006), neutropenia (RR, 0.88; 95%CI: 0.72-1.06; P = 0.18), anemia (RR, 0.96; 95%CI: 0.82-1.12; P = 0.60), and thrombocytopenia (RR, 0.76; 95%CI: 0.60-0.97; P = 0.03) compared with gemcitabine combination therapies. CONCLUSION: Gemcitabine combination therapy provides a modest improvement of survival, but is associated with more toxicity compared with gemcitabine monotherapy. © 2012 Baishideng.


Wang Z.,University of Illinois at Chicago | Wang Z.,Harbin Medical University | Dou X.,University of Illinois at Chicago | Dou X.,Zhejiang Chinese Medical University | And 5 more authors.
Hepatology | Year: 2014

Chronic alcohol consumption leads to hypertriglyceridemia, which is positively associated with alcoholic liver disease (ALD). However, whether and how it contributes to the development of fatty liver and liver injury are largely unknown. In this study we demonstrate that chronic alcohol exposure differently regulates the expression of very-low-density lipoprotein receptor (VLDLR) in adipose tissue and the liver. Whereas adipose tissue VLDLR is significantly down-regulated, its hepatic expression is dramatically increased after chronic alcohol feeding. While HepG2 cells stably overexpressing VLDLR manifests increased intracellular triglyceride accumulation, VLDLR-deficient mice are protective against fatty liver and liver injury after chronic alcohol exposure. Mechanistic investigations using both in vitro and in vivo systems reveal that oxidative stress-induced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation plays a critical role in alcohol-induced VLDLR up-regulation in hepatocytes, but not in adipocytes. Oxidative stress enhances VLDLR gene expression and protein abundance in primary hepatocytes, concomitant with the Nrf2 activation. Conversely, Nrf2 gene silencing abrogates oxidative stress-induced VLDLR up-regulation in the liver, but not in adipose tissue. In mice, alcohol exposure induces hepatic oxidative stress and Nrf2 activation. Supplementation of N-acetylcysteine alleviates fatty liver and liver injury induced by chronic alcohol exposure, which is associated with suppressed Nrf2 activation and attenuated VLDLR increase in the liver. Furthermore, in comparison to wild-type counterparts, Nrf2-deficient mice demonstrate attenuated hepatic VLDLR expression increase in response to chronic alcohol exposure. Conclusion: Chronic alcohol consumption differently alters VLDLR expression in adipose tissue and the liver. Oxidative stress-induced Nrf2 activation is mechanistically involved in VLDLR overexpression in hepatocytes in response to chronic alcohol consumption. Hepatic VLDLR overexpression plays an important role in the pathogenesis of ALD. © 2014 by the American Association for the Study of Liver Diseases.


Tao P.,Harbin Medical University | Tao P.,Curtin University Australia | Brody S.,University of West of Scotland
Journal of Sexual Medicine | Year: 2011

Introduction. Previous multivariate research in Europe found that sexual satisfaction was associated directly with frequency of penile-vaginal intercourse (PVI) but inversely with masturbation and some aspects of non-PVI partnered sex. Aims. To examine the associations of sexual satisfaction in a sample from the People's Republic of China, including not only frequencies of various sexual behaviors, but also frequencies of orgasm. Methods. Chinese industrial workers (N=158, age over 24 years) completed the sexual satisfaction scale of the Multidimensional Sexuality Questionnaire (MSQ) and a short form of the Marlowe-Crowne social desirability scale, and provided details of the one month frequencies of engaging in, and having an orgasm from, PVI, masturbation, and non-PVI partnered sex. Main Outcome Measures. Multiple regression prediction of sexual satisfaction from age, social desirability responding, and in separate analyses, frequencies of the sexual behaviors or the corresponding orgasm frequencies. Results. For men and women, sexual satisfaction was associated with frequency of PVI and of PVI orgasm (the latter for women only), but not other sexual behavior or orgasm frequency. Similar results were obtained for the MSQ satisfaction scale and for a single satisfaction item. Conclusions. Despite cultural differences (and our smaller, less diverse sample), the positive prediction of satisfaction from only PVI (and in our sample of women, PVI orgasm) frequency-but not other sexual activities-was similar to that in a Swedish sample. Future research might also examine possible occasional avoidance of ejaculation by some Chinese men. © 2010 International Society for Sexual Medicine.


Shi W.,Georgia State University | Cui N.,Georgia State University | Wu Z.,Georgia State University | Yang Y.,Georgia State University | And 4 more authors.
Journal of Biological Chemistry | Year: 2010

Sepsis is a severe medical condition causing a large number of deaths worldwide. Recent studies indicate that the septic susceptibility is attributable to the vascular ATP-sensitive K+ (KATP) channel. However, the mechanisms underlying the channel modulation in sepsis are still unclear. Here we show evidence for the modulation of vascular K ATP channel by septic pathogen lipopolysaccharides (LPS). In isolated mesenteric arterial rings, phenylephrine (PE) produced concentration-dependent vasoconstriction that was relaxed by pinacidil, a selective KATP channel opener. The PE response was disrupted with a LPS treatment. In acutely dissociated aortic smooth myocytes the LPS treatment augmented KATP channel activity, and hyperpolarized the cells. Quantitative PCR analysis showed that LPS raised Kir6.1 and SUR2B transcripts in a concentration-dependent manner, which was suppressed by transcriptional inhibition. Consistently, the same LPS treatment did not affect Kir6.1/ SUR2B channels in a heterologous expression system. The LPS effect on Kir6.1 and SUR2B expression was abolished in the presence of NF-κB inhibitors. Several other Toll-like receptor ligands also stimulated Kir6.1 and SUR2B expression to a similar degree as LPS. Thus, the effect of LPS on vasodilation involves up-regulation of K ATP channel expression, in which the NF-κB-dependent signaling plays an important role. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Liu D.,Tongji University | Liu Q.-Q.,Harbin Medical University | Eyries M.,University Pierre and Marie Curie | Wu W.-H.,Tongji University | And 4 more authors.
European Respiratory Journal | Year: 2012

Mutations of the bone morphogenetic protein type II receptor (BMPR2) gene predispose to pulmonary arterial hypertension (PAH). 290 idiopathic (I)PAH patients and 15 heritable (H)PAH were screened to determine the spectrum and rate of BMPR2 mutations in a large Chinese patient group. Gene sequencing and multiplex ligation-dependent probe amplification (MLPA1) were used to detect sequence mutations and large rearrangements (RGTs). Total mutation rate was 14.5% (n=42 out of 290) in Chinese IPAH patients, and 53.3% (n=8 out of 15) in HPAH patients. RGT mutation rate was 3.1% (n=7 out of 229) and represented 14% (n=7 out of 50) of all identified mutations. 25 BMPR2 mutations were newly identified. Patients in this study were younger than other reported PAH subjects. BMPR2 mutation carriers were ∼6 yrs younger at diagnosis than noncarriers (p=0.002), but this relationship was significant only in the female group, which was larger. The proportion of females carrying a BMPR2 mutation was half that of males (12.8% versus 25.3%; p=0.008). Our results indicate that the overall genetics of Chinese PAH patients is similar to that of other populations, but the clinical picture differs by the precocity of the disease in the whole patient group, and the lower proportion of females found to carry a BMPR2 mutation. Copyright©ERS 2012.


Chen X.,Harbin Medical University | Meng Q.,Harbin Medical University | Zhao Y.,Harbin Medical University | Liu M.,Harbin Medical University | And 6 more authors.
Cancer Letters | Year: 2013

Angiotensin II type 1 receptor (AT1R) promotes tumor invasion, migration, metastasis and angiogenesis. We explored the potential antitumor effects of AT1R antagonists in breast cancer. We found that angiotensin II promoted cell proliferation and upregulated the expression of vascular endothelial growth factor A (VEGF-A) in MCF-7 cells. Losartan downregulated the expression of VEGF-A in MCF-7 cells treated with angiotensin II. Candesartan downregulated the expression of VEGF-A in mice bearing MCF-7 xenografts and inhibited tumor growth and angiogenesis. AT1R and VEGF-A expression correlated with increased microvascular density in 102 breast cancer patients. Our data suggest that AT1R antagonists might be useful to suppress breast cancer by inhibiting the angiotensin II. © 2012 Elsevier Ireland Ltd.


Hu S.,Harbin Medical University | Wang B.,National Research Institute for Family Planning | Qi Y.,Harbin Medical University | Lin H.,Harbin Medical University
PLoS ONE | Year: 2012

Calmodulin (CaM) directly interacts with the aquaporin 0 (AQP0) C-terminus in a calcium dependent manner to regulate the water permeability of AQP0. We previously identified a missense mutation (p.R233K) in the putative CaM binding domain of AQP0 C-terminus in a congenital cataract family. This study was aimed at exploring the potential pathogenesis of this mutation causative of cataract and mainly identifying how it influenced the binding of AQP0 to CaM. Wild type and R233K mutant AQP0 with EGFP-tag were transfected separately into Hela cells to determine the expression and subcellular localizations. The co-immunoprecipitation (CoIP) assay was used to detect the interaction between AQP0 and CaM. AQP0 C-terminus peptides were synthesized with and without R233K, and the binding abilities of these peptides to CaM were assessed using a fluorescence binding assay. Localizations of wild type and R233K mutant AQP0 were determined from EGFP fluorescence, and the chimeric proteins were both localized abundantly in the plasma membrane. Protein expression levels of the culture cells showed no significant difference between them. The results from CoIP assay implied that R233K mutant presented more weakly in association with CaM than wild type AQP0. The AQP0 C-terminal mutant peptide was found to have 2.5-fold lower binding affinity to CaM than wild type peptide. These results suggested that R233K mutation did not affect the expression, location and trafficking of the protein but did influence the interaction between AQP0 and CaM. The binding affinity of AQP0 C-terminus to CaM was significantly reduced. Due to lack of the modulation of the Ca2+-calmodulin complex, the water permeability of AQP0 was subsequently augmented, which might lead to the development of this cataract. © 2012 Hu et al.


Li J.,Harbin Medical University | Xia W.,Qingdao Municipal Hospital | Feng W.,Harbin Medical University | Qu X.,Harbin Medical University
PACE - Pacing and Clinical Electrophysiology | Year: 2012

Background: Circulating asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is increased in atrial fibrillation (AF). The purpose of this study was to investigate the effects of rosuvastatin on serum ADMA levels and atrial structural remodeling in AF dogs induced by chronic rapid atrial pacing. Methods: Twenty dogs were randomly divided into the sham-operated (n = 6), control (n = 7), or rosuvastatin (n = 7) groups. Sustained AF was induced by rapid pacing of the right atrium at 400 beats per minute for 6 weeks. Rosuvastatin was administered orally (1 mg/kg d) for 3 days before rapid pacing and was continued for 6 weeks. Transthoracic and transesophageal echocardiography were performed to detect left atrial structure and function. Serum levels of nitric oxide and ADMA were measured. Interstitial fibrosis and cardiomyocyte apoptosis in the atria were also identified. Results: After 6 weeks, compared with the control group, dramatic smaller left atrium and left atrial appendage volumes and higher atrial contractile function were observed in the rosuvastatin group. Serum nitric oxide concentration was increased, whereas ADMA was decreased in the rosuvastatin group compared with the control group. The percentages of interstitial fibrosis and atrial apoptosis in the control group were significantly higher than those in the sham-operated group, and rosuvastatin attenuated these changes induced by atrial rapid pacing. Conclusion: A short course of rosuvastatin treatment decreased apoptosis and prevented atrial structural remodeling in association with a decrease in ADMA levels in AF dogs. ©2012, The Authors. Journal compilation ©2012 Wiley Periodicals, Inc.


Liu H.,Stanford University | Liu S.,Stanford University | Miao Z.,Stanford University | Deng Z.,Wuhan University | And 3 more authors.
Journal of Medicinal Chemistry | Year: 2013

Melanoma is an aggressive skin cancer with worldwide increasing incidence. Development of positron emission tomography (PET) probes for early detection of melanoma is critical for improving the survival rate of melanoma patients. In this research, 18F-picolinamide-based PET probes were prepared by direct radiofluorination of the bromopicolinamide precursors using no-carrier-added 18F-fluoride. The resulting probes, 18F-1, 18F-2 and 18F-3, were then evaluated in vivo by small animal PET imaging and biodistribution studies in C57BL/6 mice bearing B16F10 murine melanoma tumors. Noninvasive small animal PET studies demonstrated excellent tumor imaging contrasts for all probes, while 18F-2 showed higher tumor to muscle ratios than 18F-1 and 18F-3. Furthermore, 18F-2 demonstrated good in vivo stability as evidenced by the low bone uptake in biodistribution studies. Collectively, these findings suggest 18F-2 as a highly promising PET probe for translation into clinical detection of melanoma. © 2013 American Chemical Society.


Li B.-Y.,Indiana University – Purdue University Indianapolis | Li B.-Y.,Harbin Medical University | Glazebrook P.,Case Western Reserve University | Kunze D.L.,Case Western Reserve University | Schild J.H.,Indiana University – Purdue University Indianapolis
American Journal of Physiology - Cell Physiology | Year: 2011

High conductance calcium-activated potassium (BKCa) channels can modulate cell excitability and neurotransmitter release at synaptic and afferent terminals. BKCa channels are present in primary afferents of most, if not, all internal organs and are an intriguing target for pharmacological manipulation of visceral sensation. Our laboratory has a long-standing interest in the neurophysiological differences between myelinated and unmyelinated visceral afferent function. Here, we seek to determine whether there is a differential distribution of BKCa channels in myelinated and unmyelinated vagal afferents. Immunocytochemistry studies with double staining for the BK-type KCa1.1 channel protein and isolectin B4 (IB4), a reliable marker of unmyelinated peripheral afferents, reveal a pattern of IB4 labeling that strongly correlates with the expression of the KCa1.1 channel protein. Measures of cell size and immunostaining intensity for KCa1.1 and IB4 cluster into two statistically distinct (P < 0.05) populations of cells. Smaller diameter neurons most often presented with strong IB4 labeling and are presumed to be unmyelinated (n = 1,390) vagal afferents. Larger diameter neurons most often lacked or exhibited a very weak IB4 labeling and are presumed to be myelinated (n = 58) vagal afferents. Complimentary electrophysiological studies reveal that the BKCa channel blockers charybdotoxin (ChTX) and iberiotoxin (IbTX) bring about a comparable elevation in excitability and action potential widening in unmyelinated neurons but had no effect on the excitability of myelinated vagal afferents. This study is the first to demonstrate using combined immunohistochemical and electrophysiological techniques that KCa1.1 channels are uniquely expressed in unmyelinated C-type vagal afferents and do not contribute to the dynamic discharge characteristics of myelinated A-type vagal afferents. This unique functional distribution of BK-type KCa channels may provide an opportunity for afferent selective pharmacological intervention across a wide range of visceral pathophysiologies, particularly those with a reflexogenic etiology and pain. © 2011 the American Physiological Society.


Zan L.,Shanxi Cancer Hospital | Zhang X.,Shanxi Cancer Hospital | Xi Y.,Shanxi Cancer Hospital | Wu H.,Harbin Medical University | And 5 more authors.
Neuroscience | Year: 2014

Developing new strategies to treat cerebral ischemic-reperfusion injury will require a better understanding of the mechanisms that underlie vascular permeability. In this study we examined the temporal expression of Src and angiogenic factors in rat brain after focal cerebral ischemia and reperfusion and analyzed the relationships among those factors. We also investigated the effect of Src inhibitor PP1 (4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) in ischemic reperfusion. Rats were subjected to middle cerebral artery occlusion for 90. min followed by reperfusion with or without PP1 treatment. Src mRNA increased at 3. h after reperfusion and then gradually declined. Phosphorylation of Src at Y418 displayed a biphasic increase. Phosphorylation increased as early as 3. h and peaked at 6. h; after decreasing, it peaked again at 3-7. days. Increases in Src mRNA and phosphorylation correlated positively with levels of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), and negatively with levels of angiopoietin-1 (Ang-1) and zonula occludens-1 (ZO-1). Changes in the expression of these factors correlated with the progress of vascular permeability, especially early after reperfusion. Hence, dynamic temporal changes in Src Y418 phosphorylation may modulate vascular permeability after cerebral ischemia and reperfusion. PP1 effectively decreased Src Y418 phosphorylation and the expression of VEGF and Ang-2 and increased the expression of Ang-1 and ZO-1. It also reduced cerebral infarct size and neurologic dysfunction. Therefore, Src may represent a new therapeutic target for reducing tissue damage caused by increased vascular permeability. © 2014 IBRO.


Matta B.M.,University of Pittsburgh | Lott J.M.,University of Pittsburgh | Mathews L.R.,University of Pittsburgh | Liu Q.,University of Pittsburgh | And 4 more authors.
Journal of Immunology | Year: 2014

IL-33 is a recently characterized IL-1 family member that is proposed to function as an alarmin, or endogenous signal of cellular damage, as well as act as a pleiotropic cytokine. The ability of IL-33 to potentiate both Th1 and Th2 immunity supports its role in pathogen clearance and disease immunopathology. Yet, IL-33 restrains experimental colitis and transplant rejection by expanding regulatory T cells (Treg) via an undefined mechanism. We sought to determine the influence of IL-33 on hematopoietic cells that drives Treg expansion and underlies the therapeutic benefit of IL-33 administration. In this study, we identify a feedback loop in which conventional mouse CD11c+ dendritic cells (DC) stimulated by IL-33 secrete IL-2 to selectively expand IL-33R(ST2+)-suppressive CD4+Foxp3+ Treg. Interestingly, this occurs in the absence of classical DC maturation, and DC-derived (innate) IL-2 increases ST2 expression on both DC and interacting Treg. ST2+ Treg represent an activated subset of Foxp3+ cells, demonstrated to be ICOShighCD44high compared with their ST2- counterparts. Furthermore, although studies have shown that IL-33-exposed DC promote Th2 responses, we reveal that ST2+ DC are required for IL-33-mediated in vitro and in vivo Treg expansion. Thus, we have uncovered a relationship between IL-33 and innate IL-2 that promotes the selective expansion of ST2+ Treg over non-Treg. These findings identify a novel regulatory pathway driven by IL-33 in immune cells that may be harnessed for therapeutic benefit or for robust expansion of Treg in vitro and in vivo. Copyright © 2014 by The American Association of Immunologists, Inc.


Yu Z.,Harbin Medical University | Zhang B.,University of Minnesota | Cui B.,Harbin Medical University | Wang Y.,Harbin Medical University | And 2 more authors.
Cancer | Year: 2012

Background: The human double minute 2 (hdm2) oncogene is a negative regulator of the p53 gene. Expression and alternative splicing of the hdm2 gene may contribute to colorectal cancer development or progression. This study aimed to determine the presence and identification of aberrant mRNA transcripts of hdm2 in colorectal cancer tissues and cell lines, and determine the nature of their association with clinicopathological characteristics and survival of patients. Methods: A total of 69 colorectal cancer and corresponding normal tissue specimens and 10 colon cancer cell lines were recruited for polymerase chain reaction and DNA sequencing analyses of hdm2 mRNA. Genomic DNA from these tissues and cells was also extracted for p53 gene mutation analysis. The association of hdm2 fragmented transcripts and p53 gene mutation with clinicopathological data was then statistically analyzed. Results: In 62 cases (89.9%; 62 of 69) of colorectal cancer tissues the full-length hdm2 was amplified, whereas 7 cases had no hdm2 transcripts. Thirty-two of 62 cases (51.6%) and 6 of 10 cell lines (60%) showed at least 1 hdm2 spliced variant. A total of 4 hdm2 splicing variants were found in colorectal cancer tissues and cells, that is, lack of nucleotides between 157 and 292 bp in hdm2/1338, 81 to 901 bp in hdm2/707, 157 to 292, 407 to 505, and 668 to 901 bp in hdm2/1007, and 610 to 883 in hdm2/1200. Of these, hdm2/1338 is a novel hdm2 variant in colorectal cancer. Mutation in p53 was detected in 21 cases (33.8%; 21 of 62). Although there was no association found between expression of hdm2 splicing variants and p53 gene mutations, expression of hdm2 splicing variants was associated with advanced tumor stage (P =.022) and distant metastasis (P =.004) in wild-type p53 cases, and with poor survival of patients (P =.039). Conclusions: The data from the current study provide the first evidence that hdm2 mRNA is frequently mutated by alternative splicing in colorectal cancer, and may play a role in colorectal tumorigenesis or cancer progression. © 2011 American Cancer Society.


Kanwar J.R.,Deakin University | Sun X.,Harbin Medical University | Sun X.,University of Auckland | Punj V.,University of Southern California | And 5 more authors.
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2012

The incidence of neurological diseases of unknown etiology is increasing, including well-studied diseases such as Alzhiemer's, Parkinson's, and multiple sclerosis. The blood-brain barrier provides protection for the brain but also hinders the treatment and diagnosis of these neurological diseases, because the drugs must cross the blood-brain barrier to reach the lesions. Thus, attention has turned to developing novel and effective delivery systems that are capable of carrying drug and that provide good bioavailability in the brain. Nanoneurotechnology, particularly application of nanoparticles in drug delivery, has provided promising answers to some of these issues in recent years. Here we review the recent advances in the understanding of several common forms of neurological diseases and particularly the applications of nanoparticles to treat and diagnose them. In addition, we discuss the integration of bioinformatics and modern genomic approaches in the development of nanoparticles. From the Clinical Editor: In this review paper, applications of nanotechnology-based diagnostic methods and therapeutic modalities are discussed addressing a variety of neurological disorders, with special attention to blood-brain barrier delivery methods. These novel nanomedicine approaches are expected to revolutionize several aspects of clinical neurology. © 2012 Elsevier Inc.


Ma R.,Louisiana State University Health Sciences Center | Ma R.,Harbin Medical University | Gu Y.,Louisiana State University Health Sciences Center | Zhao S.,Louisiana State University Health Sciences Center | And 3 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2012

Vitamin D insufficiency/deficiency during pregnancy has been linked to increased risk of preeclampsia. Placenta dysfunction plays an important role in the pathogenesis of this pregnancy disorder. In this study, we tested the hypothesis that disturbed vitamin D metabolism takes place in preeclamptic placentas. Protein expressions of vitamin D binding protein (VDBP), 25-hydroxylase (CYP2R1), 1 α -hydroxylase (CYP27B1), 24-hydroxylase (CYP24A1), and vitamin D receptor (VDR) were examined in placentas from normotensive and preeclamptic pregnancies. By immunostaining we found that in normal placenta VDBP, CYP24A1, and VDR expressions are localized mainly in trophoblasts, whereas CYP2R1 and CYP27B1 expressions are localized mainly in villous core fetal vessel endothelium. Protein expressions of CYP2R1 and VDR are reduced, but CYP27B1 and CYP24A1 expressions are elevated, in preeclamptic compared with normotensive placentas. Because increased oxidative stress is an underlying pathophysiology in placental trophoblasts in preeclampsia, we further determined whether oxidative stress contributes to altered vitamin D metabolic system in placental trophoblasts. Trophoblasts isolated from normal-term placentas were treated with hypoxic-inducing agent CoCl2, and protein expressions of VDBP, CYP2R1, CYP27B1, CYP24A1, and VDR were determined. We found that hypoxia-induced downregulation of VDBP, CYP2R1, and VDR and upregulation of CYP27B1 and CYP24A1 expressions were consistent with that seen in preeclamptic placentas. CuZnSOD expression was also downregulated in trophoblasts treated with CoCl2. These results provide direct evidence of disrupted vitamin D metabolic homeostasis in the preeclamptic placenta and suggest that increased oxidative stress could be a causative factor of altered vitamin D metabolism in preeclamptic placentas. © 2012 the American Physiological Society.


Fan Y.-H.,Baylor College of Medicine | Yu Y.,Baylor College of Medicine | Mao R.-F.,Baylor College of Medicine | Tan X.-J.,Baylor College of Medicine | And 6 more authors.
Cell Death and Differentiation | Year: 2011

Lys63-linked polyubiquitination of transforming growth factor-Β- activated kinase 1 (TAK1) has an important role in tumor necrosis factor-α (TNFα)-induced NF-κB activation. Using a functional genomic approach, we have identified ubiquitin-specific peptidase 4 (USP4) as a deubiquitinase for TAK1. USP4 deubiquitinates TAK1 in vitro and in vivo. TNFα induces association of USP4 with TAK1 to deubiquitinate TAK1 and downregulate TAK1-mediated NF-κB activation. Overexpression of USP4 wild type, but not deuibiquitinase-deficient C311A mutant, inhibits both TNFα-and TAK1/TAB1 co-overexpression-induced TAK1 polyubiquitination and NF-κB activation. Notably, knockdown of USP4 in HeLa cells enhances TNFα-induced TAK1 polyubiquitination, IB kinase phosphorylation, IBα phosphorylation and ubiquitination, as well as NF-κB-dependent gene expression. Moreover, USP4 negatively regulates IL-1Β-, LPS-and TGFΒ-induced NF-κB activation. Together, our results demonstrate that USP4 serves as a critical control to downregulate TNFα-induced NF-κB activation through deubiquitinating TAK1. © 2011 Macmillan Publishers Limited All rights reserved.


Gu Y.,Louisiana State University Health Sciences Center | Sun J.,Harbin Medical University | Groome L.J.,Louisiana State University Health Sciences Center | Wang Y.,Louisiana State University Health Sciences Center
American Journal of Physiology - Endocrinology and Metabolism | Year: 2013

To determine placental microRNA (miRNA) expression at different gestational age, total RNA from six first and six third trimester placentas was isolated. miRNA expression was analyzed by Affymetrix miRNA microarray, and miRNA clusters were identified by web-based programs MirClust and miRGen Cluster. qRT-PCR was carried out to validate miRNA expression, and in situ hybridization (ISH) was performed to determine compartmental localization of miRNAs within villous tissue. A total of 208 miRNA transcripts, which represent 191 mature miRNAs, were found differently expressed between first and third trimester placentas. miRNAs within the miR-17-92 cluster, C14MC, miR-371 cluster, and C19MC were significantly upregulated in the first trimester placentas. In contrast, miRNAs of the let-7 family, miR-34 family, miR-29a cluster, miR-195 cluster, and miR-181c cluster were significantly upregulated in the third trimester placentas. Increased miR- 371-5p, miR-17-3p, and miR-708-5p expression and decreased miR- 125b-5p and miR-139-5p expression in the first trimester placentas were confirmed by qRT-PCR. Different expression pattern for miR- 371-5p and miR-125b-5p within villous tissue was demonstrated by ISH. Distinct miRNA cluster expression profiles between the first and third trimester placentas were identified. miRNAs that regulate innate/ adaptive immune responses are strongly expressed in both first and third trimester placentas. miRNAs that exert oncogenic, angiogenic, and antiapoptotic properties are dominantly expressed in the first trimester placentas, whereas miRNAs that promote cell differentiation and function as tumor suppressors are strongly expressed in the third trimester placentas. These results indicate that miRNAs play critical roles in placental development. © 2013 the American Physiological Society.


Kim T.H.,Guangxi Medical University | Kim J.s.,Harbin Medical University | Kim Z.h.,Nagoya University | Huang R.B.,Guangxi Medical University | Wang R.S.,Guangxi Medical University
PLoS ONE | Year: 2012

Khz is a compound derived from the fusion of Ganoderma lucidum and Polyporus umbellatus mycelia that inhibits the growth of cancer cells. The results of the present study show that Khz induced apoptosis preferentially in transformed cells and had only minimal effects on non-transformed cells. Furthermore, Khz induced apoptosis by increasing the intracellular Ca2+ concentration ([Ca2+]i) and activating JNK to generate reactive oxygen species (ROS) via NADPH oxidase and the mitochondria. Khz-induced apoptosis was caspase-dependent and occurred via a mitochondrial pathway. ROS generation by NADPH oxidase was critical for Khz-induced apoptosis, and although mitochondrial ROS production was also required, it appeared to occur secondary to ROS generation by NADPH oxidase. Activation of NADPH oxidase was demonstrated by the translocation of regulatory subunits p47phox and p67phox to the cell membrane and was necessary for ROS generation by Khz. Khz triggered a rapid and sustained increase in [Ca2+]i, which activated JNK. JNK plays a key role in the activation of NADPH oxidase because inhibition of its expression or activity abrogated membrane translocation of the p47phox and p67phox subunits and ROS generation. In summary, these data indicate that Khz preferentially induces apoptosis in cancer cells, and the signaling mechanisms involve an increase in [Ca2+]i, JNK activation, and ROS generation via NADPH oxidase and mitochondria. © 2012 Kim et al.


Li M.,Harbin Medical University | Deng H.,Wuhan University | Peng H.,Harbin Medical University | Peng H.,Iowa State University | Wang Q.,Iowa State University
Journal of Nanoscience and Nanotechnology | Year: 2014

Successful therapy and diagnosis of glioma is one of the biggest challenges in the biomedical fields. The incidence is growing gradually around the world. Annually, there are approximately 13,000 cases of glioblastoma multiforme diagnosed with historical 1-year and 5-year survival rates of 29.3% and 3.3%, respectively. The prognosis of patients with malignant glioma remains dismal. Due to its highly proliferative, infiltrative, and invasive property, development of effective preventative strategies to control the gliomas is in high demand. Meanwhile, the efficiency of drug delivery to glioma remains low owing to the non-specific, non-targeted nature of anti-tumor agents. Furthermore, the presence of the blood brain barrier and blood brain tumor barrier is another obstacle for gliomas treatments. Nanotechnology has brought a paradigm shift in the diagnosis and treatment of glioma. This review discusses the potential of various nanoparticles in the diagnosis of gliomas using some metal oxide, and in the therapy of gliomas including receptor-mediated, magnetic directing, and cell-mediated drug delivery systems. In this review, some physical techniques combined with nanoparticles (NPs) such as ultrasound therapy, thermochemotherapy, photodynamic therapy, and fluorescent magnetic NPs have also been summarized. Copyright © 2014 American Scientific Publishers All rights reserved.


Huang L.,Harbin Medical University | Yuan K.,Harbin Medical University | Liu J.,Harbin Medical University | Ren X.,Harbin Medical University | And 3 more authors.
Gene | Year: 2014

Objective: Toll-like receptor 4 (TLR4) is an important lipo-polysaccharide (LPS) receptor in gastric epithelial cell signaling transduction and plays critical roles in the development and progression of gastric cancer (GC). We investigated the effects of TLR4 gene polymorphisms and gene-environmental interactions on the risk of GC in Northeastern China. Methods: We genotyped two single-nucleotide polymorphisms (SNPs) in TLR4 (rs10116253 and rs1927911) in 217 GC patients and 294 cancer-free controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Odds ratio (OR) and 95% confidence intervals (CIs) were estimated by unconditional logistic-regression models. Results: Individuals carrying CC genotype of rs10116253 and TT genotype of rs1927911 had a significantly decreased risk of GC (adjusted OR. = 0.33, 95% CI 0.18-0.60, P<. 0.001 and adjusted OR. = 0.37, 95% CI 0.21-0.67, P= 0.001 respectively), compared with TT genotype of rs10116253 and CC genotype of rs1927911. In addition, the SNP effects were additive to the effects of some known environmental factors without any interaction between them in the susceptibility to GC. Conclusion: Our data suggested that TLR4 gene polymorphisms may be associated with a decreased risk of GC in Chinese population. And these SNPs and their combined effects with environmental factors may be associated with the risk of GC. © 2013 Elsevier B.V.


Meng S.,Harbin Medical University | Su Z.,Harbin Medical University | Liu Z.,Harbin Medical University | Wang N.,The Fourth Hospital of Harbin | Wang Z.,PLA Fourth Military Medical University
Neuroscience | Year: 2015

Background: Cerebral ischemia-reperfusion (IR) injury is a complex pathological process that can cause irreversible brain damage, neuronal injury or death from brain ischemia. Rac1 GTPase is involved in cellular protection from IR injury. However, the mechanism of protection and the molecules affected by Rac1 remain to be defined. Methods and results: C57BL/6 mice were subjected to middle cerebral artery occlusion for 1. h, followed by 24-h reperfusion. In this in vivo model of cerebral IR injury, mice treated with the Rac GTPase inhibitor NSC23766 or Rac1 small interfering RNA (siRNA) had better short-term (72. h) neurologic scores, less infarction volume, higher production of antioxidant enzymes, lower lipid peroxide, and reduced apoptosis compared with a vehicle-treated group or a control-siRNA group. However, long-term (14. day) neurologic scores were worse for the two treatments compared to controls. Microarray and quantitative polymerase chain reaction (PCR) revealed that Notch2 was downregulated under NSC23766 treatment. Notch2 protein levels decreased with NSC23766 and Rac1 siRNA in vitro and in vivo. Cell survival increased with the Notch signaling inhibitor DAPT or Notch2 siRNA and NICD2 attenuated the NSC23766 effect. In addition, immunoblotting showed that DAPT and Notch2 siRNA changed the levels of apoptosis-regulating proteins. NFkB mediated Rac1, which regulated Notch2 in an oxygen glucose deprivation model. Both inhibitors of Notch2 and Rac1 enhanced neural stem cell differentiation. Conclusions: This study demonstrated the importance of Rac1 regulation of Notch2 in mediating cerebral IR-induced production of injurious reactive oxygen species and cell death in vitro and in vivo in the short term. Targeted inhibition of Rac1 or Notch2 is new avenue for in vivo therapy aimed at protecting organs at risk from IR injury. © 2015.


Sun J.,Louisiana State University Health Sciences Center | Sun J.,Harbin Medical University | Zhong W.,Louisiana State University Health Sciences Center | Zhong W.,Harbin Medical University | And 3 more authors.
Placenta | Year: 2014

In this study, we determined if vitamin D could inhibit oxidative stress-induced thromboxane production by placental trophoblasts. Trophoblast isolated from normal placentas were stimulated with CoCl2, a hypoxic mimicking agent, with or without pretreatment of 1,25(OH)2D 3. Soluble phospholipase-A2, metabolites of thromboxane-A2 and prostacyclin, and 8-isoprostane were measured. Expression of cyclooxygenase-1 (COX-1), COX-2, and heme oxygenase-1 (HO-1) were determined. We found that pretreatment of trophoblasts with 1,25(OH) 2D3 significantly reduced 8-isoprostane and the ratio of thromboxane-A2 to prostacyclin production, and blocked COX-2 expression induced by CoCl2. These results provide evidence of the beneficial effects of vitamin D on placental trophoblasts. © 2013 Elsevier Ltd. All rights reserved.


Zhou Z.,Harbin Medical University | Wang B.,National Research Institute for Family Planning | Hu S.,Harbin Medical University | Zhang C.,Harbin Medical University | And 2 more authors.
Molecular Vision | Year: 2011

Purpose: To investigate the role of genetic variations in three known cataract-associated genes, gap junction protein α3 (GJA3), gap junction protein α8 (GJA8), lens intrinsic membrane protein 2 (LIM2), encoding lens fiber cell membrane proteins in the development of age-related cataracts. Methods: One hundred and forty-five sporadic age-related cataract patients and one hundred and fifty-six unrelated random healthy controls participated in this study. Genomic DNA was extracted from peripheral blood leukocytes. All exons of GJA3, GJA8, and LIM2 were sequenced after being amplified by polymerase chain reaction (PCR). The functional consequences of the mutations were analyzed using PolyPhen. Results: We found five novel variations in 145 patients and none of them presented in the 156 controls. There are two variations in GJA3 (c.-39C>G, c. 415G>A); one in GJA8 (c. 823G>A), and two in LIM2 (c.57G>A, c.67A>C). PolyPhen predicted that the LIM2 c.67A>C mutation may have potential pathogenicity. Conclusions: The genetic mutation in GJA3, GJA8, and LIM2 may slightly contribute to the development of age-related cataracts. This study showed a potential relationship between lens fiber cell membrane protein genes and the development of age-related cataracts in the Chinese population. © 2011 Molecular Vision.


Ma R.,Harbin Medical University | Ma R.,Louisiana State University Health Sciences Center | Gu Y.,Louisiana State University Health Sciences Center | Groome L.J.,Louisiana State University Health Sciences Center | Wang Y.,Louisiana State University Health Sciences Center
Placenta | Year: 2011

Increased trophoblast TNFα production is an important component of placental dysfunction in preeclampsia. However, the mechanism of increased TNFα production in the preeclamptic placenta is largely unknown. ADAM17 is a metallopeptidase that functions as a TNFα converting enzyme. In this study, we examined ADAM17 expression in placentas from normal and preeclamptic pregnancies and found increased ADAM17 expression in preeclamptic placentas compared to those from normal placentas, p < 0.05. Since hypoxia/oxidative stress is an underlying pathophysiology in the preeclamptic placenta, we further determined if hypoxia/oxidative stress could modulate ADAM17 expression and subsequently induce TNFα production in placental trophoblasts. Trophoblasts were isolated from normal term placentas and treated with cobalt (II) chloride (CoCl 2), a hypoxia mimetic agent, at different concentrations. Our results showed that CoCl 2induced a dose-dependent increase in TNFα production that is associated with enhanced ADAM17 expression. Trophoblast expressions of HO-1 (a sensor of cellular oxidative stress) and caspase-3 (an indicator of apoptosis) in response to CoCl 2stimulation were also examined. We further found that metallopeptidase inhibitor GM6001 and ADAM17 siRNA could block CoCl 2induced TNFα production, demonstrating the role of ADAM17 in TNFα production in placental trophoblasts. These results suggest that oxidative stress-induced increased ADAM17 expression could contribute to the increased TNFα production in preeclamptic placentas. © 2011 Elsevier Ltd. All rights reserved.


Chen H.,Harbin Medical University | Yu Y.,Shenyang University | Rong S.,Harbin Maternal and Child Health Care Hospital | Wang H.,Shenyang University
Biomarkers | Year: 2014

Background: An increasing number of methylated genes have been reported as biomarkers for the diagnosis of bladder cancer. However, the results have been inconsistent. We performed a systematic review and meta-analysis to evaluate the feasibility and accuracy of using methylated genes as diagnostic markers for bladder cancer risk. Methods: Studies were systemically searched via the PubMed, ProQuest Health & Medical Complete and Springer Link database up to September 2013. Studies reporting the sensitivity and specificity of methylated biomarkers were extracted and the diagnostic accuracies were assessed by pooled diagnostic odds ratios (DORs) with 95% confidence intervals (CIs). Results: Methylated biomarkers showed accuracy for detecting bladder cancer (urine samples: DOR=36.48, 95% CI=7.12-186.81; tissue samples: DOR=68.71, 95% CI=36.52-129.29). Summary receiver operating characteristic analysis showed that markers in urine had better diagnostic power than those in tissues (area under the curve: 0.89 versus 0.75). Conclusion: The results of this study suggest that methylated biomarkers are suitable for diagnosing cancer risk. © 2014 Informa UK Ltd. All rights reserved: reproduction in whole or part not permitted.


Yang G.,Lakehead University | Li H.,Lakehead University | Li H.,Harbin Medical University | Tang G.,University of Saskatchewan | And 5 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2012

The physiological and pathological roles of hydrogen sulfide (H 2S) in the regulation of cardiovacular functions have been recognized. Vascular smooth muscle cells (SMCs) express cystathionine gamma-lyase (CSE) and produce significant amount of H 2S. Although growing evidence demonstated the anti-atherosclerotic effect of H 2S, less is known about the contribution of the endogenous CSE/H 2S pathway to the development of vascular remodeling. This study investigated the roles of the CSE/H 2S pathway on SMC migration and neoimtimal formation by using CSE knockout (KO) mice. SMCs and aortic explants isolated from CSE KO mice exhibited more migration and outgrowth compared with that from wild-type (WT) mice, and exogenously applied NaHS (a H 2S donor) at 100μM significantly inhibited SMC migration and outgrowth. SMCs became more elongated and spread in the absence of CSE, and fibronectin significantly stimulated adhesion and migration of SMCs from CSE KO mice (KO-SMCs) in comparison with SMCs from WT mice (WT-SMCs). The expressions of α5- and β1-integrins were significantly higher in KO-SMCs, and functional blocking of α5β1-integrin effectively abrogated KO-SMC migration. CSE deficiency also enhanced matrix metalloproteinase-2 (MMP-2) expression, and the selective blocking of MMP-2 decreased KO-SMC migration. NaHS treatment decreased both the expressions of α5- and β1-integrins and MMP-2. We further found that the expressions of α5- and β1-integrins as well as MMP-2, were stimulated by fibronectin, and that the blockage of α5β1-integrin reduced but overexpression of α5β1-integrin induced MMP-2 expression in both WT-SMCs and KO-SMCs. We also noticed that CSE deficiency in mice led to increased neointima formation in carotid arteries 4weeks after ligation, which were attenuated by NaHS administration. In conclusion, inhibition of SMC migration by H 2S may be a novel target for the treatment of vascular occlusive disorder. © 2011.


Yang L.,Guangzhou University | Liu B.,Guangzhou University | Huang B.,Guangzhou University | Deng J.,Soochow University of China | And 9 more authors.
Human Molecular Genetics | Year: 2013

WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that has been reported to lose function due to genetic alterations in several cancers. WWOX maps to the common chromosomal fragile site FRA16D and several copy number variations (CNVs) were found within this gene. In this study, we investigated the association between the CNVs of WWOX and lung cancer risk in four independent case-control studies, which are on 2942 lung cancer cases and 3074 cancer-free controls of southern, eastern and northern Chinese. A common CNV-67048 was genotyped by the Taqman real-time PCR, and its biological effect was accessed with protein expression and sequencing assays. We found that in comparison with the common 2-copy genotype, the carriers of loss variant genotypes (1-copy or 0-copy) had a significantly increased risk of lung cancer (adjusted OR =; 1.39, 95%; CI =; 1.24-1.55, P = 9.01*10-9) in a dose-response manner (Ptrend = 1.12 * 10-10), and the WWOX protein expressions in lung cancer tissues were significantly lower (P = 0.036), accompanying a higher rate of exons absence (P = 0.021) in subjects with loss genotypes of CNV-67048. Our data suggest that the loss genotypes of CNV-67048 in WWOX predispose their carriers to lung cancer; this might be related with altered WWOX gene expression and exons absence in them. © The Author 2013. Published by Oxford University Press. All rights reserved.


Fu K.,Harbin Medical University | Piao T.,Harbin Children Hospital | Wang M.,Second Peoples Hospital of Guangdong Province | Zhang J.,Harbin Medical University | And 3 more authors.
International Immunopharmacology | Year: 2014

Catalpol, an iridiod glucoside isolated from Rehmannia glutinosa, has been reported to have anti-inflammatory properties. Although anti-inflammatory activity of catalpol already reported, its involvement in lung protection has not been reported. Thus, we investigated the role of catalpol on lipopolysaccharide (LPS)-induced acute lung injury in this study. Mice acute lung injury model was induced by intranasal instillation of LPS. Catalpol was administrated 1 h prior to or after LPS exposure. The severity of pulmonary injury was evaluated 12 h after LPS administration. The results showed that catalpol inhibited lung W/D ratio, myeloperoxidase activity of lung samples, the amounts of inflammatory cells and TNF-α, IL-6, IL-4 and IL-1β in BALF induced by LPS. The production of IL-10 in BALF was up-regulated by catalpol. In vitro, catalpol inhibited TNF-α, IL-6, IL-4 and IL-1β production and up-regulated IL-10 expression in LPS-stimulated alveolar macrophages. Moreover, western blot analysis showed that the activation of NF-κB and MAPK signaling pathways was inhibited by catalpol. Furthermore, catalpol was found to inhibit TLR4 expression induced by LPS. In conclusion, catalpol potently protected against LPS-induced ALI. The protective effect may attribute to the inhibition of TLR4-mediated NF-κB and MAPK signaling pathways. © 2014 Published by Elsevier B.V.


Yi F.,Harbin Medical University | He X.,Military General Hospital of Beijing | He X.,Chinese PLA General Hospital | Wang D.,Harbin Medical University
Neurochemical Research | Year: 2013

Mitochondrial dysfunction is implicated in pathogenesis of Parkinson's disease (PD). Lycopene, a member of the carotenoid family of phytochemicals, exerts its neuroprotective effects by reducing oxidative damage and improving mitochondrial function in several experimental models. In an attempt to clarify the protective effect of lycopene on toxin-insulted dopaminergic neuronal death, the present study was carried out by using a typical PD-1-methyl-4- phenylpyridinium iodide (MPP+)-induced dopaminergic SH-SY5Y cellular model. SH-SY5Y cells were preincubated with different dose of lycopene for 2 h, followed by the challenge with 500 μM MPP+ for 24 h. It is found that lycopene attenuated MPP+-induced cytotoxicity, as evidenced by the improved cell viability and the decreased apoptotic rate. Additionally, lycopene suppressed the reactive oxygen species accumulation and lipid peroxidation caused by MPP+. Lycopene also ameliorated MPP +-induced mitochondria-derived ROS production and mitochondrial morphological changes. Furthermore, lycopene attenuated MPP+-induced opening of the mitochondrial permeability transition pore and the concomitant disruption of the mitochondrial membrane potential, reversed MPP +-induced reduction in ATP concentration and decreases in mitochondrial DNA copy numbers and mitochondrial RNA transcript levels. Together, the protective effects of lycopene against MPP+-induced cytotoxicity may be attributable to its roles in improving mitochondrial function. These data suggest that lycopene may provide a valuable therapeutic strategy for the treatment of PD. © 2013 Springer Science+Business Media New York.


Cao Q.,Lakehead University | Zhang L.,Harbin Medical University | Yang G.,Lakehead University | Xu C.,Harbin Medical University | And 2 more authors.
Antioxidants and Redox Signaling | Year: 2010

Butyrate is a short-chain fatty acid that arrests growth of various types of cells. H2S can be endogenously produced by cystathionine γ-lyase (CSE) or cystathionine β-synthase (CBS) or both in colonic tissues. In this study, we observed endogenous H2S production in a colon cancer cell line (WiDr) and colonic tissues through the activity of both CSE and CBS. After 24h of incubation of WiDr cells, butyrate increased cell production of H2S and upregulated CBS and CSE expressions. Both butyrate and NaHS (a H2S donor) decreased cell viability in a dose-dependent manner. Blockade of CBS, but not CSE, decreased butyrate-stimulated H2S production and reversed butyrate-inhibited cell viability. In addition, NaHS treatment stimulated the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), but not c-Jun N-terminal kinase (JNK). Inhibition of the phosphorylation of either p38 MAPK or ERK did not abolish NaHS-induced cell death. Butyrate treatment increased the phosphorylation of ERK, not p38 MAPK and JNK, but inhibition of ERK and p38 MAPK phosphorylation did not inhibit butyrate-reduced cell viability. In conclusion, butyrate regulates endogenous H2S production by stimulating CBS expression in colon cancer cells, but butyrate and H2S inhibit cancer cell growth through different mechanisms. Antioxid. Redox Signal. 12, 0000-0000. © 2010, Mary Ann Liebert, Inc.


Zhao K.,Lakehead University | Li H.,Harbin Medical University | Li S.,Lakehead University | Yang G.,Lakehead University
Frontiers in Bioscience - Landmark | Year: 2014

Hydrogen sulfide (H2S) is a highly diffusible gasotransmitter, that influence cellular and organ functions by a number of different mechanisms. Cystathionine gamma-lyase (CSE) is one major H2S-producing enzyme with L-cysteine as the main substrate in mammalian cells. Since the discovery of endogenously-produced H2S as a biological mediator, there has been an explosion of interest in CSE expression and regulation. CSE expression and activity and ultimately the amount of H2S synthesis is controlled by a complex integration of transcriptional, posttranscriptional and post-translational mechanisms. Considering the key role that CSE/H2S system plays in both health and diseases, a better understanding of the regulation of CSE/H2S system will help us to develop novel and more effective strategies to target CSE and alter H2S production inside cells. In this review, we summarize the altered expression and activity of CSE and abnormal H2S production in various pathophysiological conditions. The current knowledge on the signaling and regulatory pathways for CSE expression and H2S production are also elucidated. As such, our understanding of the pathogenesis of human diseases will be better achieved and the corresponding new therapy can be devised.


Qu B.,Harbin Medical University | Zhao Y.-H.,Shenyang University | Sun B.-Z.,Harbin Medical University
International Journal of Medical Sciences | Year: 2012

Objective: To assess the internal validity and reliability of a multisource feedback (MSF) program by China Medical Board for resident physicians in China. Method: Multisource feedback was used to assess professionalism, interpersonal and communication skills. 258 resident physicians were assessed by attending doctors, self-evaluation, resident peers, nurses, office staffs, and patients who completed a sealed questionnaire at 19 hospitals in China. Cronbach's alpha coefficient was used to assess reliability. Validity was assessed by exploratory factor analyses and by profile ratings. Results: 4128 questionnaires were collected from this study. All responses had high internal consistency and reliability (Cronbach's α> 0.90), which suggests that both questions and form data were internally consistent. The exploratory factor analysis with varimax rotation for the evaluators' questionnaires was able to account for 70 to 74% of the total variance. Conclusion: The current MSF assessment tools are internally valid and reliable for assessing resident physician professionalism and interpersonal and communication skills in China. © Ivyspring International Publisher.


Kim S.-W.,Emory University | Kim S.-W.,Catholic Kwandong University | Kim S.-W.,International St Marys Hospital | Kim S.-W.,Dong - A University | And 8 more authors.
Journal of the American College of Cardiology | Year: 2014

Background Cell therapy for cardiovascular disease has been limited by low engraftment of administered cellsand modest therapeutic effects. Bone marrow (BM) -derived CD31+ cells are a promising cell source owing to theirhigh angiovasculogenic and paracrine activities.Results The CD31+ cells cultured in endothelial cell medium (EC-CD31+ cells) showed the highest adhesion andangiogenic activities and lowest inflammatory properties in vitro compared with uncultured or other cultured CD31+ cells.When implanted into mouse MI or HLI models, EC-CD31+ cells improved cardiac function and repaired limb ischemiato a greater extent than uncultured CD31+ cells. Histologically, injected EC-CD31+ cells exhibited higher retention,neovascularization, and cardiomyocyte proliferation. Importantly, cell retention and endothelial transdifferentiationwas sustained up to 1 year.Objectives This study sought to identify culture conditions that could augment the cell adhesion, angiogenic, andanti-inflammatory activities of BM-derived CD31+ cells, and to determine whether these cultured CD31+ cells areeffective for cardiac and vascular repair.Methods CD31+ cells were isolated from human BM by magnetic-activated cell sorting and cultured for 10 daysunder hematopoietic stem cell, mesenchymal stem cell, or endothelial cell culture conditions. These cells werecharacterized by adhesion, angiogenesis, and inflammatory assays. The best of the cultured cells were implantedinto myocardial infarction (MI) and hindlimb ischemia (HLI) models to determine therapeutic effects and underlyingmechanisms.Conclusions Short-term cultured EC-CD31+ cells have higher cell engraftment, vessel-formation, cardiomyocyteproliferation, and anti-inflammatory potential, are highly effective for both cardiac and peripheral vascularrepair, and enhance survival of mice with heart failure. These cultured CD31+ cells may be a promising source fortreating ischemic cardiovascular diseases. (J Am Coll Cardiol 2014;64:168194) © 2014 American College of Cardiology Foundation. © 2014 American College of Cardiology Foundation.


Ji Y.,Harbin Medical University | Zhang Y.-C.,Harbin Medical University | Pei L.-B.,Harbin Medical University | Shi L.-L.,Dalian Medical University | And 2 more authors.
Molecular and Cellular Biochemistry | Year: 2011

Dihydroartemisinin (DHA) exhibits antitumor activity against a wide spectrum of cancer cells. However, whether DHA has anti-tumor effect on human osteosarcoma cells remains unknown. This study aims to investigate the anti-tumor activity of DHA and the underlying mechanisms in human osteosarcoma cell lines with different p53 mutation statuses. Four human osteosarcoma cell lines were treated with different concentrations of DHA. Then, cell proliferation was determined by the CCK-8 viability assay; apoptosis and cell cycle progression were evaluated by flow cytometry; protein expression was analyzed by western blot assay; and NF-kB activity was examined by luciferase assay. The results demonstrated that DHA treatment could inhibit the proliferation of four osteosarcoma cell lines in a dose-dependent manner. P53 wild-type osteosarcoma cells were more sensitive to DHA. Moreover, the percentage of apoptotic cell and cell arrest in G 2/M phase was increased upon DHA treatment in a dose-dependent manner. Mechanistically, DHA activated caspase-3, caspase-8, and caspase-9; upregulated the expression of Bax, FAS, and cyclin D1; downregulated the expression of Bcl-2, Cdc25B, and cyclin B1; and inhibited the activity of NF-kB. In conclusion, DHA has significant anticancer effects against human osteosarcoma cells, which include induction of apoptosis and cell cycle arrest. The p53 gene may play a certain role in the DHA-induced human osteosarcoma apoptosis and cell cycle arrest. DHA is a novel anti-osteosarcoma drug candidate that merits further study. © 2011 Springer Science+Business Media, LLC.


Ma F.,Harbin Medical University | Song H.,Harbin Medical University | Guo B.,Harbin Medical University | Zhang Y.,Harbin Medical University | And 10 more authors.
Oncotarget | Year: 2015

MicroRNAs (miRs) function as key regulators of gene expression and their deregulation is associated with the carcinogenesis of various cancers. In the present study, we investigated the biological role and mechanism of miR-361-5p in colorectal carcinoma (CRC) and gastric cancer (GC). We showed that microRNA-361-5p (miR-361-5p) was down-regulated in CRC and GC in comparison to the controls. Meanwhile, the expression levels of miR-361-5p negatively correlated with lung metastasis and prognosis in clinical CRC patients. Overexpression of miR-361-5p markedly suppressed proliferation, migration and invasion of cancer cells. Additionally, this phenotype could be partially rescued by the ectopic expression of staphylococcal nuclease domain containing-1 (SND1). SND1 was identified as a target of miR-361-5p using bioinformatics analysis and in vitro luciferase reporter assays. In turn, SND1 bound to pre-miR-361-5p and suppressed the expression of miR-361-5p, thus exerting a feedback loop. Most interestingly, in vivo studies showed that restoration of miR-361-5p significantly inhibited tumor growth and especially the lung metastasis in nude mice. Therefore, it could be concluded that miR-361-5p functions as a tumor-suppressive miRNA through directly binding to SND1, highlighting its potential as a novel agent for the treatment of patients with CRC and GC.


Ju Y.,Lakehead University | Zhang W.,Harbin Medical University | Pei Y.,Shanxi University | Yang G.,Lakehead University
Canadian Journal of Physiology and Pharmacology | Year: 2013

Hydrogen sulfide (H2S) is traditionally recognized as a toxic gas with a rotten-egg smell. In just the last few decades, H2S has been found to be one of a family of gasotransmitters, together with nitric oxide and carbon monoxide, and various physiologic effects of H2S have been reported. Among the most acknowledged molecular mechanisms for the cellular effects of H2S is the regulation of intracellular redox homeostasis and post-translational modification of proteins through S-sulfhydration. On the one side, H2S can promote an antioxidant effect and is cytoprotective; on the other side, H2S stimulates oxidative stress and is cytotoxic. This review summarizes our current knowledge of the antioxidant versus pro-oxidant effects of H2S in mammalian cells and describes the Janus-faced properties of this novel gasotransmitter. The redox regulation for the cellular effects of H2S through S-sulfhydration and the role of H2S in glutathione generation is also recapitulated. A better understanding of H2S-regualted redox homeostasis will pave the way for future design of novel pharmacological and therapeutic interventions for various diseases.


Gu Y.,Harbin Medical University | Zhang M.,Harbin Medical University | Peng F.,Harbin Medical University | Fang L.,Harbin Medical University | And 7 more authors.
Oncotarget | Year: 2015

Ovarian cancer patients carrying alterations (i.e., germline mutations, somatic mutations, hypermethylations and/or deletions) of BRCA1 or BRCA2 (BRCA1/2) have a better prognosis than BRCA1/2 alteration non-carriers. However, patients with wild-type BRCA1/2 may also have a favorable prognosis as a result of other mechanisms that remain poorly elucidated, such as the deregulation of miRNAs. We therefore sought to identify BRCA1/2-directed miRNA signatures that have prognostic value in ovarian cancer patients with wild-type BRCA1/2 and study how the deregulation of miRNAs impacts the prognosis of patients treated with platinum-based chemotherapy. By analyzing multidimensional datasets of ovarian cancer patients from the TCGA data portal, we identified three miRNAs (hsa-miR-146a, hsa-miR-148a and hsa-miR-545) that target BRCA1/2 and were associated with overall survival and progression-free survival in patients with wild-type BRCA1/2. By analyzing the expression profiles and Gene Ontology functional enrichment, we found that carriers of BRCA1/2 alterations and patients with miRNA deregulation shared a common mechanism, regulation of the DNA repair-related pathways, that affects the prognosis of ovarian cancer patients. Our work highlights that a proportion of patients with wild-type BRCA1/2 ovarian cancers benefit from platinum-based chemotherapy and that the patients who benefit could be predicted from BRCA1/2-directed miRNA signature.


News Article | January 19, 2016
Site: motherboard.vice.com

*Warning, there are graphic images in this post* An Italian and Chinese scientist claim to have completed a “successful” head transplant in monkeys, and to have restored movement in mice who have had their spinal cords cut and fused back together. They also claim to have performed initial human head transplant experiments in cadavers, the latest step in ambitious—and, to many, scientifically dubious—plans to eventually carry out the first human head transplant. Italian surgeon Sergio Canavero, who is vocal about his plans to conduct the first human head transplant (or, more accurately, a full body transplant) by 2017 and heads up an international collaboration of researchers working towards this goal, sent a press release to Motherboard reporters on Skype Monday announcing the latest work. “BREAKING NEWS FROM THE HEAVEN/AHBR HEAD TRANSPLANT INTERNATIONAL COLLABORATIVE EFFORT: GEMINI LEADS TO MOTOR RECOVERY, CRITICS DISPROVEN,” the press release said, referring to the name of Canavero’s planned techniques. The release notes that Dr. Xiaoping Ren of Harbin Medical University had performed a successful monkey head transplant using the technique, which Canavero says makes a very sharp incision of the spinal cord and places the patient into a state of therapeutic hypothermia to allow the body to make a recovery. “A full monkey head transplant has been successfully accomplished by Prof Ren’s group in China with the goal of testing cross-circulation and hypothermia as an effective neuroprotective strategy,” the release said. “The first studies on human cadavers have already begun in China and will be expanded shortly.” The press release sent out by Canavero said seven scientific papers describing the research would be imminently published in the journals Surgery and CNS Neuroscience & Therapeutics. Chinese researcher Dr. Xiaoping Ren of Harbin Medical University confirmed to Motherboard that he had undertaken the work with monkeys. “We already did a couple monkeys for this procedure last year,” he said. Ren previously made headlines for transplanting heads on mice. Those experiments were reported on and filmed by the Wall Street Journal. While Ren has tempered expectations that this work would lead to a successful human head transplant (he told the WSJ in July that he is “not [yet] confident to say I can do a human transplant”), Canavero has charged ahead. Canavero has promoted every potential breakthrough before it has been published in science journals, has selected (and promoted the plight of) his first patient, a Russian man with a degenerative muscle disease named Valery Spiridonov, and has called on tech CEOs such as Mark Zuckerberg to finance the surgery. While Canavero very well might eventually attempt the procedure, he has not been forthcoming with evidence of interim progress. After he sent Motherboard the press release, Canavero would not send us drafts of the papers and would not send us photos or videos of the procedure that we could publish (Canavero sent us photos of monkeys with sutures on their necks via Skype but said we could not publish them—we took a screengrab of the YouTube embed above). One of Canavero’s assistants told us it would only be providing video footage to “television news stations for live interviews.” After contacting one of the journals in which the papers are supposedly set to be published, we were told that Canavero sent out the press release before the papers had been finalized, that they are currently not available, and that the press release was sent out without the knowledge of the journal. Motherboard spoke with Michael Sarr, a surgeon at the Mayo Clinic and editor of the journal Surgery, where three of the seven papers are set to be published. Sarr said that his journal has reviewed the science on two of the three papers—one about nerve regrowth and one about brain preservation in a potentially transplanted head. He said the articles still must be edited several times before they’re eventually published, perhaps as early as next month. “Unfortunately, I think Canavero has been a little premature with sending this out,” Sarr told Motherboard. “This head transplantation—even the term is sensationalism. I worry tremendously about that. We’re a hard surgical science journal and we’re interested in this because of what it might mean for people with traumatic spinal injuries.” Sarr said that one of the articles his journal plans to publish is about two people with spinal cord injuries who had their nerves regrow after surgical intervention to remove scar tissue. “That’s the interest our scientific journal has in this concept. The head transplant would be the proof of principle, which wouldn’t be done in the US in this point," he said. "If that works, you could take people like Christopher Reeve, reoperate on them, take out one vertebra, bring the spinal cord together and you might be able to recover functionality in the muscles and sensation downstream from the transection. That would be an unbelievably huge event.” Sarr said when the articles are eventually published, he will make clear in a preface that the papers don’t necessarily mean a head transplant is actually going to work. “As an editor of a scientific journal, I don’t want to be sensationalist, but I do want to point out that there may be a new approach to spinal cord paralysis due to spinal cord injuries,” he said. “What we’re going to do, there’s going to be a preface written by myself and my co-editor, and we’re going to say before you start reading this, here’s why we’re interested in this topic. It’s not because of the head transplantation, it’s because they are claiming to have found a way to regrow the nerves.” This is all to say that fantastic feats of successful monkey head transplants and future human work have been claimed, and while the proof to back it up may exist, they’re being made before going through the traditional science publishing steps. If a transplant did indeed take place, this would not be the first time monkey head transplants have been attempted. American neurosurgeon Robert White attempted a monkey head transplant in the 1970s; the monkey died after nine days. Ren said the point of the monkey head transplant experiments was not long-term survival of the animals but to test techniques for the surgery, such as how to maintain blood circulation (which is necessary to protect the brain). Canavero explained that the monkey was euthanized shortly afterwards. “We didn’t want to see the monkey suffer for more days, such as Dr. White did,” said Canavero. In a Skype conversation with Spiridonov published by RIA Novosti, Canavero told his prospective patient that “the monkey survived perfectly without injury for 24… for 20 hours before being euthanized, because of course we didn’t want to keep the animal alive.” “I will not show you the human images because they are too strong, but the first human decapitation [in cadavers] has already taken place in China under the leadership of Xiaoping Ren,” Canavero added in his Skype call with Spiridonov. Canavero claimed Ren’s work was “to re-prove that a brain could really survive detachment and re-attachment” in the monkey model. Until the papers are released for scrutiny, it’s naturally advisable to take the claimed outcomes with a hefty grain of salt and a raised eyebrow. Canavero’s project has many critics who, as well as expressing ethical concerns, question whether a head transplant is at all scientifically possible. What Canavero’s claims do show, however, is that he and his collaborators are keen to push ahead with their experiments. Next, Ren is turning his attention to human cadavers. Canavero also showed Motherboard an image of a human head that had purportedly been severed in the same way it could be for a transplant (which he appeared unwilling to show Spiridonov). The team additionally reported that Korean researchers had performed further work in mice in an attempt to restore motor function after the spine is sliced through and then reconnected using polyethylene glycol, or PEG, as a kind of glue. Canavero showed me videos in which mice that had purportedly had their spine detached and reconnected four weeks previously (but keeping their heads attached) were able to move around, albeit clumsily. “We proved without a hint at doubt that what the critics said—that the spinal cord could not be reconstructed—they were wrong, we were right,” Canavero said.


News Article | December 12, 2016
Site: www.chromatographytechniques.com

The increased risk of hyperglycemia associated with prenatal exposure to famine is also passed down to the next generation, according to a new study of hundreds of families affected by widespread starvation in mid-20th century China. Hyperglycemia is a high blood glucose level and a common sign of diabetes. The new study in the American Journal of Clinical Nutrition reports that hundreds of people who were gestated during a horrific famine that afflicted China between 1959 and 1961 had significantly elevated odds of both hyperglycemia and type 2 diabetes. Even more striking, however, was that their children also had significantly higher odds of hyperglycemia, even though the famine had long since passed when they were born. Public health researchers at Brown University and Harbin Medical University in China were able to make the findings by studying more than 3,000 local residents and their children. Some of the subjects were gestated during famine and some were gestated just afterward. Some of the studied offspring were born to two, one or no parents who had been famine-exposed. This study population allowed the scientists, who interviewed and took blood samples from the participants in 2012, to make well-controlled, multigenerational comparisons of the effects of in utero famine exposure that would never be ethical to intentionally create. "These were unique 'experiments,' so to speak, that were unfortunately done to those populations at a time when the society was under revolutionary, social and political upheavals," said Simin Liu, the study's co-corresponding author and a professor of epidemiology and of medicine at Brown. "By studying these families we could determine multiple-generational exposure to nutritional factors and genetic interactions that occur due to famine." Among 983 people gestated during the famine years, 31.2 percent had hyperglycemia and 11.2 percent had type 2 diabetes. By comparison, among 1,085 people gestated just after the famine ended, the prevalence of hyperglycemia was 16.9 percent, and the prevalence of type 2 diabetes as 5.6 percent. Controlling for factors such as gender, smoking, physical activity, calorie consumption and body-mass index, the researchers calculated that in utero famine exposure was associated with 1.93-times higher odds of hyperglycemia and a 1.75 times greater chance of type 2 diabetes. The next generation sustained the significant risk of hyperglycemia when both parents had been famine-exposed. Overall in the second generation, hyperglycemia prevalence were 5.7 percent for 332 people with no famine-exposed parents, 10.0 percent for 251 people with famine-exposed fathers, 10.6 percent for 263 people with famine-exposed mothers, and 11.3 percent for the 337 people for whom both parents had famine exposure. Adjusting for all the same lifestyle factors, the offspring of two famine-exposed parents had 2.02 times the odds of hyperglycemia of people with no famine-exposed parents. The odds of hyperglycemia from one-parent exposure were also substantially elevated but not quite statistically significant. The odds of type 2 diabetes were not statistically significant after adjustment for multiple comparisons among the second generation, but co-corresponding author Sun Changhao, professor of nutrition and dean of the School of Public Health at Harbin, noted that these people were only in their 20s and 30s and could still be at increased risk as they age and that the research team will continue to follow up on these participants. How is this possible? Because the study only shows an association between metabolic changes and in utero famine exposure, it can't prove causality or the biological mechanism underlying a cause. But prior research on the effects of famine in humans and in laboratory animals suggest that famine does indeed cause such health risks, the study authors said. "It is indeed a remarkable finding that is consistent what with what one would have expected from prior findings from animal experiments," said lead author Jie Li, a Brown postdoctoral fellow. A prior team's study in mice showed a multigenerational effect on metabolism, and other studies of famine exposure in people have produced evidence of changes in the endocrine systems and in prenatal gene expression in reproductive systems. Liu said he hopes to continue working with colleagues and participants in China to further investigate how gene and environmental interaction may affect health outcomes across generations. Findings of such work would have implications not only for improving biological understanding of mechanisms but also for clinical and public health interventions. "Genetic, epigenetic reprogramming, and subsequent gene-diet interaction are all possible explanations," he said. "By establishing this Chinese famine cohort of families, we hope to conduct a much more comprehensive and in-depth assessment of the whole genome and epigenome along with metabolic biomarkers of these participants moving forward."


Yingkun N.,Harbin Medical University | Lvsong Z.,Northeast Forestry University | Huimin Y.,Harbin Medical University
Canadian Journal of Physiology and Pharmacology | Year: 2010

This study investigated the potential of shikonin as an anticancer agent against liver cancer and an in vitro human hepatoma cancer model system. The HepG2 cell line was the hepatoma cancer model in the present study. The inhibitory effect of shikonin on the growth of HepG2 cells was measured by MTT assay. To explore the underlying mechanism of cell growth inhibition of shikonin, the cell cycle distribution, DNA fragmentation, mitochondrial membrane potential (Δψm) disruption, and expression of Bax and Bcl-2 were measured in HepG2 cells. The activity of shikonin in inducing apoptosis was investigated through the detection of Annexin V signal and CD95 expression by flow cytometry and electron microscopy, respectively. Shikonin inhibited the growth of HepG2 cells in a dose-dependent manner. The IC50 value (inhibiting cell growth by 50%) was 4.30 mg/mL. Shikonin inhibited cell growth in a dose-dependent manner and blocked HepG2 cell cycle progression at the S phase. The changes in mitochondrial morphology, dose-dependently decreased in Δψ, were observed in different concentrations of the drug treatment group. Western blot analysis showed that cajanol inhibited Bcl-2 expression and induced Bax expression. Furthermore, we show that shikonin increases Annexin V signal and CD95 (Fas/APO) expression, resulting in apoptotic cell death of HepG2 cells. In addition, lump formation of intranuclear chromatin, pyknosis of cell nucleus, deletion of microvillus, vacuolar degeneration of mitochondria, reduction of rough endoplasmic reticulum, and resolution of free ribosome, etc., associated with apoptosis were discovered by electron microscopy in HepG2 cells after 48 h treatment. Shikonin inhibited HepG2 cells, possibly through the pathway of inducing early apoptosis, and was beneficial for restoring the apoptotic sensitivity of HepG2 cells by CD95, and should therefore be considered as a candidate agent for the prevention or treatment of human hepatoma.


Wang J.,University of Electronic Science and Technology of China | Zhou X.,University of Electronic Science and Technology of China | Zhu J.,University of Electronic Science and Technology of China | Zhou C.,University of Electronic Science and Technology of China | And 2 more authors.
BMC Bioinformatics | Year: 2010

Background: Semantic similarity scores for protein pairs are widely applied in functional genomic researches for finding functional clusters of proteins, predicting protein functions and protein-protein interactions, and for identifying putative disease genes. However, because some proteins, such as those related to diseases, tend to be studied more intensively, annotations are likely to be biased, which may affect applications based on semantic similarity measures. Thus, it is necessary to evaluate the effects of the bias on semantic similarity scores between proteins and then find a method to avoid them.Results: First, we evaluated 14 commonly used semantic similarity scores for protein pairs and demonstrated that they significantly correlated with the numbers of annotation terms for the proteins (also known as the protein annotation length). These results suggested that current applications of the semantic similarity scores between proteins might be unreliable. Then, to reduce this annotation bias effect, we proposed normalizing the semantic similarity scores between proteins using the power transformation of the scores. We provide evidence that this improves performance in some applications.Conclusions: Current semantic similarity measures for protein pairs are highly dependent on protein annotation lengths, which are subject to biological research bias. This affects applications that are based on these semantic similarity scores, especially in clustering studies that rely on score magnitudes. The normalized scores proposed in this paper can reduce the effects of this bias to some extent. © 2010 Wang et al; licensee BioMed Central Ltd.


Li Z.,Dalian University of Technology | Lian M.,Harbin Medical University | Yang F.,Dalian University of Technology | Meng Q.,Dalian University of Technology | Gao Z.,Dalian University of Technology
European Journal of Organic Chemistry | Year: 2014

A new framework derived from the commercially available diterpenoid alkaloid lappaconitine was evaluated as a Brønsted base catalyst for the enantioselective α-hydroxylation of β-dicarbonyl compounds by using 30% hydrogen peroxide as a green and highly practical source of oxygen. This protocol allows convenient access to the corresponding α-hydroxy-β- oxo esters, α-hydroxy-β-oxo amides and (-)-kjellmanianone with up to 98% yield and 92% ee. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Wang J.,University of Electronic Science and Technology of China | Zhou X.,University of Electronic Science and Technology of China | Zhu J.,University of Electronic Science and Technology of China | Gu Y.,Harbin Medical University | And 4 more authors.
Briefings in Bioinformatics | Year: 2012

In high-throughput studies of diseases, terms enriched with disease-related genes based on Gene Ontology (GO) are routinely found. However, most current algorithms used to find significant GO terms cannot handle the redundancy that results from the dependencies of GO terms. Simply based on some numerical considerations, current algorithms developed for reducing this redundancy may produce results that do not account for biologically interesting cases. In this article, we present several rules used to design a tool called GO-function for extracting biologically relevant terms from statistically significant GO terms for a disease. Using one gene expression profile for colorectal cancer, we compared GO-function with four algorithms designed to treat redundancy. Then, we validated results obtained in this data set by GO-function using another data set for colorectal cancer. Our analysis showed that GO-function can identify disease-related terms that are more statistically and biologically meaningful than those found by the other four algorithms. © The Author 2011. Published by Oxford University Press.


Guo H.,Dalian University of Technology | Jing Y.,Dalian University of Technology | Yuan X.,Dalian University | Ji S.,Dalian University of Technology | And 3 more authors.
Organic and Biomolecular Chemistry | Year: 2011

Two highly selective OFF-ON green emitting fluorescent thiol probes (1 and 2) with intense absorption in the visible spectrum (molar extinction coefficient ε is up to 73800 M-1 cm-1 at 509 nm) based on dyads of BODIPY (as electron donor of the photo-induced electron transfer, i.e.PET) and 2,4-dinitrobenzenesulfonyl (DNBS) (as electron acceptor of the PET process) were devised. The single crystal structures of the two probes were determined. The distance between the electron donor (BODIPY fluorophore) and the electron acceptor (DNBS) of probe 2 is larger than that of probe 1, as a result the contrast ratio (or the PET efficiency) of probe 2 is smaller than that of probe 1. However, fluorescence OFF-ON switching effects were observed for both probe 1 and probe 2 in the presence of cysteine (the emission enhancement is 300-fold for probe 1 and 54-fold for probe 2). The fluorescence OFF-ON sensing mechanism is rationalized by DFT/TDDFT calculations. We demonstrated with DFT calculations that DNBS is ca. 0.76 eV more potent to accept electrons than the maleimide moiety. The probes were used for fluorescent imaging of cellular thiols. © 2011 The Royal Society of Chemistry.


Wei L.,Harbin Medical University | Wei L.,University of New Mexico | Griego A.M.,University of New Mexico | Chu M.,Harbin Medical University | Ozbun M.A.,University of New Mexico
Carcinogenesis | Year: 2014

High-risk human papillomavirus (HR-HPV) infections are necessary but insufficient agents of cervical and other epithelial cancers. Epidemiological studies support a causal, but ill-defined, relationship between tobacco smoking and cervical malignancies. In this study, we used mainstream tobacco smoke condensate (MSTS-C) treatments of cervical cell lines that maintain either episomal or integrated HPV16 or HPV31 genomes to model tobacco smoke exposure to the cervical epithelium of the smoker. MSTS-C exposure caused a dose-dependent increase in viral genome replication and correspondingly higher early gene transcription in cells with episomal HPV genomes. However, MSTS-C exposure in cells with integrated HR-HPV genomes had no effect on genome copy number or early gene transcription. In cells with episomal HPV genomes, the MSTS-C-induced increases in E6 oncogene transcription led to decreased p53 protein levels and activity. As expected from loss of p53 activity in tobacco-exposed cells, DNA strand breaks were significantly higher but apoptosis was minimal compared with cells containing integrated viral genomes. Furthermore, DNA mutation frequencies were higher in surviving cells with HPV episomes. These findings provide increased understanding of tobacco smoke exposure risk in HPV infection and indicate tobacco smoking acts more directly to alter HR-HPV oncogene expression in cells that maintain episomal viral genomes. This suggests a more prominent role for tobacco smoke in earlier stages of HPV-related cancer progression. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.


Cheng F.,Harbin Medical University | Song W.,Harbin Medical University | Kang Y.,Harbin Medical University | Yu S.,University of Missouri - Kansas City | Yuan H.,Harbin Medical University
Molecular Vision | Year: 2011

Purpose: The paired box gene 6 (PAX6) on human chromosome 11p13 is an essential transcription factor for eye formation in animals. Mutations in PAX6 can lead to varieties of autosomal-dominant ocular malformations with aniridia as the major clinical signs. Known genetic alterations causing haplo-insufficiency of PAX6 include nonsense mutations, frameshift mutations, splicing errors, or genomic deletions. The purpose of this study was to identify genetic defects as the underlying cause of familial aniridia in a large Chinese family. Methods: All exons of PAX6 in the proband were sequenced by the Sanger sequencing technique. The genome of the proband was evaluated by a microarray-based comparative genomic hybridization (aCGH). Quantitative real-time PCR was applied to verify the abnormal aCGH findings in the proband and to test five other family members. Results: There were no detectable pathogenic mutations in the exons of PAX6 in the proband. The aCGH analysis showed two copies of PAX6 but revealed a 566 kb hemizygous deletion of chromosome 11p13, including four annotated genes doublecortin domain containing 1 (DCDC1), DnaJ homolog subfamily C member 24 (DNAJC24), IMP1 inner mitochondrial membrane (IMMP1L), and elongation factor protein 4 (ELP4) downstream of PAX6. Quantitative real-time PCR verified the deletion in the proband and further identified the deletion in a blind fashion in four affected family members but not in the one with a normal phenotype. Conclusions: The 566 kb hemizygous deletion of chromosome 11p13 downstream of PAX6 should be the cause of the familial aniridia in this Chinese family, although two copies of PAX6 are intact. aCGH evaluation should be applied if there is a negative result for the mutation detection of PAX6 in patients with aniridia. © 2011 Molecular Vision.


Ji S.,Dalian University of Technology | Guo H.,Dalian University of Technology | Yuan X.,Dalian University | Li X.,Dalian University | And 6 more authors.
Organic Letters | Year: 2010

(Figure presented) An OFF-ON red-emitting phosphorescent thiol probe is designed by using the 3MLCT photophysics of Ru(II) complexes, i.e., with Ru(II) as the electron donor. The probe is non-luminescent because the MLCT is corrupted by electron transfer from Ru(II) to an intramolecular electron sink (2,4-dinitrobenzenesulfonyl). Thiols cleave the electron sink, and the MLCT is re-established. Phosphorescence at 598 nm was enhanced by 90-fold, with a 143 nm (5256 cm-1) Stokes shift and a 1.1 μs luminescent lifetime. © 2010 American Chemical Society.


O'Brien Jr. J.E.,Harbin Medical University | Kibiryeva N.,Harbin Medical University | Zhou X.-G.,Harbin Medical University | Marshall J.A.,Harbin Medical University | And 4 more authors.
Circulation: Cardiovascular Genetics | Year: 2012

Background- The importance of noncoding RNAs (ncRNA), especially microRNAs (miRNAs), for maintaining stability in the developing vertebrate heart has recently become apparent; however, there is little known about the expression pattern of ncRNA in the human heart with developmental anomalies. Methods and Results- We examined the expression of miRNAs and small nucleolar RNAs (snoRNAs) in right ventricular myocardium from 16 infants with nonsyndromic tetralogy of Fallot (TOF) without a 22q11.2 deletion, 3 fetal heart samples, and 8 normally developing infants. We found 61 miRNAs and 135 snoRNAs to be significantly changed in expression in myocardium from children with TOF compared with normally developing comparison subjects. The pattern of ncRNA expression in TOF myocardium had a surprising resemblance to expression patterns in fetal myocardium, especially for the snoRNAs. Potential targets of miRNAs with altered expression were enriched for gene networks of importance to cardiac development. We derived a list of 229 genes known to be critical to heart development and found 44 had significantly changed expression in TOF myocardium relative to normally developing myocardium. These 44 genes had significant negative correlation with 33 miRNAs, each of which also had significantly changed expression. The primary function of snoRNAs is targeting specific nucleotides of ribosomal RNAs and spliceosomal RNAs for biochemical modification. The targeted nucleotides of the differentially expressed snoRNAs were concentrated in the 28S and 18S ribosomal RNAs and 2 spliceosomal RNAs, U2 and U6. In addition, in myocardium from children with TOF, we observed splicing variants in 51% of genes that are critical for cardiac development. Taken together, these observations suggest a link between levels of snoRNA that target spliceosomal RNAs, spliceosomal function, and heart development. Conclusions- This is the first report characterizing ncRNA expression in a congenital heart defect. The striking shift in expression of ncRNAs reflects a fundamental change in cell biology, likely impacting expression, transcript splicing, and translation of developmentally important genes and possibly contributing to the cardiac defect. © 2012 American Heart Association, Inc.


Yu S.,University of Missouri - Kansas City | Zhou X.-G.,University of Missouri - Kansas City | Zhou X.-G.,Harbin Medical University | Fiedler S.D.,University of Missouri - Kansas City | And 3 more authors.
Circulation: Cardiovascular Genetics | Year: 2011

Background-The GATA4 gene is critical to regulating myocardial differentiation and function. Haploinsufficiency of GATA4 is strongly associated with congenital heart defects (CHD). However, it is inconclusive whether duplicated GATA4 causes CHD. Methods and Results-We evaluated 1645 consecutive pediatric patients with various developmental disorders by highresolution microarray-based comparative genomic hybridization and found 8 probands and 2 relatives with pathogenic genomic imbalances containing GATA4. Four probands contain an≃4.0-Mb interstitial duplication of 8p23.1 flanked by the 2 olfactory receptor gene clusters REPD and REPP, representing 0.24% (4/1645) of the patients analyzed. None of the 4 patients has CHD or any other heart diseases and 1 mother who transmitted the duplication to her child has a history of aortic stenosis. Two patients who carry multiple genomic abnormalities, including a duplication containing GATA4, have complex CHD. Only 1 of the 3 individuals carrying genomic deletion containing GATA4 has atrial septal and ventricular septal defects. Conclusions-Cardiac defects are infrequent findings in individuals with 8p23.1 genomic duplications containing GATA4. A 0.24% detection rate of this duplication in this study is significantly higher than previously estimated. Observation in 2 patients with multiple genomic abnormalities and complex CHD is consistent with a 2-hit model that emphasizes accumulative effects of>1 insult to the genome, leading to a visible or more severe clinical manifestation. Haploinsufficient GATA4 may show variable expressivity with a wide spectrum of clinical findings, including CHD. © 2011 American Heart Association, Inc.


Song W.,Harbin Medical University | Shan L.,Harbin Medical University | Cheng F.,Harbin Medical University | Fan P.,Harbin Medical University | And 4 more authors.
Ophthalmology | Year: 2011

Purpose: To assess the prevalence and types of glaucoma in a rural population in northern China. Design: Population-based cross-sectional study. Participants: Subjects randomly selected from the population 40 years of age and older in Kailu County, Tongliao, Inner Mongolia. Methods: Each subject underwent a screening examination consisting of an interview and ophthalmic examinations, including applanation tonometry, central corneal thickness, gonioscopy, slit-lamp examination, dilated fundus evaluation, and a screening visual field test using frequency-doubling technology. Main Outcome Measures: Glaucoma was diagnosed using International Society of Geographical and Epidemiological Ophthalmology criteria. Results: Of 5949 individuals 40 years of age and older, 5197 (87.36%) were examined. Of these, 169 (3.28%) had diagnosed glaucoma, giving an age- and gender-standardized prevalence of 2.90% (95% confidence interval, 2.02%3.78%). The age- and gender-standardized prevalence of primary angle-closure glaucoma (PACG) was 1.42% (95% confidence interval, 0.82%2.02%) and that for primary open-angle glaucoma (POAG) was 1.41% (95% confidence interval, 0.79%2.02%). Of the 169 subjects with glaucoma, 54 (60%) and 3 (4.1%) had a previous known history of PACG or POAG, respectively. Unilateral blindness resulting from primary glaucoma was observed in 27 subjects (16.56%; 19 PACG/8 POAG), and bilateral blindness was present in 12 subjects (7.36%; 6 PACG/6 POAG). The prevalence of all types of glaucoma was increased with older age. Conclusions: The adjusted prevalence of glaucoma in this Chinese population was 2.90%, comparable with other data from Asia. The ratio of PACG to POAG was approximately equal. More than 90% of POAG cases previously were undetected, and nearly 30% of subjects with glaucoma were blind in at least 1 eye. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. © 2011 American Academy of Ophthalmology.


Liu T.,Harbin Medical University | Xia B.,Harbin Medical University | Lu Y.,Heilongjiang Province Hospital | Xu Y.,Harbin Medical University | Lou G.,Harbin Medical University
Human Pathology | Year: 2014

Here, we correlated tumor necrosis factor α-induced protein 8 (TNFAIP8) messenger RNA (mRNA) expression with clinicopathological parameters and investigated the involvement of TNFAIP8 overexpression in platinum resistance of epithelial ovarian cancer (EOC). The status of TNFAIP8 protein was evaluated by Western blot analysis (n = 25) and immunohistochemistry (n = 134). TNFAIP8 mRNA expression was assessed with real-time polymerase chain reaction in fresh frozen EOC tissues (n = 40). TNFAIP8 overexpression at both mRNA and protein levels in platinum-resistant disease was clearly higher than that in platinum-sensitive disease (P <.05). Platinum resistance was independently correlated with residual tumor size (P =.025), ascites (P =.027), and TNFAIP8 overexpression (P =.003). In particular, TNFAIP8 overexpression was correlated with platinum resistance in EOCs with optimal cytoreduction (P =.001). TNFAIP8 mRNA expression was strongly associated with residual tumor size (P =.019). In conclusion, our findings indicate that TNFAIP8 overexpression is an independent predictor of platinum resistance and may be a potential biomarker for targeted therapy. © 2014 Elsevier Inc.


Wang Y.,Harbin Medical University | Wang Y.,University of Saskatchewan | Sun M.,Chinese University of Hong Kong | Bao H.,Harbin Medical University | White A.P.,University of Saskatchewan
PLoS ONE | Year: 2013

Motivation: Type III Secretion Systems (T3SSs) play important roles in the interaction between gram-negative bacteria and their hosts. T3SSs function by translocating a group of bacterial effector proteins into the host cytoplasm. The details of specific type III secretion process are yet to be clarified. This research focused on comparing the amino acid composition within the N-terminal 100 amino acids from type III secretion (T3S) signal sequences or non-T3S proteins, specifically whether each residue exerts a constraint on residues found in adjacent positions. We used these comparisons to set up a statistic model to quantitatively model and effectively distinguish T3S effectors. Results: In this study, the amino acid composition (Aac) probability profiles conditional on its sequentially preceding position and corresponding amino acids were compared between N-terminal sequences of T3S and non-T3S proteins. The profiles are generally different. A Markov model, namely T3_MM, was consequently designed to calculate the total Aac conditional probability difference, i.e., the likelihood ratio of a sequence being a T3S or a non-T3S protein. With T3_MM, known T3S and non-T3S proteins were found to well approximate two distinct normal distributions. The model could distinguish validated T3S and non-T3S proteins with a 5-fold cross-validation sensitivity of 83.9% at a specificity of 90.3%. T3_MM was also shown to be more robust, accurate, simple, and statistically quantitative, when compared with other T3S protein prediction models. The high effectiveness of T3_MM also indicated the overall Aac difference between N-termini of T3S and non-T3S proteins, and the constraint of Aac exerted by its preceding position and corresponding Aac. Availability: An R package for T3_MM is freely downloadable from: http://biocomputer.bio.cuhk.edu.hk/softwares/T3_MM. T3_MM web server: http://biocomputer.bio.cuhk.edu.hk/T3DB/T3_MM.php. © 2013 Wang et al.


Sun T.,Harbin Medical University | Wang C.,Northeast Agricultural University | Xing J.,Harbin Medical University | Wu D.,Harbin Medical University
European Journal of Cancer | Year: 2011

Aim: MicroRNAs (miRNAs) are a recently discovered class of small non-coding RNAs that regulate gene expression and may contribute to the development and progression of many cancers. In this study, our goal was to investigate the regulation of miR-429 in gastric cancer and explored the mechanism/s by which it influenced pathogenesis of gastric cancer. Methods: We used real-time reverse transcriptase-polymerase chain reaction to quantify the expression level of miR-429 in 52 gastric cancer tissues and their paracancerous tissues. Bioinformatics was used to predict downstream target genes of miR-429. SGC-7901 gastric cancer cells were transfected with miR-429 mimics and endogenous c-myc expression was detected by western blots. We performed functional assays using the 3′UTR of the c-myc gene as a miR-429 target in a luciferase reporter assay system. Results: We showed that miR-429 was downregulated in human gastric carcinoma tissue and in SGC-7901 cells. Cell viability, proliferation and attachment were inhibited in miR-429-transfected cells. miR-429 significantly downregulated endogenous c-myc expression in SGC-7901 cells. Action of miR/429 on c-myc 3′UTR was confirmed. The levels of miR-429 in tumour tissue of patients with lymph node metastasis were significantly lower than in those without lymph node metastasis. Conclusions: Our results suggested that miR-429 played a role in the pathogenesis of gastric carcinoma and may function as a recessive cancer gene. c-myc is an important miR-429 target gene. © 2011 Elsevier Ltd. All rights reserved.


Gu J.,Cleveland Clinic | Gu J.,Harbin Medical University | Stocchi L.,Cleveland Clinic | Geisler D.P.,Cleveland Clinic | Kiran R.P.,Cleveland Clinic
Surgical Endoscopy and Other Interventional Techniques | Year: 2011

Background The aim of this study was to compare outcomes of laparoscopic and open completion proctectomy (CP) and ileal-pouch anal anastomosis (IPAA) after a previous laparoscopic subtotal colectomy (STC). Methods From a prospectively maintained ileal pouch database, outcomes for patients who underwent laparoscopic CP after laparoscopic STC (LSTC-LCP group) for ulcerative or indeterminate colitis were compared to those for patients who underwent open CP (LSTC-OCP group). A control group of open CP after open STC (OSTC-OCP group) was case-matched to LSTC-OCP at a ratio of 1:2 for age at surgery, gender, body mass index (BMI), year of operation, and American Society of Anesthesiologists (ASA) classification. Demographics, perioperative data, and pouch function were compared. Quality of life was evaluated using the Cleveland Global Quality of Life Scale (CGQL). Results Between 1997 and 2009, 47 patients underwent LSTC followed by LCP (LSTC-LCP), and 48 patients underwent OCP after LSTC (LSTC-OCP); the latter group was matched to 96 open-open patients (OSTC-OCP). There were no significant differences in demographic and preoperative data among the three groups, except that the OSTCOCP group patients were younger. Postoperative morbidity, pouch function, and CGQL were similar. LSTC-LCP patients had lower estimated blood loss (EBL) (p < 0.001), less commonly described intraoperative adhesiolysis (p < 0.001), reduced length of hospital stay (LOS) (p = 0.002) but longer operating time (p = 0.001) at CP/IPAA when compared with open-open patients. For patients with previous LSTC, LCP was associated with less commonly described intraoperative adhesiolysis (p = 0.003) and shorter LOS (p = 0.003) than OCP but a longer operating time (p = 0.036). Conclusions Laparoscopic CP and IPAA can be performed with safety comparable to that of open surgery after previous laparoscopic STC. The laparoscopic approach is associated with advantages including reduced intraoperative blood loss and earlier recovery as demonstrated by shorter length of hospital stay. © Springer Science+Business Media, LLC 2011.


Zhang C.-L.,Harbin Medical University | Song F.,Harvard University | Zhang J.,Harbin Medical University | Song Q.H.,Novartis
Biochemical and Biophysical Research Communications | Year: 2010

Angiogenesis and apoptosis are reciprocal processes in endothelial cells. Bcl-2, an anti-apoptotic protein, has been found to have angiogenic activities. The purpose of this study was to determine the role of Bcl-2 in hypoxia-induced angiogenesis in endothelial cells and to investigate the underlying mechanisms. Human aortic endothelial cells (HAECs) were exposed to hypoxia followed by reoxygenation. Myocardial ischemia and reperfusion mouse model was used and Bcl-2 expression was assessed. Bcl-2 expression increased in a time-dependent manner in response to hypoxia from 2 to 72 h. Peak expression occurred at 12 h (3- to 4-fold, p < 0.05). p38 inhibitor (SB203580) blocked hypoxia-induced Bcl-2 expression, whereas PKC, ERK1/2 and PI3K inhibitors did not. Knockdown of Bcl-2 resulted in decreased HAECs' proliferation and migration. Over-expression of Bcl-2 increased HAECs' tubule formation, whereas knockdown of Bcl-2 inhibited this process. In this model of myocardial ischemia and reperfusion, Bcl-2 expression was increased and was associated with increased p38 MAPK activation. Our results showed that hypoxia induces Bcl-2 expression in HAECs via p38 MAPK pathway.


Sun S.,Harbin Medical University | Sun P.,Harbin Medical University | Wang C.,Northeast Agricultural University | Sun T.,Harbin Medical University
Oncology Reports | Year: 2014

MicroRNAs (miRNAs) are a recently discovered class of small non-coding RNAs that regulate gene expression. miRNAs can contribute to cancer development and progression and are differentially expressed in normal tissue and cancer. In the present study, our aim was to investigate the expression of miR-155 in gastric cancer and to explore the mechanisms by which it influences gastric cancer cells. The level of miR-155 in 52 gastric carcinoma and corresponding non-tumor tissues was quantified by real-time reverse transcriptase-polymerase chain reaction. We used the data from EdU, CASY and cell adhesion assays to show how the expression of miR-155 affects viability and proliferation in SGC-7901 cancer cells. We also performed functional assays using the 3′-untranslated region (3′-UTR) of the c-myc gene as a miR-155 target in a luciferase reporter assay system. Our results indicated that miR-155 is downregulated in both human gastric carcinoma tissues and SGC-7901 cells. The high expression level of miR-155 may significantly downregulate cancer cell viability, proliferation and attachment. The level of miR-155 could influence endogenous c-myc expression in SGC-7901 cells, and may decrease its expression by binding to 3′-UTR of c-myc. In conclusion, our results suggest that miR-155 is extensively involved in the cancer pathogenesis of gastric carcinoma and support its function as recessive cancer genes. c-myc is an important miR-155 target gene.


Cai Z.,Texas A&M University | Cai Z.,Guangdong Medical College | Zhao Y.,Harbin Medical University | Zhao B.,Guangdong Medical College
Current Alzheimer Research | Year: 2012

Evidence from basic molecular biology has noted a critical role of GSK-3 in Alzheimer's disease (AD) pathogenesis such as beta-amyloid (Aβ) production and accumulation, the formation of neurofibrillary tangle (NFT), and neuronal degeneration. Aβ generation and deposition represents a key feature and is generated from APP by the sequential actions of two proteolytic enzymes: β-secretase and γ-secretase. GSK-3 could play a critical role in Aβ production via enhancing β-secretase activity. GSK-3 not only modulates APP processing in the process of Aβ generation, but regulates Aβ production by interfering with APP cleavage at the γ-secretase complex step since the APP and PS1 (a component of γ- secretase complex) are substrates of GSK-3 as well. GSK-3 may downregulate α-secretase through inhibiting PKC and ADAMs activity which are the substrates of GSK-3 contributing to Aβ production. Meanwhile, Aβ accumulation can induce GSK-3 activation through Aβ-mediated neuroinflammation and oxidative stress. Considering that active GSK-3 and some common GSK-3-shared factors induce the hyperphosphorylation of tau and neurofibrillary lesions, GSK-3 is a possible linking between amyloid plaques and NFT pathology. Additionally, GSK-3 could disrupt acetylcholine activity, and accelerate axon degeneration and failures in axonal transport, and lead to cognitive impairment in AD. Preclinical and clinical studies have supported that GSK-3β inhibitors could be useful in the treatment of AD. Consequently, an effective measure to inhibit GSK-3 activity may be a very attractive drug target in AD. © 2012 Bentham Science Publishers.


Gu X.,Guangdong Medical College | Yao L.,Guangdong Medical College | Ma G.,Guangdong Medical College | Cui L.,Guangdong Medical College | And 4 more authors.
Neuro-Oncology | Year: 2014

BackgroundThe translationally controlled tumor protein (TCTP) is a multifunctional protein that plays important roles in immune responses, cell proliferation, tumorigenicity and cell apoptosis. Here, we examined the clinical value of TCTP in glioma patient survival and investigated the functional roles and mechanism of TCTP in glioma development.MethodsTCTP expression was determined through immunohistochemical staining, immunoblotting, and quantitative real-time PCR (qRT-PCR). TCTP or TCF-4 expression was silenced using short hairpin (sh) RNA. In vitro cell proliferation was detected using MTT, BrdU and colony formation assays, and in vivo tumor growth was performed using the xenograft model. TCTP/TCF-4/β-catenin association was detected using a co-immunoprecipitation (co-IP) assay. TCF-4 transcription activity was detected using a TOPflash/FOPflash report gene assay. Wnt/β-catenin- targeted gene expression was detected through Western blotting.ResultsTCTP protein levels were significantly elevated in high-grade gliomas compared with low-grade gliomas and normal brain tissues. Importantly, the expression of TCTP was significantly associated with poorer overall survival and disease-free survival, and TCTP also reduced the survival rate after treatment with radiotherapy and temozolomide (RT-TMZ) for glioma patients. The ectopic expression of TCTP enhanced glioma cell proliferation both in vitro and in vivo, whereas the knockdown of TCTP inhibited this effect. Similarly, the overexpression of TCTP increased β-catenin binding to TCF-4, TOPflash report gene transcription activity, and the expression of Wnt/β-catenin signaling target genes including c-Myc and cyclin D1; notably, the knockdown of TCTP reduced these effects. The knockdown of TCF-4 using shRNA rescued the enhanced cell proliferation induced by the overexpression of TCTP.ConclusionTCTP is associated with reduced survival of glioma patients and induces glioma tumor growth through enhanced Wnt/β-catenin signaling. © 2013 © The Author(s) 2013.


Li C.,Northeast Agricultural University | Li Y.,Northeast Agricultural University | Cheng X.,Harbin Medical University | Feng L.,Northeast Agricultural University | And 2 more authors.
Bioresource Technology | Year: 2013

In this study, a unique biofilm consisting of three bacterial strains with high biofilm-forming capability (Bacillus subtilis E2, E3, and N4) and an acetonitrile-degrading bacterium (Rhodococcus rhodochrous BX2) was established for acetonitrile-containing wastewater treatment. The results indicated that this biofilm exhibited strong resistance to acetonitrile loading shock and displayed a typical spatial and structural heterogeneity and completely depleted the initial concentration of acetonitrile (800mgL-1) within 24h in a moving-bed-biofilm reactor (MBBR) after operation for 30days. The immobilization of BX2 cells in the biofilm was confirmed by PCR-DGGE. It has been demonstrated that biofilm-forming bacteria can promote the immobilization of contaminant-degrading bacteria in the biofilms and can subsequently improve the degradation of contaminants in wastewater. This approach offers a novel strategy for enhancing biological oxidation of toxic pollutants in wastewater. © 2012 Elsevier Ltd.


Wang X.,Texas A&M University | Wang S.,Texas A&M University | Li C.,Texas A&M University | Li C.,Harbin Medical University | And 12 more authors.
PLoS Genetics | Year: 2012

Family with sequence similarity 20,-member C (FAM20C) is highly expressed in the mineralized tissues of mammals. Genetic studies showed that the loss-of-function mutations in FAM20C were associated with human lethal osteosclerotic bone dysplasia (Raine Syndrome), implying an inhibitory role of this molecule in bone formation. However, in vitro gain- and loss-of-function studies suggested that FAM20C promotes the differentiation and mineralization of mouse mesenchymal cells and odontoblasts. Recently, we generated Fam20c conditional knockout (cKO) mice in which Fam20c was globally inactivated (by crossbreeding with Sox2-Cre mice) or inactivated specifically in the mineralized tissues (by crossbreeding with 3.6 kb Col 1a1-Cre mice). Fam20c transgenic mice were also generated and crossbred with Fam20c cKO mice to introduce the transgene in the knockout background. In vitro gain- and loss-of-function were examined by adding recombinant FAM20C to MC3T3-E1 cells and by lentiviral shRNA-mediated knockdown of FAM20C in human and mouse osteogenic cell lines. Surprisingly, both the global and mineralized tissue-specific cKO mice developed hypophosphatemic rickets (but not osteosclerosis), along with a significant downregulation of osteoblast differentiation markers and a dramatic elevation of fibroblast growth factor 23 (FGF23) in the serum and bone. The mice expressing the Fam20c transgene in the wild-type background showed no abnormalities, while the expression of the Fam20c transgene fully rescued the skeletal defects in the cKO mice. Recombinant FAM20C promoted the differentiation and mineralization of MC3T3-E1 cells. Knockdown of FAM20C led to a remarkable downregulation of DMP1, along with a significant upregulation of FGF23 in both human and mouse osteogenic cell lines. These results indicate that FAM20C is a bone formation "promoter" but not an "inhibitor" in mouse osteogenesis. We conclude that FAM20C may regulate osteogenesis through its direct role in facilitating osteoblast differentiation and its systemic regulation of phosphate homeostasis via the mediation of FGF23. © 2012 Wang et al.


Yang M.-M.,Chinese University of Hong Kong | Yang M.-M.,Harbin Medical University | Lai T.Y.Y.,Chinese University of Hong Kong | Luk F.O.J.,Chinese University of Hong Kong | Pang C.-P.,Chinese University of Hong Kong
Retina | Year: 2014

Background: Uveitis is a diverse group of intraocular inflammatory disease and is a significant cause of visual loss worldwide. Recent studies have identified various endogenous immune mechanisms and genetic factors that are involved in the pathogenesis of uveitis. This review provides an overview on the role of genetics in the development and clinical course of uveitis. Methods: PUBMED was used for literature search, and articles published from 1970 to 2012 that evaluated the genetic associations and mechanisms involved in the development and clinical features of uveitis were included. Results: Studies have demonstrated associations between various genetic factors and the development and clinical course of intraocular inflammatory conditions. Genes involved included genes expressing interleukins, chemokines, chemokine receptors, and tumor necrosis factor and genes involved in complement system, oxidation, and other intracellular molecular pathways. Conclusion: Multiple genetic factors play important roles in the pathogenesis of uveitis and may influence the clinical course of uveitis. Further studies to investigate the genetic mechanisms of uveitis might identify additional genetic associations and might have the potential for identifying novel therapeutic targets in the treatment of intraocular inflammation. Copyright © 2014 by Ophthalmic Communications Society, Inc.


Li J.-S.,Wenzhou Medical College | Bi Y.-T.,Wenzhou Medical College | Dong C.,Harbin Medical University | Yang J.-F.,Wenzhou Medical College | Liang W.-D.,Wenzhou Medical College
PLoS ONE | Year: 2011

Streptococcus thermophilus, a gram-positive facultative anaerobe, is one of the most important lactic acid bacteria widely used in the dairy fermentation industry. In this study, we have analyzed the global transcriptional profiling of S. thermophilus upon temperature change. During a temperature shift from 42°C to 50°C, it is found that 196 (10.4%) genes show differential expression with 102 up-regulated and 94 down-regulated at 50°C. In particular, 1) Heat shock genes, such as DnaK, GroESL and clpL, are identified to be elevated at 50°C; 2) Transcriptional regulators, such as HrcA, CtsR, Fur, MarR and MerR family, are differentially expressed, indicating the complex molecular mechanisms of S. thermophilus adapting to heat shock; 3) Genes associated with signal transduction, cell wall genes, iron homeostasis, ABC transporters and restriction-modification system were induced; 4) A large number of the differentially expressed genes are hypothetical genes of unknown function, indicating that much remains to be investigated about the heat shock response of S. thermophilus. Experimental investigation of selected heat shock gene ClpL shows that it plays an important role in the physiology of S. thermophilus at high temperature and meanwhile we confirmed ClpL as a member of the CtsR regulon. Overall, this study has contributed to the underlying adaptive molecular mechanisms of S. thermophilus upon temperature change and provides a basis for future in-depth functional studies. © 2011 Li et al.


Zhao Y.,Harbin Medical University | Xiao M.,Nanjing Medical University | He W.,Hubei University of Medicine | Cai Z.,Hubei University of Medicine
Neuropsychiatric Disease and Treatment | Year: 2015

Background and purpose: The cAMP response element binding protein (CREB) plays an important role in the mechanism of cognitive impairment and is also pivotal in the switch from short-term to long-term memory. Brain-derived neurotrophic factor (BDNF) seems a promising avenue in the treatment of cerebral ischemia injury since this neurotrophin could stimulate structural plasticity and repair cognitive impairment. Several findings have displayed that the dysregulation of the CREB–BDNF cascade has been involved in cognitive impairment. The aim of this study was to investigate the effect of cerebral ischemia on learning and memory as well as on the levels of CREB, phosphorylated CREB (pCREB), and BDNF, and to determine the effect of minocycline on CREB, pCREB, BDNF, and behavioral functional recovery after cerebral ischemia. Methods: The animal model was established by permanent bilateral occlusion of both common carotid arteries. Behavior was evaluated 5 days before decapitation with Morris water maze and open-field task. Four days after permanent bilateral occlusion of both common carotid arteries, minocycline was administered by douche via the stomach for 4 weeks. CREB and pCREB were examined by Western blotting, reverse transcription polymerase chain reaction, and immunohistochemistry. BDNF was measured by immunohistochemistry and Western blotting. Results: The model rats after minocycline treatment swam shorter distances than control rats before finding the platform (P=0.0007). The number of times the platform position was crossed for sham-operation rats was more than that of the model groups in the corresponding platform location (P=0.0021). The number of times the platform position was crossed for minocycline treatment animals was significantly increased compared to the model groups in the corresponding platform position (P=0.0016). CREB, pCREB, and BDNF were downregulated after permanent bilateral occlusion of both common carotid arteries in the model group. Minocycline increased the expression of CREB, pCREB, and BDNF, and improved cognitive suffered from impairment of permanent bilateral occlusion of both common carotid arteries. Conclusion: Minocycline improved cognitive impairment from cerebral ischemia via enhancing CREB, pCREB, and BDNF activity in the hippocampus. © 2015 Zhao et al.


Fu D.,The University of Oklahoma Health Sciences Center | Fu D.,Harbin Medical University | Wu M.,The University of Oklahoma Health Sciences Center | Zhang J.,The University of Oklahoma Health Sciences Center | And 6 more authors.
Diabetologia | Year: 2012

Aims/hypothesis In previous studies we have shown that extravasated, modified LDL is associated with pericyte loss, an early feature of diabetic retinopathy (DR). Here we sought to determine detailed mechanisms of this LDLinduced pericyte loss. Methods Human retinal capillary pericytes (HRCP) were exposed to 'highly-oxidised glycated' LDL (HOG-LDL) (a model of extravasated and modified LDL) and to 4-hydroxynonenal or 7-ketocholesterol (components of oxidised LDL), or to native LDL for 1 to 24 h with or without 1 h of pretreatment with inhibitors of the following: (1) the scavenger receptor (polyinosinic acid); (2) oxidative stress (N-acetyl cysteine); (3) endoplasmic reticulum (ER) stress (4-phenyl butyric acid); and (4) mitochondrial dysfunction (cyclosporin A). Oxidative stress, ER stress, mitochondrial dysfunction, apoptosis and autophagy were assessed using techniques including western blotting, immunofluorescence, RT-PCR, flow cytometry and TUNEL assay. To assess the relevance of the results in vivo, immunohistochemistry was used to detect the ER stress chaperon, 78 kDa glucose-regulated protein, and the ER sensor, activating transcription factor 6, in retinas from a mouse model of DR that mimics exposure of the retina to elevated glucose and elevated LDL levels, and in retinas from human participants with and without diabetes and DR. Results Compared with native LDL, HOG-LDL activated oxidative and ER stress in HRCP, resulting in mitochondrial dysfunction, apoptosis and autophagy. In a mouse model of diabetes and hyperlipidaemia (vs mouse models of either condition alone), retinal ER stress was enhanced. ER stress was also enhanced in diabetic human retina and correlated with the severity of DR. Conclusions/interpretation Cell culture, animal, and human data suggest that oxidative stress and ER stress are induced by modified LDL, and are implicated in pericyte loss in DR. © Springer-Verlag 2012.


Huang J.,Stanford University | Huang J.,CAS Beijing National Laboratory for Molecular | Bu L.,Stanford University | Bu L.,Harbin Medical University | And 6 more authors.
ACS Nano | Year: 2010

The effect of nanoparticle size (30-120 nm) on magnetic resonance imaging (MRI) of hepatic lesions in vivo has been systematically examined using polyvinylpyrrolidone (PVP)-coated iron oxide nanoparticles (PVP-IOs). Such biocompatible PVP-IOs with different sizes were synthesized by a simple one-pot pyrolysis method. These PVP-IOs exhibited good crystallinity and high T 2 relaxivities, and the relaxivity increased with the size of the magnetic nanoparticles. It was found that cellular uptake changed with both size and surface physiochemical properties, and that PVP-IO-37 with a core size of 37 nm and hydrodynamic particle size of 100 nm exhibited higher cellular uptake rate and greater distribution than other PVP-IOs and Feridex. We systematically investigated the effect of nanoparticle size on MRI of normal liver and hepatic lesions in vivo. The physical and chemical properties of the nanoparticles influenced their pharmacokinetic behavior, which ultimately determined their ability to accumulate in the liver. The contrast enhancement of PVP-IOs within the liver was highly dependent on the overall size of the nanoparticles, and the 100 nm PVP-IO-37 nanoparticles exhibited the greatest enhancement. These results will have implications in designing engineered nanoparticles that are optimized as MR contrast agents or for use in therapeutics. © 2010 American Chemical Society.


Sun C.,Lund University | Sun C.,Harbin Medical University | Rosendahl A.H.,Lund University | Wang X.D.,Fudan University | And 2 more authors.
Current Medicinal Chemistry | Year: 2012

Polysaccharide-K (PSK, Krestin) is one of the most commonly used medicinal mushroom extracts with a long history as an additive in cancer therapy in Asia, especially in Japan. PSK has a documented anti-tumor activity both in vitro and in vitro, in various types of cancers, including colorectal, gastric, breast, liver, pancreatic, and lung cancer. Despite PSK having been studied for about 40 years as an immune modulator and biological response modifier, the mechanisms of action by PSK have not yet been clearly and completely elucidated. This review aims to provide an up-to-date account for the effects of PSK in cancer with the hope of thereby providing an increased understanding of the molecular mechanisms of PSK and also its potential as an additive in modern cancer therapy. © 2012 Bentham Science Publishers.


Wang J.J.-Y.,King Abdullah University of Science and Technology | Wang Y.,Ohio State University | Zhao S.,Harbin Medical University | Gao X.,King Abdullah University of Science and Technology
Engineering Applications of Artificial Intelligence | Year: 2015

In this paper, a novel pattern classification approach is proposed by regularizing the classifier learning to maximize mutual information between the classification response and the true class label. We argue that, with the learned classifier, the uncertainty of the true class label of a data sample should be reduced by knowing its classification response as much as possible. The reduced uncertainty is measured by the mutual information between the classification response and the true class label. To this end, when learning a linear classifier, we propose to maximize the mutual information between classification responses and true class labels of training samples, besides minimizing the classification error and reducing the classifier complexity. An objective function is constructed by modeling mutual information with entropy estimation, and it is optimized by a gradient descend method in an iterative algorithm. Experiments on two real world pattern classification problems show the significant improvements achieved by maximum mutual information regularization. © 2014 Elsevier Ltd.


Jiang Z.,Fudan University | Li C.,Harbin Medical University | Xu Y.,Fudan University | Cai S.,Fudan University
International Journal of Colorectal Disease | Year: 2010

Purpose: Studies on polymorphism of X-ray repair cross-complementing group 1 (XRCC1), group 3 (XRCC3), and colorectal cancer risk are inconclusive. The purpose of this study is to evaluate the role of XRCC1 R399Q, R194W, and XRCC3 T241M genotypes in colorectal cancer susceptibility. Methods: We performed a meta-analysis on all available studies that provided 3,514/4,686 cases/controls for R399Q, 2,767/3,907 cases/controls for R194W and 3,183/3,926 cases/controls for T241M. Results: Overall, no apparent effects of 194 W allele compared to 194R on colorectal cancer risk were found in all subjects and subgroups (Asians and Caucasians). Insignificant effects were also found under other genetic contrasts (homologous contrast, dominant model, and recessive model). The same pattern of results was produced in T241M polymorphism. The 399Q allele compared to 399R showed no significant association with colorectal cancer risk in all subjects and subgroups. However, protective effects of 399QQ genotype were observed under recessive model (QQ/QR + RR) [P=0.02, OR=0.84, 95% CI (0.72, 0.97)] and homozygote contrast (QQ/RR) [P=0.01, OR=0.81; 95% CI (0.69, 0.95)] in all subjects. Conclusion: Results suggested that 399Q allele might act as a recessive allele in its association with colorectal cancer. © 2009 Springer-Verlag.


Meng W.,Harbin Medical University | Zhao W.,University of Tennessee Health Science Center | Zhao T.,University of Tennessee Health Science Center | Liu C.,Harbin Medical University | And 3 more authors.
American Journal of Hypertension | Year: 2014

BACKGROUND Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin (Ang) II to generate Ang1-7, which mediates cellular actions through Mas receptors (MasR). Hypertension is accompanied by high or low circulating AngII levels and cardiac/renal injury. The purpose of this study is to explore (i) whether circulating AngII affects ACE2/MasR expressions in the hypertensive heart and kidney; and (ii) whether Ang1-7 regulates cardiac repair/remodeling responses through MasR during hypertension. METHODS In the first portion of the study, rats received either an AngII infusion (400ng/kg/min) for 4 weeks, leading to hypertension with high circulating AngII, or an aldosterone (ALDO, 0.75 μg/h) infusion for 4 weeks, leading to hypertension with low/normal circulating AngII. Cardiac and renal ACE2/MasR expressions were examined. We found that cardiac ACE2 was increased and MasR attenuated in both AngII and ALDO groups. However, renal ACE2 and MasR remained unchanged in both AngII- and ALDO-treated animals. RESULTS In the second portion, rats received AngII infusion with/without MasR antagonist (A779, 1mg/kg/day) for 4 weeks. The roles of MasR blockade in cardiac inflammation, fibrosis, apoptosis, and ventricular function were examined. Chronic AngII infusion caused scattered cardiac injuries, and A779 cotreatment exacerbated cardiac injury, resulting in aggravated inflammatory, fibrogenic, and apoptotic responses compared with the AngII group. Cardiac function, however, was unaltered in the AngII and A779 groups. CONCLUSIONS ACE2 and MasR expressions in the hypertensive heart and kidney are not regulated by circulating AngII levels. Ang1-7 is involved in multiple repair responses, suggesting that therapeutic strategies aimed at administering Ang1-7 hold potential for the management of cardiac remodeling. © 2013 American Journal of Hypertension, Ltd. All rights reserved.


Kim M.H.,Dong - A University | Jin E.,Harbin Medical University | Zhang H.-Z.,Dong - A University | Kim S.-W.,Dong - A University
International Journal of Cardiology | Year: 2013

Background: Recently, we showed the angio-vasculogenic potential of uncultured human peripheral blood (hPB)-derived CD31+ cells. However, thus far, the angiogenic property of the cultured hPB-derived CD31+ (C-31+) cells is unknown. Thus, this study aimed to assess the angiogenic potency of C-31+ cells on experimental ischemia. Methods: CD31+ and CD31- cells were isolated by magnetic bead separation technique, and cultured in EBM-2 complete medium for 6 days. The expression of multiple angiogenic genes in these cells was measured using qRT-PCR. In addition, endothelial progenitor cell culture and matrigel network formation assays were performed. A mouse model of hindlimb ischemia induced by surgical resection of the right femoral artery was used, and the C-31 + cells were intramuscularly transplanted into the ischemic area. Immunohistochemical analysis was also performed. Results: C-31+ cells exclusively showed higher colony-forming activity, and gave rise to EPCs. C-31+ cells also induced higher endothelial network formation, and exhibited higher pro-angiogenic and lower inflammatory gene expression. In our ischemic hindlimb model, transplantation of C-31+ cells induced increased blood perfusion (0.652±0.03 vs. 0.47±0.04; P<0.01) and increased capillary density (85±5.5 vs. 57±4.1; P<0.01) as compared to C-31- cells. In addition, angiogenic factors were markedly upregulated after the transplantation of C-31+ cells, indicating that C-31+ cells contributed to the neovascularization. Conclusions: The high angiogenic and therapeutic potential of C-31+ cells observed in our ischemic animal model suggests a novel role of hPB-derived cultured CD31+ cells in the treatment of ischemic cardiovascular diseases. © 2011 Elsevier Ireland Ltd. All rights reserved.


Hatta K.,Toronto General Research Institute | Hatta K.,University of Toronto | Huang M.-L.,Harbin Medical University | Weisel R.D.,Toronto General Research Institute | And 3 more authors.
Journal of Cellular and Molecular Medicine | Year: 2012

Previous studies have shown that telocytes are found in a variety of tissues. Here, we report the presence of telocytes in the human endometrium. In addition, telocytes were isolated from the rat endometrium and cultured. Immunohistochemistry was performed in vitro and in vivo. Cultured cells showed that telocytes expressed CD34, and similar results were found in the uterine tissue. In both species, telocytes also stained positive for vimentin and connexin 43. Telopodes were observed connecting cell colonies and connecting distant cells. Our findings suggest that telocytes may have a role in cell-to-cell communication over short and long distances within the endometrium. © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.


Li Y.,Harbin Medical University | Zhuang L.,Harbin Medical University | Wang Y.,Harbin Medical University | Hu Y.,Harbin Medical University | And 5 more authors.
Autophagy | Year: 2013

In recent years, substantial research interests have arisen to decipher miRNA function in cell death modules such as apoptosis and autophagy. Despite enormous success, it is increasingly evident that systems biology approaches that analyze the intra- and inter-modular connectivity are essential to uncover the generic organizing principles of the miRNA-mediated cell death network. We therefore constructed the miRDeathDB database to archive experimentally confirmed programmed cell death (PCD)- associated miRNAs together with their target proteins. Based on global analysis of the miRNA-mediated cell death network, we find there are two classes of miRNAs important to the cell death output. One class tends to have more regulatory links to proteins within death modules, whereas the other one lies on the boundary between modules, and tends to connect with more protein pairs across the modules. These findings indicate that miRNAs provide a novel communication mechanism between PCD-related proteins involved in both intra- and inter-cell death modules. Furthermore, miRDeathDB can also facilitate researcher access to a variety of resources centered on PCD-associated miRNAs. © 2013 Landes Bioscience.


Zhang L.,Harbin Medical University | Hadley G.A.,Ohio State University
Chinese Medical Journal | Year: 2010

Background Previous studies using knockout mice document a key role for the integrin CD103 in promoting organ allograft rejection and graft-versus-host disease. However, a determination of whether blockade of the CD103 pathway represents a viable therapeutic strategy for intervention in these processes has proven problematic due to the lack of reagents that efficiently deplete CD103 + cells from wild type hosts. To circumvent this problem, in the present study, we invented an anti-CD103 immunotoxin (M290-SAP). We investigated whether M290-SAP has capacity to eliminate CD103-expressing cells in vivo and protect transplanted islets from destroying by host immune cells. Methods Flow cytometry was used to analyze the efficacy of M290-SAP in depleting CD103-expressing cells in vivo. Then using allogenic islet transplantation models as well as NOD mice with recent onset type 1 diabetes, the therapeutic efficacy of CD103-expressing cell depletion was addressed. Results M290-SAP dramatically reduces the frequency and absolute numbers of CD103-expressing leukocytes in peripheral lymphatic tissues of treated mice. Balb/c islets transplanted into streptozotocin-induced diabetic C57BL/6 mice under single M290-SAP treatment showed an indefinite survival time compared with untreated mice, M290-treated mice and IgG-SAP treated mice (mean survival time, >100 days vs. <20 days). C57BL/6 islets transplanted into hyperglycemic NOD mice under single M290-SAP treatment showed a pronounced delay in allograft rejection compared with untreated mice (mean survival time 12-13 days vs. <7 days). Immunological analysis of mice with long-term islet allograft survival revealed an obvious atrophy thymus and severe downregulation of alloimmunity of CD8 subpopulation response to allogenic stimulation. Conclusion Regardless of the underlying mechanisms, these data document that depletion of CD103-expressing cells represents a viable strategy for therapeutic intervention in islet allograft rejection.


Zhao T.,University of Tennessee Health Science Center | Zhao W.,University of Tennessee Health Science Center | Meng W.,Harbin Medical University | Liu C.,Harbin Medical University | And 2 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2014

Vascular endothelial growth factor (VEGF)-C is a key mediator of lymphangiogenesis. Our recent study shows that VEGF-C/VEGF receptors (VEGFR)-3 are significantly increased in the infarcted rat myocardium, where VEGFR-3 is expressed not only in lymph ducts but also in myofibroblasts, indicating that VEGF-C has an unrevealed role in fibrogenesis during cardiac repair. The current study is to explore the regulation and molecular mechanisms of VEGF-C in fibrogenesis. The potential regulation of VEGF-C on myofibroblast differentiation/growth/migration, collagen degradation/synthesis, and transforming growth factor (TGF)-β and ERK pathways was detected in cultured cardiac myofibroblasts. Our results showed that VEGF-C significantly increased myofibroblast proliferation, migration, and type I/III collagen production. Matrix metalloproteinase (MMP)-2 and -9 were significantly elevated in the medium of VEGF-C-treated cells, coincident with increased tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Furthermore, VEGF-C activated the TGF-β1 pathway and ERK phosphorylation, which was significantly suppressed by TGF-β or ERK blockade. This is the first study indicating that in addition to lymphangiogenesis, VEGF-C is also involved in fibrogenesis through stimulation of myofibroblast proliferation, migration, and collagen synthesis, via activation of the TGF-β1 and ERK pathways. © 2014 the American Physiological Society.


Li C.,Harbin Medical University | Jiang Z.,Fudan University | Liu X.,Harbin Medical University
Molecular Biology Reports | Year: 2010

Studies on the polymorphisms of Xeroderma Pigmentosum Group D (XPD) have shown inconclusive trends in the risk of bladder cancer. The purpose of this study is to evaluate the role of XPD single nucleotide polymorphisms in bladder cancer susceptibility. We performed a meta-analysis on all available studies, which included 5,368 and 6,683 XPD Lys751Gln cases and controls and 3,220 and 4,391 Asp312Asn cases and controls, respectively. Overall, Significant risk effects of Lys751Gln genotype was found under recessive model contrast [Gln/Gln vs. (Gln/Lys + Lys/Lys)] [P = 0.04, OR = 1.12; 95% CI (1.01, 1.26)], and subtle but insignificantly increased risks between Lys751Gln and bladder cancer were observed under allele contrast (Gln vs. Lys) and homologous contrast (Gln/Gln vs. Lys/Lys) in all subjects. The 751Gln allele had no significant effect on bladder cancer in all subgroups (Asian, Caucasian and USA). Significant risk effects of Asp 312Asn polymorphism on bladder susceptibility were observed in all subjects under all genetic contrasts, however, stratified analyses showed that the 312Asn allele showed different risk effects in USA and Caucasian. The Gln/Gln genotype acts as a risk factor in its association with bladder cancer, and the effect of Lys751Gln polymorphism on bladder susceptibility should be studied with larger, stratified population; the 312Asn allele has an important role in the etiology of bladder cancer whereas the ethnic background should be carefully concerned in further studies. © 2009 Springer Science+Business Media B.V.


Li F.,Harbin Medical University | Li C.,Harbin Medical University | Jiang Z.,Fudan University | Ma N.,Harbin Medical University | Gao X.,Harbin Medical University
Urology | Year: 2011

Objectives To evaluate the role of the X-ray repair cross complementing group 3 (XRCC3) T241M polymorphism in bladder cancer susceptibility. Studies of the polymorphism of XRCC3 have shown inconclusive trends in the risk of bladder cancer. Methods We performed a meta-analysis of all available studies, which included 5298 cases and 6614 controls. Results Overall, a significant risk effect of the T241M polymorphism was found under homologous contrast (MM vs TT; P = .02, odds ratio [OR] 1.16, 95% confidence interval [CI] 1.02-1.33). Subtle, but insignificantly increased, risks were observed under recessive model contrast [MM vs (MT+TT); P = .05, OR 1.13, 95% CI 1.00-1.27] in all subjects, with homologous contrast (P = .05, OR 1.16, 95% CI 1.00-1.34) and recessive model contrast (P = .06, OR 1.13, 95% CI 0.99-1.29) observed in the European subgroup. Conclusions Taken together, our meta-analysis had suggested an increased risk role of XRCC3 241MM genotype in bladder cancer among all subjects, and the effect of T241M polymorphism on bladder susceptibility should be studied with a larger, stratified population. © 2011 Elsevier Inc.


Jiang Z.,Fudan University | Li C.,Harbin Medical University | Xu Y.,Fudan University | Cai S.,Fudan University | Wang X.,Harbin Medical University
Breast Cancer Research and Treatment | Year: 2010

Studies on polymorphisms of Xeroderma Pigmentosum Group D Protein (XPD) and breast cancer risk are inconclusive. To elucidate the role of XPD genotypes, all available studies were considered in this meta-analysis. The study provided 11,362/10,622 cases/