Hanzhong, China
Hanzhong, China

Nanjing Medical University is a university in Nanjing, Jiangsu Province, China. It was established in 1934 in Zhenjiang, but subsequently relocated to Nanjing in 1957. The university has two main campuses: Wutai and Jiangning, both of which have international student apartments.In 2014, Academic Ranking of World Universities ranked it between 401-500 in the world and 26-32 in China. It was one of the first universities to offer an English taught Bachelor of Medicine, Bachelor of Surgery program, as approved by the Ministry of Education of the People's Republic of China . Wikipedia.


Time filter

Source Type

Zhang F.,Nanjing Medical University | Yang B.,Nanjing Medical University | Chen H.,Nanjing Medical University | Ju W.,Nanjing Medical University | And 3 more authors.
Heart Rhythm | Year: 2013

Background No randomized controlled study has prospectively compared the performance and clinical outcomes of remote magnetic control (RMC) vs manual catheter control (MCC) during ablation of right ventricular outflow tract (RVOT) ventricular premature complexes (VPC) or ventricular tachycardia (VT). Objective The purpose of this study was to prospectively evaluate the efficacy and safety of using either RMC vs MCC for mapping and ablation of RVOT VPC/VT. Methods Thirty consecutive patients with idiopathic RVOT VPC/VT were referred for catheter ablation and randomized into either the RMC or MCC group. A noncontact mapping system was deployed in the RVOT to identify origins of VPC/VT. Conventional activation and pace-mapping was performed to guide ablation. If ablation performed using 1 mode of catheter control was acutely unsuccessful, the patient crossed over to the other group. The primary endpoints were patients' and physicians' fluoroscopic exposure and times. Results Mean procedural times were similar between RMC and MCC groups. The fluoroscopic exposure and times for both patients and physicians were much lower in the RMC group than in the MCC group. Ablation was acutely successful in 14 of 15 patients in the MCC group and 10 of 15 in the RMC group. Following crossover, acute success was achieved in all patients. No major complications occurred in either group. During 22 months of follow-up, RVOT VPC recurred in 2 RMC patients. Conclusion RMC navigation significantly reduces patients' and physicians' fluoroscopic times by 50.5% and 68.6%, respectively, when used in conjunction with a noncontact mapping system to guide ablation of RVOT VPC/VT. © 2013 Heart Rhythm Society. All rights reserved.


Tang H.-L.,Peking University | Li Y.,Peking University | Hu Y.-F.,Peking University | Xie H.-G.,Nanjing Medical University | Zhai S.-D.,Peking University
PLoS ONE | Year: 2013

Background: There are inconsistent conclusions about whether CYP2C19 variants could affect H. pylori eradication rate in patients treated with the proton pump inhibitor (PPI)-based therapy. We therefore performed a meta-analysis of randomized clinical trials (RCTs) to re-evaluate the impact of CYP2C19 variants on PPI-based triple therapy for the above indication. Methods: All relevant RCTs in the PubMed, Cochrane Library, EMBASE, Web of Science and two Chinese databases (up to February 2013) were systematically searched, and a pooled analysis was performed with the odds ratio (OR) and 95% confidence interval (CI) by the STATA software. Results: Sixteen RCT datasets derived from 3680 patients were included. There was no significant heterogeneity across the data available in this meta-analysis. There were significant differences in that rate between homozygous (HomEMs) and heterozygous (HetEMs) extensive metabolizers (OR 0.724; 95% CI 0.594-0.881), between HomEMs and poor metabolizers (PM) (OR 0.507; 95%CI 0.379-0.679), or between HetEMs and PMs (OR 0.688; 95%CI 0.515-0.920), regardless of the PPI being taken. Furthermore, sub-analysis of individual PPIs was carried out to explore the difference across all the PPIs used. A significantly low rate was seen in HomEMs vs. HetEMs taking either omeprazole (OR 0.329; 95%CI 0.195-0.553) or lansoprazole (OR 0.692; 95%CI 0.485-0.988), and also in HomEMs vs. PMs for omeprazole (OR 0.232; 95%CI 0.105-0.515) or lansoprazole (OR 0.441; 95%CI 0.252-0.771). However, there was no significant difference between HetEMs and PMs taking either one. No significant differences were observed for rabeprazole or esomeprazole across the CYP2C19 genotypes of interest. Conclusions: Carriage of CYP2C19 loss-of-function variants is associated with increased H. pylori eradication rate in patients taking PPI-based triple therapies when omeprazole or lansoprazole is chosen. However, there is no a class effect after use of rabeprazole or esomeprazole. © 2013 Tang 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.


Chen S.-L.,Nanjing Medical University | Chen S.-L.,Nanjing Heart Center | Zhang F.-F.,Nanjing Medical University | Xu J.,Nanjing Medical University | And 4 more authors.
Journal of the American College of Cardiology | Year: 2013

Objectives This study was designed to test the safety and efficacy of pulmonary artery (PA) denervation (PADN) for patients with idiopathic PA hypertension (IPAH) not responding optimally to medical therapy. Background Baroreceptors and sympathetic nerve fibers are localized in or near the bifurcation area of the main PA. We previously demonstrated that PADN completely abolished the experimentally elevated PA pressure responses to occlusion of the left interlobar PA. Methods Of a total of 21 patients with IPAH, 13 patients received the PADN procedure, and the other 8 patients who refused the PADN procedure were assigned to the control group. PADN was performed at the bifurcation of the main PA, and at the ostial right and left PA. Serial echocardiography, right heart catheterization, and a 6-min walk test (6MWT) were performed. The primary endpoints were the change of PA pressure (PAP), tricuspid excursion (Tei) index, and 6MWT at 3 months follow-up. Results Compared with the control group, at 3 months follow-up, the patients who underwent the PADN procedure showed significant reduction of mean PAP (from 55 ± 5 mm Hg to 36 ± 5 mm Hg, p < 0.01), and significant improvement of the 6MWT (from 324 ± 21 m to 491 ± 38 m, p < 0.006) and of the Tei index (from 0.7 ± 0.04 to 0.50 ± 0.04, p < 0.001). Conclusions We report for the first time the effect of PADN on functional capacity and hemodynamics in patients with IPAH not responding optimally to medical therapy. Further randomized study is required to confirm the efficacy of PADN. (First-in-Man Pulmonary Artery Denervation for Treatment of Pulmonary Artery Hypertension [PADN-1] study; chiCTR-ONC-12002085). © 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.


Yang N.,Nanjing Medical University | Cao Y.,Shanghai University | Han P.,Nanjing Medical University | Zhu X.,Nanjing University | And 3 more authors.
Analytical Chemistry | Year: 2012

Mammalian Argonaute2 (Ago2) protein is the key player of RNA-induced silencing complexes (RISCs), regulating gene function through RNA interference. In this paper, a method to investigate the RNA endonuclease activity of Ago2 is reported using electrochemical technique with G-quadruplex-hemin complexes as signal transduction probes. Experimental results reveal that Ago2 may exhibit its slicer activity without any biological partners or ATP in wide pH and temperature ranges; thus, a method to assay the activity of the enzyme is proposed. For purified samples, the endonuclease activity of Ago2 can be quantified in the range from 6.25 to 25 nM with a detection limit of 5.02 nM. In the case of porcine cardiocyte lysates which contain a certain amount of Ago2, a linear correlation can be also obtained between the electrochemical signal and the dilution radio of the lysates. The proposed method shows desirable sensitivity, high selectivity, and excellent reproducibility, implying that this method may hold considerable potential for functional studies of Ago2 and clinical diagnosis in the future. © 2012 American Chemical Society.


Cao Y.,Shanghai University | Zhu S.,Nanjing Medical University | Yu J.,Shanghai University | Zhu X.,Nanjing University | And 3 more authors.
Analytical Chemistry | Year: 2012

Based on small molecule-linked DNA and the nicking endonuclease-assisted amplification (NEA) strategy, a novel electrochemical method for protein detection is proposed in this work. Specifically, the small molecule-linked DNA (probe 1) can be protected from exonuclease-catalyzed digestion upon binding to the protein target of the small molecule, so the DNA strand may hybridize with another DNA strand (probe 2) that is previously immobilized onto an electrode surface. Consequently, the NEA process is triggered, resulting in continuous removal of the DNA strands from the electrode surface, and the blocking effect against the electrochemical species [Fe(CN) 6] 3-/4- becomes increasingly lower; thus, increased electrochemical waves can be achieved. Because the whole process is activated by the target protein, an electrochemical method for protein quantification is developed. Taking folate receptor (FR) as an example in this work, we can determine the protein in a linear range from 0.3 to 15 ng/mL with a detection limit of 0.19 ng/mL. Furthermore, because the method can be used for the assay of FR in serum samples and for the detection of other proteins such as streptavidin by simply changing the small molecule moiety of the DNA probes, this novel method is expected to have great potential applications in the future. © 2012 American Chemical Society.


Ding W.,Nanjing Medical University | Zhang X.,Nanjing Medical University | Huang H.,Nanjing Medical University | Ding N.,Nanjing Medical University | Zhang S.,Nanjing Medical University
PLoS ONE | Year: 2014

Obstructive sleep apnea syndrome (OSAS) is associated with many cardiovascular disorders such as heart failure, hypertension, atherosclerosis, and arrhythmia and so on. Of the many associated factors, chronic intermittent hypoxia (CIH) in particular is the primary player in OSAS. To assess the effects of CIH on cardiac function secondary to OSAS, we established a model to study the effects of CIH on Wistar rats. Specifically, we examined the possible underlying cellular mechanisms of hypoxic tissue damage and the possible protective role of adiponectin against hypoxic insults. In the first treatment group, rats were exposed to CIH conditions (nadir O2, 5-6%) for 8 hours/day, for 5 weeks. Subsequent CIHinduced cardiac dysfunction was measured by echocardiograph. Compared with the normal control (NC) group, rats in the CIH-exposed group experienced elevated levels of left ventricular end-systolic dimension and left ventricular end-systolic volume and depressed levels of left ventricular ejection fraction and left ventricular fractional shortening (p<0.05). However, when adiponectin (Ad) was added in CIH + Ad group, we saw a rescue in the elevations of the aforementioned left ventricular function (p<0.05). To assess critical cardiac injury, we detected myocardial apoptosis by Terminal deoxynucleotidyl transfer-mediated dUTP nick end-labeling (TUNEL) analysis. It was showed that the apoptosis percentage in CIH group (2.948%) was significantly higher than that in NC group (0.4167%) and CIH + Ad group (1.219%) (p<0.05). Protein expressions of cleaved caspase-3, cleaved caspase-9, and cleaved-caspase-12 validated our TUNEL results (p<0.05). Mechanistically, our results demonstrated that the proteins expressed with endoplasmic reticulum stress and the expression of reactive oxygen species (ROS) were significantly elevated under CIH conditions, whereas Ad supplementation partially decreased them. Overall, our results suggested that Ad augmentation could improve CIH-induced left ventricular dysfunction and associated myocardial apoptosis by inhibition of ROS-dependent ER stress. © 2014 Ding et al.


Li C.,Nanjing Medical University | Hirsh J.,MacMaster University | Xie C.,MacMaster University | Johnston M.A.,Henderson Hospital | Eikelboom J.W.,Hamilton General Hospital
Journal of Thrombosis and Haemostasis | Year: 2012

Background: Guidelines recommend stopping aspirin and clopidogrel 7 to 10days before surgery to allow time for replacement of permanently inhibited platelets by newly released uninhibited platelets.Objectives: The purpose of the present study was to determine the rate of offset of the anti-platelet effects of aspirin and clopidogrel after stopping treatment and the proportion of untreated donor platelets that are required to reverse their anti-platelet effects. Methods: Cohort 1 consisted of 15 healthy subjects who received aspirin 81mgday -1 or clopidogrel 75mgday -1 for 7days and underwent serial blood sampling until platelet function testing results normalized. Cohort 2 consisted of 36 healthy subjects who received aspirin 325mgday -1, clopidogrel 75mgday -1, aspirin 81mgday -1 plus clopidogrel 75mgday -1 or no treatment for 7days and underwent a single blood sampling. Results: In cohort 1, arachidonic acid (AA)-induced light transmission aggregation (LTA) returned to baseline levels in all subjects within 4days of stopping aspirin, coinciding with the partial recovery of plasma thromboxane B 2 concentrations. ADP-induced LTA did not return to baseline levels until 10days after stopping clopidogrel. In cohort 2, AA-induced LTA in patient treated with aspirin reached control levels after mixing with 30% untreated donor platelets whereas ADP-induced LTA in patients treated with clopidogrel reached control levels only after the addition of 90% or more donor platelets. Conclusions: Platelet aggregation recovers within 4days of stopping aspirin but clopidogrel must be stopped for 10days to achieve a normal aggregatory response. © 2012 International Society on Thrombosis and Haemostasis.


Hu Y.,Nanjing Medical University | Zhang S.,Nanjing Medical University | Luo C.,Nanjing Medical University | Liu Q.,Jiangsu Family Planning Institute | Zhou Y.-H.,Nanjing Medical University
BMC Infectious Diseases | Year: 2012

Background: Hepatitis B virus (HBV) infection is endemic in China; perinatal transmission is the main source of chronic HBV infection. Simultaneous administration of hepatitis B immune globulin (HBIG) and hepatitis B vaccine is highly effective to prevent perinatal transmission of HBV; however, the effectiveness also depends on full adherence to the recommended protocols in daily practice. In the present investigation, we aimed to identify gaps in immunoprophylaxis of perinatal transmission of HBV between recommendations and routine practices in Jiangsu Province, China.Methods: Totally 626 children from 6 cities and 8 rural areas across Jiangsu Province, China, born from February 2003 to December 2004, were enrolled; 298 were born to mothers with positive hepatitis B surface antigen (HBsAg) and 328 were born to HBsAg-negative mothers. Immunoprophylactic measures against hepatitis B were retrospectively reviewed for about half of the children by checking medical records or vaccination cards and the vaccine status was validated for most of children.Results: Of 298 children born to HBV carrier mothers, 11 (3.7%) were HBsAg positive, while none of 328 children born to non-carrier mothers was HBsAg positive (P < 0.01). The rates of anti-HBs ≥ 10 mIU/ml in children of carrier and non-carrier mothers were 69.5% and 69.2% respectively (P = 0.95). The hepatitis B vaccine coverage in two groups was 100% and 99.4% respectively (P = 0.50), but 15.1% of HBV-exposed infants did not receive the timely birth dose. Prenatal HBsAg screening was performed only in 156 (52.3%) of the carrier mothers. Consequently, only 112 (37.6%) of HBV-exposed infants received HBIG after birth. Furthermore, of the 11 HBV-infected children, only one received both HBIG and hepatitis B vaccine timely, seven missed HBIG, two received delayed vaccination, and one missed HBIG and received delayed vaccination.Conclusions: There are substantial gaps in the prevention of perinatal HBV infection between the recommendations and routine practices in China, which highlights the importance of full adherence to the recommendations to eliminate perinatal HBV infection in the endemic regions. © 2012 Hu et al.; licensee BioMed Central Ltd.


Li Y.,Peking University | Tang H.-L.,Peking University | Hu Y.-F.,Peking University | Xie H.-G.,Nanjing Medical University
Journal of Thrombosis and Haemostasis | Year: 2012

Background:A large number of clinical studies have documented that a loss-of-function variant CYP2C19*2 affects clinical profiles of clopidogrel (efficacy and safety). However, data on the impact of a gain-of-function variant CYP2C19*17 on the response to that drug seem to be less consistent. Objectives:To systematically summarize all available clinical data assessing the role of the CYP2C19*17 variant in patients taking clopidogrel. Methods:A literature search was conducted and a meta-analysis was performed for 11 eligible studies. The endpoints included the major adverse cardiovascular events (MACE, representing non-fatal myocardial infarction, stroke, revascularization, or death), bleeding events, mortality, stent thrombosis and high platelet reactivity (HPR). Results:Data from six clinical studies demonstrated that carriers of the CYP2C19*17 variant had a marked protection against recurrent cardiovascular events in patients with coronary artery disease compared with non-carriers, as measured by a 16% decrease in the incidence of MACE (10.0% vs. 11.9%; OR, 0.82; 95% CI, 0.72-0.94; P=0.005). On the other hand, carriers had an increased risk of developing bleeding as expected (8.0% vs. 6.5%; OR, 1.25; 95% CI, 1.07-1.47; P=0.006; four studies). Moreover, the presence of the CYP2C19*17 variant might lead to increased response to clopidogrel, as shown by a marked lower prevalence of HPR in carriers than in non-carriers (37.9% vs. 50.8%; OR, 0.60; 95% CI, 0.45-0.79; P=0.0003; three studies). Conclusions:Carriers of the CYP2C19*17 variant have greater therapeutic responsiveness to clopidogrel than non-carriers, but they have an increased risk of developing bleeding as well. © 2011 International Society on Thrombosis and Haemostasis.


Zhang Y.-D.,Peking University | Zhang Y.-D.,Nanjing Medical University | Wang J.,Peking University | Zhang J.,Peking University | And 2 more authors.
Radiology | Year: 2014

Purpose: To assess the hemodynamic effect of iodinated contrast media (CM) on glomerular filtration rate (GFR) by using dynamic three-dimensional magnetic resonance (MR) renography in a rabbit model. Materials and Methods: This study was approved by the university animal care and use committee. Twelve healthy male New Zealand rabbits (body mass range, 2.5-3.0 kg) were included. Two of them were sacrificed before MR examination to obtain renal histologic samples as controls. The other ten rabbits completed 4-minute dynamic contrast material-enhanced MR imaging 24 hours before and 20 minutes after intravenous injection of iopamidol (370 mg of iodine per milliliter) at a dose of 6 mL per kilogram of body weight. Blood volume (VB), GFR, and tubule volume (VE) of the renal cortex were determined with a two-compartment kinetic model. Maximum upslope (Km), peak concentration (P c), and initial 60-second area under the curve (IAUC) of the whole kidney renogram curve were measured with semiquantitative analysis. The self-control data were compared by using the Student paired t test. Results: Iopamidol significantly decreased cortical VB (mean, 42.53% ± 10.16 [standard deviation] before CM administration vs 27.23% ± 16.13 after CM administration; P <.01), VE (mean, 22.40% ± 11.69 before CM administration vs 11.51% ± 6.58 after CM administration; P <.01), and GFR (mean, 31.92 mL/100 g per minute ± 12.52 before CM administration vs 21.48 mL/100 g per minute ± 10.02 after CM administration; P <.01). Results of whole-kidney renogram analysis showed a decrease in Km, Pc, and IAUC caused by iopamidol administration. Conclusion: High-dose iopamidol resulted in a marked decrease in renal function, which could be detected at dynamic three-dimensional MR renography. © RSNA, 2013.


Yan B.,Nanjing Medical University | Liu J.-Y.,Nanjing Medical University | Li X.-M.,Nanjing Medical University | Wang X.-Q.,Nanjing Medical University | And 5 more authors.
Circulation Research | Year: 2015

Rationale: Pathological angiogenesis is a critical component of diseases, such as ocular disorders, cancers, and atherosclerosis. It is usually caused by the abnormal activity of biological processes, such as cell proliferation, cell motility, immune, or inflammation response. Long noncoding RNAs (lncRNAs) have emerged as critical regulators of these biological processes. However, the role of lncRNA in diabetes mellitus-induced microvascular dysfunction is largely unknown. Objective: To elucidate whether lncRNA-myocardial infarction-associated transcript (MIAT) is involved in diabetes mellitus-induced microvascular dysfunction. Methods and Results: Using quantitative polymerase chain reaction, we demonstrated increased expression of lncRNA-MIAT in diabetic retinas and endothelial cells cultured in high glucose medium. Visual electrophysiology examination, TUNEL staining, retinal trypsin digestion, vascular permeability assay, and in vitro studies revealed that MIAT knockdown obviously ameliorated diabetes mellitus-induced retinal microvascular dysfunction in vivo, and inhibited endothelial cell proliferation, migration, and tube formation in vitro. Bioinformatics analysis, luciferase assay, RNA immunoprecipitation, and in vitro studies revealed that MIAT functioned as a competing endogenous RNA, and formed a feedback loop with vascular endothelial growth factor and miR-150-5p to regulate endothelial cell function. Conclusions: This study highlights the involvement of lncRNA-MIAT in pathological angiogenesis and facilitates the development of lncRNA-directed diagnostics and therapeutics against neovascular diseases. © 2015 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.


Li H.,Nanjing University | Xie H.,Nanjing University | Yang N.,Nanjing Medical University | Huang Y.,Nanjing University | And 3 more authors.
Chemical Communications | Year: 2013

A bi-functional peptide is designed to incorporate protein recognition and signal amplification functions into a single short peptide sequence. © 2013 The Royal Society of Chemistry.


Wu B.,Yeshiva University | Zhou B.,Yeshiva University | Zhou B.,Nanjing Medical University
Trends in Cardiovascular Medicine | Year: 2013

Heart valves arise from the cardiac endocardial cushions located at the atrioventricular canal (AVC) and cardiac outflow tract (OFT) during development. A subpopulation of cushion endocardial cells undergoes endocardial to mesenchymal transformation (EMT) and generates the cushion mesenchyme, which is then remodeled into the interstitial tissue of the mature valves. The cushion endocardial cells that do not undertake EMT proliferate to elongate valve leaflets. During EMT and the post-EMT valve remodeling, endocardial cells at the cushions highly express nuclear factor in activated T cell, cytoplasmic 1 (Nfatc1), a transcription factor required for valve formation in mice. In this review, we present the current knowledge of Nfatc1 roles in the ontogeny of heart valves with a focus on the fate decision of the endocardial cells in the processes of EMT and valve remodeling. © 2013 Elsevier Inc.


Zhang F.,Nanjing Medical University | Yang B.,Nanjing Medical University | Chen H.,Nanjing Medical University | Ju W.,Nanjing Medical University | And 3 more authors.
Heart Rhythm | Year: 2013

Background There is limited data on outcomes after noncontact mapping (NCM)-guided right ventricular outflow tract (RVOT) ventricular arrhythmia (VA) ablation. Objectives To assess outcomes of NCM-guided RVOT VA ablation in a large cohort with extended follow-up, to determine optimal ablation site, and to analyze limitations of conventional mapping techniques. Methods In consecutive patients undergoing RVOT VA ablation, 2 sites of early activation - earliest activation (EA) and breakout (BO) sites - were identified on NCM maps. Pace mapping and activation mapping were performed at both sites. The area of depolarized myocardium during the first 10 ms of spontaneous VA and pacing was measured. The initial site of ablation was randomized to either EA or BO sites, with crossover to the alternate site if ablation was not successful. Results In 136 patients, prematurity of local activation and pace maps were similar at EA and BO sites. More myocardium was depolarized 10 ms after pacing than during spontaneous VA (12.9 ± 7.8 cm2 vs 5.3 ± 3.9 cm 2; P <.01). Clinical success was more likely achieved when initial ablation was directed toward the EA site (P <.05). A wider EA-BO separation was associated with acute procedural failure (P <.01). With a follow-up of 36.2 ± 17.5 months, the success rate after a single procedure without antiarrhythmic agents was 86.8%. Conclusions NCM-guided RVOT VA ablation is highly effective, and clinical success is best achieved by ablating the EA site. Broad regions of early activation are associated with worsened clinical outcomes. Spatial resolution of activation and pace mapping is limited by rapid electrical propagation in the RVOT. © 2013 Heart Rhythm Society.


Tao L.,Nanjing Medical University | Bei Y.,Shanghai University | Zhang H.,Nanjing Medical University | Xiao J.,Shanghai University | Li X.,Nanjing Medical University
Oncotarget | Year: 2015

Physical exercise, a potent functional intervention in protecting against cardiovascular diseases, is a hot topic in recent years. Exercise has been shown to reduce cardiac risk factors, protect against myocardial damage, and increase cardiac function. This improves quality of life and decreases mortality and morbidity in a variety of cardiovascular diseases, including myocardial infarction, cardiac ischemia/reperfusion injury, diabetic cardiomyopathy, cardiac aging, and pulmonary hypertension. The cellular adaptation to exercise can be associated with both endogenous and exogenous factors: 1) exercise induces cardiac growth via hypertrophy and renewal of cardiomyocytes, and 2) exercise induces endothelial progenitor cells to proliferate, migrate and differentiate into mature endothelial cells, giving rise to endothelial regeneration and angiogenesis. The cellular adaptations associated with exercise are due to the activation of several signaling pathways, in particular, the growth factor neuregulin1 (NRG1)-ErbB4-C/EBPß and insulin-like growth factor (IGF)-1-PI3k-Akt signaling pathways. Of interest, microRNAs (miRNAs, miRs) such as miR-222 also play a major role in the beneficial effects of exercise. Thus, exploring the mechanisms mediating exercise-induced benefits will be instrumental for devising new effective therapies against cardiovascular diseases.


Objective: To provide appropriate evidence for treatment planning of patients with an impacted proximal ureteral stones ≥1.5 cm in size, by analyzing the therapeutic outcomes for those undergoing minimally invasive percutaneous antegrade ureterolithotripsy and retrograde ureterolithotripsy. Patients and methods: From September 2010 to November 2011, eligible patients with impacted proximal ureteral stones ≥1.5 cm in size referred to our institute were considered for this study. The closed envelope method was used to randomize the enrolled patients to mini-PCNL (30) or retrograde ureterolithotripsy (29). The efficiency quotient (EQ) was calculated to specifically address the efficiency for both the techniques. All preoperative and postoperative data for both groups were recorded. Results: The initial stone-free rate was 93.3 % in the mini-PCNL group and 41.4 % in the URSL group (p < 0.001). However, the overall stone-free rate at the 1-month follow-up visit after initial treatment was 100 % in the mini-PCNL group and 89.7 % in the URSL group (p = 0.07). The EQs for the mini-PCNL and URSL groups were 0.83 and 0.50, respectively. Conclusions: Our study shows that mini-PCNL removal of large impacted proximal ureteral calculi can achieve higher stone-free rates and safe. © 2013 Springer-Verlag Berlin Heidelberg.


Tao L.,Nanjing Medical University | Bei Y.,Shanghai University | Zhou Y.,Nanjing Medical University | Xiao J.,Shanghai University | Li X.,Nanjing Medical University
Oncotarget | Year: 2015

Developing new therapeutic strategies which could enhance cardiomyocyte regenerative capacity is of significant clinical importance. Though promising, methods to promote cardiac regeneration have had limited success due to the weak regenerative capacity of the adult mammalian heart. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs, miRs) and long non-coding RNAs (lncRNAs), are functional RNA molecules without a protein coding function that have been reported to engage in cardiac regeneration and repair. In light of current regenerative strategies, the regulatory effects of ncRNAs can be categorized as follows: Cardiac proliferation, cardiac differentiation, cardiac survival and cardiac reprogramming. miR-590, miR-199a, miR-17-92 cluster, miR302-367 cluster and miR-222 have been reported to promote cardiomyocyte proliferation while miR-1 and miR-133 suppress that. miR-499 and miR-1 promote the differentiation of cardiac progenitors into cardiomyocyte while miR-133 and H19 inhibit that. miR-21, miR-24, miR-221, miR-199a and miR-155 improve cardiac survival while miR-34a, miR-1 and miR-320 exhibit opposite effects. miR-1, miR-133, miR-208 and miR-499 are capable of reprogramming fibroblasts to cardiomyocyte-like cells and miR-284, miR-302, miR-93, miR-106b and lncRNA-ST8SIA3 are able to enhace cardiac reprogramming. Exploring non-coding RNA-based methods to enhance cardiac regeneration would be instrumental for devising new effective therapies against cardiovascular diseases.


Jia Z.,Nanjing Medical University | Wu A.,Interventional Imaging | Tam M.,University of Essex | Spain J.,Ohio State University | And 2 more authors.
Circulation | Year: 2015

Background-Limited penetration into the caval wall is an important securing mechanism for inferior vena cava (IVC) filters; however, caval penetration can also cause unintentional complications. The aim of this study was to assess the incidence, severity, clinical consequences, and management of filter penetration across a range of commercially available IVC filters. Methods and Results-The MEDLINE database was searched for all studies (1970-2014) related to IVC filters. A total of 88 clinical studies and 112 case reports qualified for analysis; these studies included 9002 patients and 15 types of IVC filters. Overall, penetration was reported in 19% of patients (1699 of 9002), and 19% of those penetrations (322 of 1699) showed evidence of organ/structure involvement. Among patients with penetration, 8% were symptomatic, 45% were asymptomatic, and 47% had unknown symptomatology. The most frequently reported symptom was pain (77%, 108 of 140). Major complications were reported in 83 patients (5%). These complications required interventions including surgical removal of the IVC filter (n=63), endovascular stent placement or embolization (n=11), endovascular retrieval of the permanent filter (n=4), and percutaneous nephrostomy or ureteral stent placement (n=3). Complications led to death in 2 patients. A total of 87% of patients (127 of 146) underwent premature filter retrieval or interventions for underlying symptoms or penetration-related complications. Conclusions-Caval penetration is a frequent but clinically underrecognized complication of IVC filter placement. Symptomatic patients accounted for nearly 1/10th of all penetrations; most of these cases had organ/structure involvement. Interventions with endovascular retrieval and surgery were required in most of these symptomatic patients. © 2015 American Heart Association, Inc.


Hu Z.,Nanjing Medical University | Xia Y.,Nanjing Medical University | Guo X.,Nanjing Medical University | Dai J.,Nanjing Medical University | And 17 more authors.
Nature Genetics | Year: 2012

Non-obstructive azoospermia (NOA) is one of the most severe forms of male infertility. Its pathophysiology is largely unknown, and few genetic influences have been defined. To identify common variants contributing to NOA in Han Chinese men, we performed a three-stage genome-wide association study of 2,927 individuals with NOA and 5,734 controls. The combined analyses identified significant (P < 5.0 × 10 -8) associations between NOA risk and common variants near PRMT6 (rs12097821 at 1p13.3: odds ratio (OR) = 1.25, P = 5.7 × 10 -10), PEX10 (rs2477686 at 1p36.32: OR = 1.39, P = 5.7 × 10 -12) and SOX5 (rs10842262 at 12p12.1: OR = 1.23, P = 2.3 × 10 -9). These findings implicate genetic variants at 1p13.3, 1p36.32 and 12p12.1 in the etiology of NOA in Han Chinese men. © 2012 Nature America, Inc. All rights reserved.


Zhou L.,Nanjing Medical University | Yin J.,Nanjing Medical University | Wang C.,Nanjing Medical University | Liao J.,Peking University | And 2 more authors.
Human Molecular Genetics | Year: 2014

The Seipin gene was originally found to be responsible for type 2 congenital lipodystrophy and involved in lipid droplet formation. Seipin is highly expressed in the central nervous systemas well. Seipin mutations have been identified in motor neuron diseases such as Silver syndrome and spastic paraplegia. In this study,wegenerated neuron-specific seipin knockout mice (seipin-nKO) to investigate the influence of seipin deficiency on locomotion and affective behaviors. In comparison with control mice, 8-week-old male seipin-nKOmice, but not female mice, displayed anxiety-and depression-like behaviors as assessed by open-field, elevated plus-maze, forced swim and tail suspension tests. However, neither male nor female seipin-nKO mice showed locomotion deficits in swimming tank and rotarod tests. Interestingly, the mRNA and protein levels of peroxisome proliferator-activated receptor gamma (PPARg) in the hippocampus and cortex were lower in male seipin-nKO mice, but not female mice, than controls. In seipin-nKO mice, plasma levels of sex hormones including 17β-estradiol (E2) in females and testosterone in males as well as corticosterone were not altered compared with controls. The treatment of male seipin-nKO mice with E2 ameliorated the anxiety-and depression-like behaviors and remarkably increased PPARγ levels. The PPARγ agonist rosiglitazone alleviated affective disorders in male seipin-nKO mice. Notably, anxiety-and depression-like behaviors appeared in female seipin-nKO mice after ovariectomy, which was associated with low PPARγ expression. Collectively, these results indicate that neuronal seipin deficiency causing reduced PPARγ levels leads to affective disorders in male mice that are rescued by E2-increased PPARγ expression. © The Author 2014. Published by Oxford University Press. All rights reserved.


Jeong Y.,Stanford University | Du R.,Nanjing Medical University | Zhu X.,Nanjing Medical University | Yin S.,Nanjing Medical University | And 3 more authors.
Journal of Leukocyte Biology | Year: 2014

The MAPK pathway mediates TLR signaling during innate immune responses. We discovered previously that MKP-1 is acetylated, enhancing its interaction with its MAPK substrates and deactivating TLR signaling. As HDACs modulate inflammation by deacetylating histone and nonhistone proteins, we hypothesized that HDACs may regulate LPS-induced inflammation by deacetylating MKP-1. We found that mouse macrophages expressed a subset of HDAC isoforms (HDAC1, HDAC2, and HDAC3), which all interacted with MKP-1. Genetic silencing or pharmacologic inhibition of HDAC1, -2, and -3 increased MKP-1 acetylation in cells. Furthermore, knockdown or pharmacologic inhibition of HDAC1, -2, and -3 decreased LPS-induced phosphorylation of the MAPK member p38. Also, pharmacologic inhibition of HDAC did not decrease MAPK signaling in MKP-1 null cells. Finally, inhibition of HDAC1, -2, and -3 decreased LPS-induced expression of TNF-α, IL-1β, iNOS (NOS2), and nitrite synthesis. Taken together, our results show that HDAC1, -2, and -3 deacetylate MKP-1 and that this post-translational modification increases MAPK signaling and innate immune signaling. Thus, HDAC1, -2, and -3 isoforms are potential therapeutic targets in inflammatory diseases. © Society for Leukocyte Biology.


Feng Y.,Nanjing University of Posts and Telecommunications | Tu X.,Nanjing Medical University
Transactions of the Institute of Measurement and Control | Year: 2015

The consensus problem for a class of mixed-order multi-agent systems is investigated in this paper, where the multi-agent system is composed of first- and second-order dynamic agents. Firstly, consensus protocols are proposed for solving the finite-time consensus problem for mixed-order multi-agent systems. By employing the finite-time stability theory and LaSalle's invariance principle, some sufficient conditions for finite-time consensus are given for multi-agent systems with directed communication topologies. Then, a class of nonlinear consensus protocols are given to solve the asymptotic consensus problem for mixed-order multi-agent systems. In addition, an invariant quantity is introduced to specify the expressions of the final consensus states when asymptotic consensus is reached. Finally, a simulation example is provided to demonstrate the effectiveness of the theoretical results. © The Author(s) 2014.


Hu L.-F.,National University of Singapore | Lu M.,National University of Singapore | Lu M.,Nanjing Medical University | Tiong C.X.,National University of Singapore | And 3 more authors.
Aging Cell | Year: 2010

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra (SN). The present study was designed to examine the therapeutic effect of hydrogen sulfide (H2S, a novel biological gas) on PD. The endogenous H2S level was markedly reduced in the SN in a 6-hydroxydopamine (6-OHDA)-induced PD rat model. Systemic administration of NaHS (an H2S donor) dramatically reversed the progression of movement dysfunction, loss of tyrosine-hydroxylase positive neurons in the SN and the elevated malondialdehyde level in injured striatum in the 6-OHDA-induced PD model. H2S specifically inhibited 6-OHDA evoked NADPH oxidase activation and oxygen consumption. Similarly, administration of NaHS also prevented the development of PD induced by rotenone. NaHS treatment inhibited microglial activation in the SN and accumulation of pro-inflammatory factors (e.g. TNF-α and nitric oxide) in the striatum via NF-κB pathway. Moreover, significantly less neurotoxicity was found in neurons treated with the conditioned medium from microglia incubated with both NaHS and rotenone compared to that with rotenone only, suggesting that the therapeutic effect of NaHS was, at least partially, secondary to its suppression of microglial activation. In summary, we demonstrate for the first time that H2S may serve as a neuroprotectant to treat and prevent neurotoxin-induced neurodegeneration via multiple mechanisms including anti-oxidative stress, anti-inflammation and metabolic inhibition and therefore has potential therapeutic value for treatment of PD. © 2010 The Authors Journal compilation © Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 2010.


Li H.,Nanjing University | Xie H.,Nanjing University | Cao Y.,Shanghai University | Ding X.,Nanjing Medical University | And 3 more authors.
Analytical Chemistry | Year: 2013

Protein-binding peptide is recently recognized as an effective artificial affinity reagent for protein assays. However, its application is hampered by the limited choices of available signal readout methods. Herein, we report a general electrochemical signal readout method for protein-binding peptides exploiting the host-guest chemistry of cucurbituril. Via the formation of supermolecules among cucurbituril, electrochemical reporter, and the peptide, a protein-binding peptide can be noncovalently coupled with the electrochemical reporter. To assay the target protein, the protein-binding peptides are first self-assembled in the sensing layer, and after the capturing of the target protein, a portion of the peptides become protein-bound. The protein-free peptides are then coupled with the electrochemical reporter to yield a signal readout inversely proportional to the amount of the captured target proteins. Since the only requirement of supermolecule formation is the incorporation of aromatic amino acids in the peptide sequence, this strategy is universally applicable to many protein-binding peptides. The generality and target specificity of the proposed method are successfully demonstrated in the assays of two kinds of target proteins: tumor necrosis factor-α and amyloid β 1-42 soluble oligomer, respectively. The feasibility of our method is also tested in the monitoring of tumor necrosis factor-α secretion activity of HL-60 cells. These results indicate that our method can have great use in protein detection in the future. © 2012 American Chemical Society.


Gu B.,Nanjing Medical University | Gu B.,University of California at Los Angeles | Kelesidis T.,University of California at Los Angeles | Tsiodras S.,National and Kapodistrian University of Athens | And 2 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2013

The oxazolidinone antibiotic linezolid has demonstrated potent antimicrobial activity against Gram-positive bacterial pathogens, including methicillin-resistant staphylococci. This article systematically reviews the published literature for reports of linezolid-resistant Staphylococcus (LRS) infections to identify epidemiological, microbiological and clinical features for these infections. Linezolid remains active against >98% of Staphylococcus, with resistance identified in 0.05% of Staphylococcus aureus and 1.4% of coagulase-negative Staphylococcus (CoNS). In all reported cases, patients were treated with linezolid prior to isolation of LRS, with mean times of 20.0 ± 47.0 months for S. aureus and 11.0 ± 8.0 days for CoNS. The most common mechanisms for linezolid resistance were mutation (G2576T) to the 23S rRNA (63.5% of LRSA and 60.2% of LRCoNS) or the presence of a transmissible cfr ribosomal methyltransferase (54.5% of LRSA and 15.9% of LRCoNS). The emergence of linezolid resistance in Staphylococcus poses significant challenges to the clinical treatment of infections caused by these organisms, and in particular CoNS. © The Author 2012. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.


Yang S.-M.,Peking University | Li J.-Y.,Nanjing Medical University | Gale R.P.,Imperial College London | Huang X.-J.,Peking University | Huang X.-J.,Peking Tsinghua Center for Life science
Blood Reviews | Year: 2015

Chronic lymphocytic leukemia/small lymphocytic lymphoma is common in persons of predominately European descent but rare in Asians. Why is unknown but is likely genetically-determined. Environmental factors may also operate but are likely to be less important. When CLL occurs in Asians it has different features than CLL in persons of predominately European descent. The reason(s) for this is also not understood. We reviewed data on CLL in Asians (mostly Han Chinese but also other ethnic groups) and compared these data with those from persons of predominately European descent with CLL. CLL incidence was about 5-10-fold less in Asians. Asians with CLL are younger, have atypical morphologic and immunologic features, an increased proportion of IGHV mutations and rearrangements and briefer freedom-from-progression than persons of predominately European descent with CLL. These observations provide clues to the etiology and biology of CLL. But the mystery continues; more research is needed. © 2014 Elsevier Ltd.


Huang X.-E.,Nanjing Medical University
Asian Pacific Journal of Cancer Prevention | Year: 2013

Purpose: To investigate short-term response rate, quality of life and toxicities of mannan peptide combined with TP regimen in treating patients with non-small cell lung cancer (NSCLC). Patients and Methods: Forty one patients with NSCLC were divided into an experimental group treated with TP regimen combined with mannan peptide (21 patients) and a control group treated with TP alone (20 patients). Results: Response rates were 61.9% (13/21) for the experimental and 60% (12/20) for the control group (p>0.05). Regarding toxicity, white blood cell decreased more frequently in the control group (65%, 13/20) than in the experimental group (33.3%, 7/21) (p<0.05); nausea and vomiting also occurred more frequently in the control group (55%, 11/20 vs 23.8%, 5/21) (p<0.05). In terms of quality of life, this index was improved by 57.1% (12/21) and 25% (5/20) in experimental and control groups, respectively (p<0.05). Conclusions: Response rate of TP after combined with mannan peptide is mildly increased, while this combination alleviates bone marrow suppression as well as nausea and vomiting of TP, and improves quality of life when treating patients with NSCLC. However, this conclusion should be confirmed by randomized clinical trails.


Guo G.,National University of Singapore | Guo G.,Genome Institute of Singapore | Huss M.,Genome Institute of Singapore | Tong G.Q.,Genome Institute of Singapore | And 6 more authors.
Developmental Cell | Year: 2010

Three distinct cell types are present within the 64-cell stage mouse blastocyst. We have investigated cellular development up to this stage using single-cell expression analysis of more than 500 cells. The 48 genes analyzed were selected in part based on a whole-embryo analysis of more than 800 transcription factors. We show that in the morula, blastomeres coexpress transcription factors specific to different lineages, but by the 64-cell stage three cell types can be clearly distinguished according to their quantitative expression profiles. We identify Id2 and Sox2 as the earliest markers of outer and inner cells, respectively. This is followed by an inverse correlation in expression for the receptor-ligand pair Fgfr2/. Fgf4 in the early inner cell mass. Position and signaling events appear to precede the maturation of the transcriptional program. These results illustrate the power of single-cell expression analysis to provide insight into developmental mechanisms. The technique should be widely applicable to other biological systems. © 2010 Elsevier Inc.


Zhou X.,Michigan State University | Zhou X.,Nanjing Medical University | Hollern D.,Michigan State University | Liao J.,University of California at Riverside | And 2 more authors.
Cell Death and Disease | Year: 2013

N-methyl-D-aspartate receptors (NMDAR) overactivation is linked to neurodegeneration. The current prevailing theory suggests that synaptic and extrasynaptic NMDAR (syn- and ex-NMDAR) impose counteracting effects on cell fate, and neuronal cell death is mainly mediated by the activation of ex-NMDAR. However, several lines of evidence implicate the limitation of this theory. Here, we demonstrate that activation of NMDAR bi-directionally regulated cell fate through stimulating pro-survival or pro-death signaling. While low-dose NMDA preferentially activated syn-NMDAR and stimulated the extracellular signal-regulated kinase -cAMP responsive element-binding protein-brain-derived neurotrophic factor pro-survival signaling, higher doses progressively activated increasing amount of ex-NMDAR along with syn-NMDAR and triggered cell death program. Interestingly, the activation of syn- or ex-NMDAR alone did not cause measurable cell death. Consistently, activation of syn- or ex-NMDAR alone stimulated pro-survival but not pro-death signaling. Next, we found that memantine, which was previously identified as an ex-NMDAR blocker, inhibited intracellular signaling mediated by syn- or ex-NMDAR. Simultaneous blockade of syn- and ex- NMDAR by memantine dose-dependently attenuated NMDAR-mediated death. Moreover, long- but not short-term treatment with high-dose NMDA or oxygen-glucose deprivation triggered cell death and suppressed pro-survival signaling. These data implicate that activation of syn- or ex-NMDAR alone is not neurotoxic. The degree of excitotoxicity depends on the magnitude and duration of syn- and ex-NMDAR coactivation. Finally, genome-wide examination demonstrated that the activation of syn- and ex-NMDAR lead to significant overlapping rather than counteracting transcriptional responses. © 2013 Macmillan Publishers Limited.


Xie H.-G.,Nanjing Medical University | Xie H.-G.,U.S. Food and Drug Administration | Wang S.-K.,Nanjing Medical University | Cao C.-C.,Nanjing Medical University | Harpur E.,Northumbria University
Pharmacology and Therapeutics | Year: 2013

The kidney is one of the major organs drug toxicity may target. Some renal safety biomarkers have been proposed to measure kidney injury and function accordingly. Despite the widespread use for diagnosis and monitoring of renal injury and function for decades, serum creatinine and blood urea nitrogen are nonspecific biomarkers with insensitive and delayed response in the clinical setting. There is an urgent need to identify and qualify novel kidney safety biomarkers that would be used to detect and predict drug-induced nephrotoxicity in preclinical toxicological studies, clinical trials and patient care in sequence. To do that, eight novel renal safety biomarkers have been well characterized and qualified for preclinical drug safety screening, and their clinical bridging validation is underway as well. Of them, some are used to detect or predict proximal tubular injury, and others are used to diagnose and monitor glomerular damage. Thus, measurement of a panel of kidney safety biomarkers in parallel would help maximally capture all potential safety signals for a more informative decision to be made in drug research and development as well as for optimal selection of the drug and its dose in clinical practice. © 2012 Elsevier Inc.


Hu X.,Nanjing Medical University | Song X.,Peking University | Yuan Y.,Nanjing Southeast University | Li E.,Nanjing Medical University | And 3 more authors.
Movement Disorders | Year: 2015

Depressive symptoms are common in Parkinson's disease (PD), but the pathophysiology and neural basis underlying depression in PD is not well understood. Abnormal functional connectivity of the amygdala with various cortical and subcortical areas has been observed in major depressive disorder, indicating that dysfunction of the corticolimbic network may be involved in the pathogenesis of major depressive disorder. However, little is known about alterations of amygdala functional connectivity in depressed PD patients. In the present study, 20 depressed PD patients, 40 nondepressed PD patients, and 43 matched healthy controls underwent neuropsychological tests and resting-state functional MRI scanning. Between-group differences in amygdala functional connectivity network were examined using t tests. Compared to the nondepressed PD patients, depressed PD patients showed increased left amygdala functional connectivity with the bilateral mediodorsal thalamus, right amygdala functional connectivity with the left superior temporal gyrus, and left calcarine gyrus. Compared to the healthy controls, the depressed PD group also showed increased left amygdala functional connectivity with the bilateral mediodorsal thalamus, but decreased left amygdala functional connectivity with the left putamen, left inferior frontal gyrus, and the right cerebellum, as well as decreased right amygdala functional connectivity with the left inferior orbitofrontal gyrus, the left gyrus rectus, and the right putamen. The increased connectivity between limbic regions and decreased connectivity between the corticolimbic networks may reflect impaired high-order cortical regulatory effects on the emotion-related limbic areas, which may lead to mood dysregulation. Our study should advance the understanding of neural mechanisms underlying depression in PD. © 2014 International Parkinson and Movement Disorder Society.


Wang D.,Nanjing Medical University | Li J.,Jiangsu University | Zhang Y.,Peoples Hospital of Jiangsu Province | Zhang M.,Jiangsu Provincial Peoples Hospital | And 4 more authors.
Arthritis Research and Therapy | Year: 2014

Introduction: In our present single-center pilot study, umbilical cord (UC)-derived mesenchymal stem cells (MSCs) had a good safety profile and therapeutic effect in severe and refractory systemic lupus erythematosus (SLE). The present multicenter clinical trial was undertaken to assess the safety and efficacy of allogeneic UC MSC transplantation (MSCT) in patients with active and refractory SLE.Methods: Forty patients with active SLE were recruited from four clinical centers in China. Allogeneic UC MSCs were infused intravenously on days 0 and 7. The primary endpoints were safety profiles. The secondary endpoints included major clinical response (MCR), partial clinical response (PCR) and relapse. Clinical indices, including Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, British Isles Lupus Assessment Group (BILAG) score and renal functional indices, were also taken into account.Results: The overall survival rate was 92.5% (37 of 40 patients). UC-MSCT was well tolerated, and no transplantation-related adverse events were observed. Thirteen and eleven patients achieved MCR (13 of 40, 32.5%) and PCR (11 of 40, 27.5%), respectively, during 12 months of follow up. Three and four patients experienced disease relapse at 9 months (12.5%) and 12 months (16.7%) of follow-up, respectively, after a prior clinical response. SLEDAI scores significantly decreased at 3, 6, 9 and 12 months follow-up. Total BILAG scores markedly decreased at 3 months and continued to decrease at subsequent follow-up visits. BILAG scores for renal, hematopoietic and cutaneous systems significantly improved. Among those patients with lupus nephritis, 24-hour proteinuria declined after transplantation, with statistically differences at 9 and 12 months. Serum creatinine and urea nitrogen decreased to the lowest level at 6 months, but these values slightly increased at 9 and 12 months in seven relapse cases. In addition, serum levels of albumin and complement 3 increased after MSCT, peaked at 6 months and then slightly declined by the 9- and 12-month follow-up examinations. Serum antinuclear antibody and anti-double-stranded DNA antibody decreased after MSCT, with statistically significant differences at 3-month follow-up examinations.Conclusion: UC-MSCT results in satisfactory clinical response in SLE patients. However, in our present study, several patients experienced disease relapse after 6 months, indicating the necessity to repeat MSCT after 6 months.Trial registry: ClinicalTrials.gov identifier: NCT01741857. Registered 26 September 2012. © 2014 Wang et al.; licensee BioMed Central Ltd.


Dai Z.,University of Hong Kong | Miao D.,Nanjing Medical University | Lau K.S.,University of Hong Kong | Chan A.W.H.,University of Hong Kong | Kung A.W.C.,University of Hong Kong
Journal of Bone and Mineral Research | Year: 2011

myo-Inositol (MI) plays an essential role in several important processes of cell physiology, is involved in the neural system, and provides an effective treatment for some psychiatric disorders. Its role in osteogenesis and bone formation nonetheless is unclear. Sodium/MI cotransporter 1 (SMIT1, the major cotransporter of MI) knockout (SMIT1-/-) mice with markedly reduced tissue MI levels were used to characterize the essential roles of MI and SMIT1 in osteogenesis. SMIT1-/- embryos had a dramatic delay in prenatal mineralization and died soon after birth owing to respiratory failure, but this could be rescued by maternal MI supplementation. The rescued SMIT1-/- mice had shorter limbs, decreased bone density, and abnormal bone architecture in adulthood. Deletion of SMIT1 resulted in retarded postnatal osteoblastic differentiation and bone formation in vivo and in vitro. Continuous MI supplementation partially restored the abnormal bone phenotypes in adult SMIT1-/- mice and strengthened bone structure in SMIT1+/+ mice. Although MI content was much lower in SMIT1-/- mesenchymal cells (MSCs), the I(1,4,5)P3 signaling pathway was excluded as the means by which SMIT1 and MI affected osteogenesis. PCR expression array revealed Fgf4, leptin, Sele, Selp, and Nos2 as novel target genes of SMIT1 and MI. SMIT1 was constitutively expressed in multipotential C3H10T1/2 and preosteoblastic MC3T3-E1 cells and could be upregulated during bone morphogenetic protein 2 (BMP-2)-induced osteogenesis. Collectively, this study demonstrated that deficiency in SMIT1 and MI has a detrimental impact on prenatal skeletal development and postnatal bone remodeling and confirmed their essential roles in osteogenesis, bone formation, and bone mineral density (BMD) determination. © 2011 American Society for Bone and Mineral Research. Copyright © 2011 American Society for Bone and Mineral Research.


Zhao J.,Shanghai University | He X.,Shanghai University | Bo B.,Nanjing Medical University | Liu X.,Nanjing University | And 3 more authors.
Biosensors and Bioelectronics | Year: 2012

In this paper, we report a "signal-on" electrochemical aptasensor for simultaneous determination of two tumor markers MUC1 and VEGF 165, by using a ferrocene-labeled aptamer-complementary DNA (cDNA) as probe. Since the cDNA immobilized on an electrode surface can hybridize with both MUC1 aptamer and VEGF 165 aptamer to form a long double strand with ferrocene far away from the electrode surface, the probe cannot give electrochemical signal. Nevertheless, the presence of the two tumor markers will inhibit the hybridization of cDNA with the aptamers, thus the distance between ferrocene and the electrode is changed, and a "signal-on" electrochemical method to detect two tumor markers is developed. Experimental results show that the electrochemical signal increases with the addition of either tumor markers, but the biggest electrochemical signal can only be obtained when both tumor markers are present. Therefore, the proposed electrochemical aptasensor can not only detect the two markers but also distinguish their co-existence. It may also display high selectivity and sensitivity towards the detection of the tumor markers, so it might have potential clinical application in the future. © 2012 Elsevier B.V.


Yang Y.,Nanjing Medical University | Sun W.,Nanjing Medical University | Wu S.M.,Stanford University | Xiao J.,Nanjing Medical University | And 2 more authors.
Journal of Cellular and Molecular Medicine | Year: 2014

Valve interstitial cells (VICs) are responsible for maintaining the structural integrity and dynamic behaviour of the valve. Telocytes (TCs), a peculiar type of interstitial cells, have been recently identified by Popescu's group in epicardium, myocardium and endocardium (visit www.telocytes.com). The presence of TCs has been identified in atria, ventricles and many other tissues and organ, but not yet in heart valves. We used transmission electron microscopy and immunofluorescence methods (double labelling for CD34 and c-kit, or vimentin, or PDGF Receptor-β) to provide evidence for the existence of TCs in human heart valves, including mitral valve, tricuspid valve and aortic valve. TCs are found in both apex and base of heart valves, with a similar density of 27-28 cells/mm2 in mitral valve, tricuspid valve and aortic valve. Since TCs are known for the participation in regeneration or repair biological processes, it remains to be determined how TCs contributes to the valve attempts to re-establish normal structure and function following injury, especially a complex junction was found between TCs and a putative stem (progenitor) cell. © 2014 The Authors.


Qiu X.,Peking University | Qiu X.,Nanjing Medical University | Zhang M.,Nanjing Medical University | Yang X.,Nanjing Medical University | And 2 more authors.
Journal of Crohn's and Colitis | Year: 2013

Background and aims: Faecalibacterium prausnitzii (F. prausnitzii) is a common anaerobic bacteria colonized in the human gut and inflammatory bowel disease (IBD) patients are usually lack of F. prausnitzii. The aims of this study were to evaluate the anti-inflammatory and immunomodulatory capacity of F. prausnitzii by comparing it with Bifidobacterium longum (B. longum) in both cellular and animal experiments. Methods: Human peripheral blood mononuclear cells (PBMCs) and 2, 4, 6-trinitrobenzenesulphonic acid (TNBS)-induced colitis rat models were treated with F. prausnitzii, B. longum, F. prausnitzii supernatant or F. prausnitzii medium, respectively. Interleukin (IL)-10, TGF-β1 and IL-12p70 in human PBMCs culture supernatant and rat blood serum were detected. The frequency of CD25+Foxp3+Treg in human PBMCs, rat PBMCs and rat splenocytes were investigated. Besides, the T-bet, GATA-3, ROR-γt and Foxp3 mRNA in human PBMCs, histopathologic characteristics of the intestinal mucosal and weight loss in the rat models were examined. Results: F. prausnitzii, B. longum and F. prausnitzii supernatant clearly facilitated the induction of IL-10 and TGF-β1, while induced relatively mild production of IL-12p70 in both cellular and animal models. The F. prausnitzii, B. longum and supernatant differed in their capacity to induce T-bet, GATA-3 and ROR-γt mRNA expression in human PBMCs (both bacterial strains inhibited the expression of ROR-γt while supernatant inhibited the T-bet and GATA-3). However, all of them induced the Foxp3 and Treg production and ameliorated the TNBS-induced colitis. In addition, F. prausnitzii supernatant exhibited the supreme anti-inflammatory capacity. Conclusions: F. prausnitzii and its unidentified metabolites in the supernatant are promising candidates in treating IBD, and further research remains necessary to elucidate the safety, efficacy, optimum and mechanism of this bacterium in the clinical practice. © 2013 European Crohn's and Colitis Organisation.


Yang H.,Nanjing Southeast University | Liang W.,Jiangsu Province Blood Center | He N.,Nanjing Southeast University | Deng Y.,Nanjing Southeast University | Li Z.,Nanjing Medical University
ACS Applied Materials and Interfaces | Year: 2015

Previously, the unique advantages provided by chemiluminescence (CL) and magnetic particles (MPs) have resulted in the development of many useful nucleic acid detection methods. CL is highly sensitive, but when applied to MPs, its intensity is limited by the inner filter-like effect arising from excess dark MPs. Herein, we describe a modified strategy whereby CL labels are released from MPs to eliminate this negative effect. This approach relies on (1) the magnetic capture of target molecules on long spacer arm-functionalized magnetic particles (LSA-MPs), (2) the conjugation of streptavidin-alkaline phosphatase (SA-AP) to biotinylated amplicons of target pathogens, (3) the release of CL labels (specifically, AP tags), and (4) the detection of the released labels. CL labels were released from LSA-MPs through LSA ultrasonication or DNA enzymolysis, which proved to be the superior method. In contrast to conventional MPs, LSA-MPs exhibited significantly improved CL detection, because of the introduction of LSA, which was made of water-soluble carboxymethylated β-1,3-glucan. Detection of hepatitis B virus with this technique revealed a low detection limit of 50 fM, high selectivity, and excellent reproducibility. Thus, this approach may hold great potential for early stage clinical diagnosis of infectious diseases. © 2014 American Chemical Society.


Yang J.,Shanghai University | Ni B.,Shanghai University | Liu J.,Nanjing Medical University | Zhu L.,Shanghai University | Zhou W.,Nanjing University of Technology
Spine Journal | Year: 2011

Background context: Epidural adhesion and fibrosis attribute to the prevalence of pain in normal wound healing after laminectomy surgery. Hydroxycamptothecin (HCPT), an antitumor drug, has proved to be effective in preventing fibroblast proliferation and reducing epidural adhesion after laminectomy in vivo animal study. However, HCPT's disadvantages, such as poor solubility and short half-life, limit its application clinically. Compared with HCPT, the liposome-encapsulated HCPT (L-HCPT) could reduce epidural fibrosis by preventing the proliferation of fibroblast in the scar tissues with longer half-life and increased solubility. Purpose: To evaluate the suitability of L-HCPT in the laminectomy models on rabbits and to explore the mechanisms in the prevention of epidural scar formation. Study design: An original investigation that characterizes the novel delivery system in the combinational application of HCPT and liposome (L-HCPT). Patient sample: The sample comprises 24 mature New Zealand white adult rabbits. Methods: Lumbar laminectomies at L4 and L6 with an L5 disc injury were performed on 24 mature New Zealand white adult rabbits. The rabbits were then randomized into three groups. In Group I, the laminectomy site was treated with a cotton pad soaked with HCPT solution (1 mg/mL) for 5 minutes (HCPT group) and was flushed with saline completely. In Group II, 1 mL of L-HCPT was seeded on the laminectomy area (L-HCPT group). In Group III, the laminectomy area was flushed with saline before wound closure (control group). After 28 days, the animals underwent magnetic resonance imaging. The animals were euthanized; the spinal section was removed for macroscopic evaluation, and hydroxyproline in the scar tissue was quantified. Results: Operation in all the animals yielded a reproducible laminectomy, without complication or mortality. In the laminectomy sites treated with L-HCPT, the dura mater was clean without any evident adhesion. Magnetic resonance imaging analysis implied that L-HCPT treatment could reduce the epidural scar significantly compared with saline control group, which was further proved by the decreased concentration of hydroxyproline in the scar tissues. Conclusion: These results demonstrate that the treatment of postlaminectomy wounds in rabbits with L-HCPT reduces the severity of adhesion. © 2011 Elsevier Inc. All rights reserved.


News Article | November 17, 2016
Site: www.eurekalert.org

Glioblastoma multiforme remains the most common and highly lethal brain cancer and is known for its ability to relapse. Researchers at The University of Texas MD Anderson Cancer Center have identified a pathway by which cancer cells aggressively spread and grow in the brain, opening up new possibilities for treatment. Study findings were published in the Nov. 17 online version of Cell. Co-authors included Baoli Hu, Ph.D., senior research scientist, Y. Alan Wang, Ph.D., associate professor, and Ronald A. DePinho, M.D., professor, all of Cancer Biology, and Qianghu Wang Ph.D., Bioinformatics and Computational Biology. "The poor prognosis of glioblastoma relates to the near universal recurrence of tumors despite robust treatment including surgery, radiotherapy and chemotherapy," said Hu. "Our study shows the potential for a new therapeutic strategy based on targeting the mechanisms allowing glioma to re-grow aggressively in the brain." Hu and his colleagues developed a glioblastoma model to locate glioma stem cells, which, like all stem calls, have the ability to become other cell types. The researchers further found that the gene, WNT5A, when activated, allowed glioma stem cells to transition, leading to invasive tumor growth. "We uncovered a process by which glioma stem cells mediated by the WNT5A gene become endothelial-like cells," said Hu. "These new cells known as GdECs, recruit existing endothelial cells to form a niche supporting the growth of invasive glioma cells away from the primary tumor, and often leading to satellite "lesions" and disease recurrence." Clinical data revealed higher WNT5A and GdECs expression in these satellite lesions and recurrent tumors than was observed in the primary tumors, affirming the tie between WNT5A-mediated stem cell differentiation and glioma cell spread throughout the brain, and contributing to the cancer's lethalness. The study established WNT5A as a key factor in glioma stem cells transitioning to GdECs. The team believes this opens up the possibility for a new therapeutic strategy for patients with glioblastoma. Recent clinical data show the FDA-approved drug, bevacizumab, did not benefit patients as a first line treatment of recurrent glioblastoma by targeting vascular endothelial growth factors (VEGF). With this new information, the study team proposes an additional therapeutic approach targeting WNT5A and VEGF signaling pathways for recurrent glioblastoma. "Our preliminary data show that bevacizumab may increase WNT5A-mediated GdECs differentiation and recruitment of existing endothelial cells resulting in no proven benefit to patients with glioblastoma" said Hu. "This new strategy should improve the outcome of brain cancer patients undergoing VEGF therapy, by limiting new tumor growth and invasion, and disease recurrence," said Hu. MD Anderson study team members included Y. Alan Wang, Ph.D., Sujun Hua, Ph.D., Charles-Etienne Sauvé, Derrick Ong, Ph.D., Zheng Lan, Ph.D., Yan Wing Ho, Ph.D., Marta Monasterio, Ph.D., Xin Lu, Ph.D., Pingna Deng, Guocan Wang, Ph.D., Wen-Ting Liao, Ph.D., Denise Spring, Ph.D., Jian Hu, Ph.D., and Ronald DePinho, M.D., all of Cancer Biology; Roeland Verhaak, Ph.D., Bioinformatics and Computational Biology; Jianhua Zhang, Ph.D., and Lynda Chin, M.D., Genomic Medicine; Yi Zong, Ph.D., Epigenetics and Molecular Carcinogenesis; Zhi Tan, Experimental Therapeutics; Lynda Corley and Gregory Fuller, M.D., Ph.D., Pathology; and Erik Sulman, M.D., Ph.D., Radiation Oncology. Other participating institutions included Dana-Farber Cancer Institute, Boston; Nanjing Medical University, Nanjing, China; Guangdong 999 Brain Hospital, Guangzhou, China; the Fondazione IRCCS Istituto Neurologico C. Besta, Milan; and the University of California, San Francisco. The study was funded by National Institutes of Health (P50 CA097257, 2P50CA127001, 5P01CA095616, and P30CA16672).


SHANGHAI, China and CUPERTINO, Calif., Nov. 29, 2016 (GLOBE NEWSWIRE) -- Cellular Biomedicine Group Inc. (NASDAQ:CBMG) (“CBMG” or the “Company”), a clinical-stage biomedicine firm engaged in the development of effective immunotherapies for cancer and stem cell therapies for degenerative diseases, is pleased to announce the approval and commencement of patient enrollment in China for its CARD-1 (“CAR-T Against DLBCL”) Phase I clinical trial utilizing its optimized proprietary C-CAR011 construct of CD19 chimeric antigen receptor T-cell (CAR-T) therapy for the treatment of patients with refractory Diffuse Large B-cell Lymphoma (DLBCL). The CARD-1 trial has begun enrollment with final data expected to be available in the second half of 2017. Based on the CARD-1 results, CBMG expects to initiate a larger Phase II clinical trial as soon as practicable. “Our CARD-1 trial represents the first CBMG-sponsored clinical trial after CBMG’s acquisition of its CAR-T technology and data from the PLA General Hospital (PLAGH, also known as 301 Hospital) in Beijing. We are proud of this major corporate milestone where CBMG has taken existing technology and improved it with proprietary optimization and initiated new clinical trials in China,” said Tony (Bizuo) Liu, Chief Executive Officer of CBMG. “We believe we are one of the very few companies that uniquely possesses internal viral vector production and transduction capabilities within our own integrated GMP facility. This allows CBMG to move quickly and efficiently from R&D to manufacturing CAR-T cells for clinical use.” According to a recent large, multi-cohort dataset analysis, patients with refractory DLBCL have clinical response rates of only 20%-30% with a median overall survival of approximately six months. These poor refractory DLBCL patient outcomes represent a significant unmet medical need. CBMG’s CARD-1 Phase I dose-escalation trial will use the traditional 3x3 design to evaluate the safety, efficacy and persistence of C-CAR011 in refractory DLBCL patients. “DLBCL is the largest subtype of Non-Hodgkin Lymphoma (NHL), and those refractory patients whose treatment has failed have limited options and a very poor prognosis compared to relapsed patients who had previously responded to treatment,” said Dr. Jianyong Li from Jiangsu Provincial People’s Hospital in Nanjing China, the Principal Investigator for the CARD-1 trial. “I am excited to be able to participate in the trial of C-CAR011 which may someday provide a treatment option for these refractory patients.” “We are very excited as CARD-1 represents the first of a planned series of clinical trials utilizing CBMG’s optimized CAR-T drug candidates,” said Dr. Yihong Yao, Chief Scientific Officer of CBMG. “We look forward to announcing additional trials and CAR-T candidates in the future.” About the CARD-1 Clinical Trial CARD-1 is a Phase I single-site, single-arm dose-escalating trial consisting of three patient cohorts using escalating C-CAR011 cell dosing levels with three patients in each cohort. The primary end points are Dose-Limiting Toxicity (DLT) and Treatment Emergent Adverse Events (TEAE). Secondary endpoints will measure Overall Response Rate (Complete plus Partial Responses) at 4 weeks and 12 weeks and Disease Control Rate (Complete plus Partial Responses plus Stable Disease) at 12 weeks according to the International Working Group (IWG) revised criteria. The trial summary is registered with clinicaltrials.gov under the number NCT02976857. The trial will be conducted by Dr. Jianyong Li at the Jiangsu Provincial People’s Hospital in Nanjing China. The Jiangsu Provincial People’s Hospital (also known as the First Affiliated Hospital of Nanjing Medical University, Jiangsu Clinical Medicine Research Institute and the Red Cross Hospital of Jiangsu) was founded in 1936 and performs medical treatment, provides education, and conducts advanced research. The hospital has 3,000 beds and over 4,000 employees with total floor space of 3 million square feet covering 50 acres. The Department of Clinical Medicine of Nanjing Medical University is located inside the hospital, offering clinical medicine doctoral degree and postdoctoral research programs, with 45 teaching and research sections and more than 200 professors. The hospital maintains cooperative relationships with other research hospitals and laboratories in countries such as the US, Japan, Canada, Australia and Italy. About C-CAR011 CBMG’s proprietary anti-CD19 chimeric antigen receptor T-cell (CAR-T) construct represents advancement over CBMG’s prior CBM-C19.1 construct. C-CAR011 is entirely engineered and manufactured in CBMG’s own GMP manufacturing facility in China. About Diffuse Large B-Cell Lymphoma (DLBCL) Diffuse Large B-Cell Lymphoma (DLBCL) is the most common form of Non-Hodgkin Lymphoma (NHL) with DLBCL representing approximately 30% of newly diagnosed NHL cases in the United States and an even higher percentage of newly diagnosed NHL cases in China. DLBCL is an aggressive form of lymphoma that advances quickly and occurs in both men and women although slightly more common in men. The incidence of DLBCL increases with age with most patients over the age of 60. The current treatment options include chemotherapy, anti-CD20 targeted therapy, radiation and stem cell transplantation. However, for patients with refractory DLBCL (failed to respond to treatment) the poor clinical response rates of 20%-30% with median overall survival of approximately 6 months represents a significant unmet medical need. About Cellular Biomedicine Group (CBMG) Cellular Biomedicine Group, Inc. develops proprietary cell therapies for the treatment of cancer and degenerative diseases. Our immuno-oncology and stem cell projects are the result of research and development by CBMG’s scientists and clinicians from both China and the United States. Our GMP facilities in China, consisting of twelve independent cell production lines, are designed and managed according to both China and U.S. GMP standards. To learn more about CBMG, please visit: www.cellbiomedgroup.com Forward-Looking Statements Statements in this press release relating to plans, strategies, trends, specific activities or investments, and other statements that are not descriptions of historical facts may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking information is inherently subject to risks and uncertainties, and actual results could differ materially from those currently anticipated due to a number of factors, which include risks inherent in doing business, trends affecting the global economy, including the devaluation of the RMB by China in August 2015 and other risks detailed from time to time in CBMG’s reports filed with the Securities and Exchange Commission, quarterly reports on form 10-Q, current reports on form 8-K and annual reports on form 10-K. Forward-looking statements may be identified by terms such as "may," "will," "expects," "plans," "intends," "estimates," "potential," or "continue," or similar terms or the negative of these terms. Although CBMG believes the expectations reflected in the forward-looking statements are reasonable, they cannot guarantee that future results, levels of activity, performance or achievements will be obtained. CBMG does not have any obligation to update these forward-looking statements other than as required by law.


SHANGHAI, China and CUPERTINO, Calif., Nov. 29, 2016 (GLOBE NEWSWIRE) -- Cellular Biomedicine Group Inc. (NASDAQ:CBMG) (“CBMG” or the “Company”), a clinical-stage biomedicine firm engaged in the development of effective immunotherapies for cancer and stem cell therapies for degenerative diseases, is pleased to announce the approval and commencement of patient enrollment in China for its CARD-1 (“CAR-T Against DLBCL”) Phase I clinical trial utilizing its optimized proprietary C-CAR011 construct of CD19 chimeric antigen receptor T-cell (CAR-T) therapy for the treatment of patients with refractory Diffuse Large B-cell Lymphoma (DLBCL). The CARD-1 trial has begun enrollment with final data expected to be available in the second half of 2017. Based on the CARD-1 results, CBMG expects to initiate a larger Phase II clinical trial as soon as practicable. “Our CARD-1 trial represents the first CBMG-sponsored clinical trial after CBMG’s acquisition of its CAR-T technology and data from the PLA General Hospital (PLAGH, also known as 301 Hospital) in Beijing. We are proud of this major corporate milestone where CBMG has taken existing technology and improved it with proprietary optimization and initiated new clinical trials in China,” said Tony (Bizuo) Liu, Chief Executive Officer of CBMG. “We believe we are one of the very few companies that uniquely possesses internal viral vector production and transduction capabilities within our own integrated GMP facility. This allows CBMG to move quickly and efficiently from R&D to manufacturing CAR-T cells for clinical use.” According to a recent large, multi-cohort dataset analysis, patients with refractory DLBCL have clinical response rates of only 20%-30% with a median overall survival of approximately six months. These poor refractory DLBCL patient outcomes represent a significant unmet medical need. CBMG’s CARD-1 Phase I dose-escalation trial will use the traditional 3x3 design to evaluate the safety, efficacy and persistence of C-CAR011 in refractory DLBCL patients. “DLBCL is the largest subtype of Non-Hodgkin Lymphoma (NHL), and those refractory patients whose treatment has failed have limited options and a very poor prognosis compared to relapsed patients who had previously responded to treatment,” said Dr. Jianyong Li from Jiangsu Provincial People’s Hospital in Nanjing China, the Principal Investigator for the CARD-1 trial. “I am excited to be able to participate in the trial of C-CAR011 which may someday provide a treatment option for these refractory patients.” “We are very excited as CARD-1 represents the first of a planned series of clinical trials utilizing CBMG’s optimized CAR-T drug candidates,” said Dr. Yihong Yao, Chief Scientific Officer of CBMG. “We look forward to announcing additional trials and CAR-T candidates in the future.” About the CARD-1 Clinical Trial CARD-1 is a Phase I single-site, single-arm dose-escalating trial consisting of three patient cohorts using escalating C-CAR011 cell dosing levels with three patients in each cohort. The primary end points are Dose-Limiting Toxicity (DLT) and Treatment Emergent Adverse Events (TEAE). Secondary endpoints will measure Overall Response Rate (Complete plus Partial Responses) at 4 weeks and 12 weeks and Disease Control Rate (Complete plus Partial Responses plus Stable Disease) at 12 weeks according to the International Working Group (IWG) revised criteria. The trial summary is registered with clinicaltrials.gov under the number NCT02976857. The trial will be conducted by Dr. Jianyong Li at the Jiangsu Provincial People’s Hospital in Nanjing China. The Jiangsu Provincial People’s Hospital (also known as the First Affiliated Hospital of Nanjing Medical University, Jiangsu Clinical Medicine Research Institute and the Red Cross Hospital of Jiangsu) was founded in 1936 and performs medical treatment, provides education, and conducts advanced research. The hospital has 3,000 beds and over 4,000 employees with total floor space of 3 million square feet covering 50 acres. The Department of Clinical Medicine of Nanjing Medical University is located inside the hospital, offering clinical medicine doctoral degree and postdoctoral research programs, with 45 teaching and research sections and more than 200 professors. The hospital maintains cooperative relationships with other research hospitals and laboratories in countries such as the US, Japan, Canada, Australia and Italy. About C-CAR011 CBMG’s proprietary anti-CD19 chimeric antigen receptor T-cell (CAR-T) construct represents advancement over CBMG’s prior CBM-C19.1 construct. C-CAR011 is entirely engineered and manufactured in CBMG’s own GMP manufacturing facility in China. About Diffuse Large B-Cell Lymphoma (DLBCL) Diffuse Large B-Cell Lymphoma (DLBCL) is the most common form of Non-Hodgkin Lymphoma (NHL) with DLBCL representing approximately 30% of newly diagnosed NHL cases in the United States and an even higher percentage of newly diagnosed NHL cases in China. DLBCL is an aggressive form of lymphoma that advances quickly and occurs in both men and women although slightly more common in men. The incidence of DLBCL increases with age with most patients over the age of 60. The current treatment options include chemotherapy, anti-CD20 targeted therapy, radiation and stem cell transplantation. However, for patients with refractory DLBCL (failed to respond to treatment) the poor clinical response rates of 20%-30% with median overall survival of approximately 6 months represents a significant unmet medical need. About Cellular Biomedicine Group (CBMG) Cellular Biomedicine Group, Inc. develops proprietary cell therapies for the treatment of cancer and degenerative diseases. Our immuno-oncology and stem cell projects are the result of research and development by CBMG’s scientists and clinicians from both China and the United States. Our GMP facilities in China, consisting of twelve independent cell production lines, are designed and managed according to both China and U.S. GMP standards. To learn more about CBMG, please visit: www.cellbiomedgroup.com Forward-Looking Statements Statements in this press release relating to plans, strategies, trends, specific activities or investments, and other statements that are not descriptions of historical facts may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking information is inherently subject to risks and uncertainties, and actual results could differ materially from those currently anticipated due to a number of factors, which include risks inherent in doing business, trends affecting the global economy, including the devaluation of the RMB by China in August 2015 and other risks detailed from time to time in CBMG’s reports filed with the Securities and Exchange Commission, quarterly reports on form 10-Q, current reports on form 8-K and annual reports on form 10-K. Forward-looking statements may be identified by terms such as "may," "will," "expects," "plans," "intends," "estimates," "potential," or "continue," or similar terms or the negative of these terms. Although CBMG believes the expectations reflected in the forward-looking statements are reasonable, they cannot guarantee that future results, levels of activity, performance or achievements will be obtained. CBMG does not have any obligation to update these forward-looking statements other than as required by law.


SHANGHAI, China and CUPERTINO, Calif., Nov. 29, 2016 (GLOBE NEWSWIRE) -- Cellular Biomedicine Group Inc. (NASDAQ:CBMG) (“CBMG” or the “Company”), a clinical-stage biomedicine firm engaged in the development of effective immunotherapies for cancer and stem cell therapies for degenerative diseases, is pleased to announce the approval and commencement of patient enrollment in China for its CARD-1 (“CAR-T Against DLBCL”) Phase I clinical trial utilizing its optimized proprietary C-CAR011 construct of CD19 chimeric antigen receptor T-cell (CAR-T) therapy for the treatment of patients with refractory Diffuse Large B-cell Lymphoma (DLBCL). The CARD-1 trial has begun enrollment with final data expected to be available in the second half of 2017. Based on the CARD-1 results, CBMG expects to initiate a larger Phase II clinical trial as soon as practicable. “Our CARD-1 trial represents the first CBMG-sponsored clinical trial after CBMG’s acquisition of its CAR-T technology and data from the PLA General Hospital (PLAGH, also known as 301 Hospital) in Beijing. We are proud of this major corporate milestone where CBMG has taken existing technology and improved it with proprietary optimization and initiated new clinical trials in China,” said Tony (Bizuo) Liu, Chief Executive Officer of CBMG. “We believe we are one of the very few companies that uniquely possesses internal viral vector production and transduction capabilities within our own integrated GMP facility. This allows CBMG to move quickly and efficiently from R&D to manufacturing CAR-T cells for clinical use.” According to a recent large, multi-cohort dataset analysis, patients with refractory DLBCL have clinical response rates of only 20%-30% with a median overall survival of approximately six months. These poor refractory DLBCL patient outcomes represent a significant unmet medical need. CBMG’s CARD-1 Phase I dose-escalation trial will use the traditional 3x3 design to evaluate the safety, efficacy and persistence of C-CAR011 in refractory DLBCL patients. “DLBCL is the largest subtype of Non-Hodgkin Lymphoma (NHL), and those refractory patients whose treatment has failed have limited options and a very poor prognosis compared to relapsed patients who had previously responded to treatment,” said Dr. Jianyong Li from Jiangsu Provincial People’s Hospital in Nanjing China, the Principal Investigator for the CARD-1 trial. “I am excited to be able to participate in the trial of C-CAR011 which may someday provide a treatment option for these refractory patients.” “We are very excited as CARD-1 represents the first of a planned series of clinical trials utilizing CBMG’s optimized CAR-T drug candidates,” said Dr. Yihong Yao, Chief Scientific Officer of CBMG. “We look forward to announcing additional trials and CAR-T candidates in the future.” About the CARD-1 Clinical Trial CARD-1 is a Phase I single-site, single-arm dose-escalating trial consisting of three patient cohorts using escalating C-CAR011 cell dosing levels with three patients in each cohort. The primary end points are Dose-Limiting Toxicity (DLT) and Treatment Emergent Adverse Events (TEAE). Secondary endpoints will measure Overall Response Rate (Complete plus Partial Responses) at 4 weeks and 12 weeks and Disease Control Rate (Complete plus Partial Responses plus Stable Disease) at 12 weeks according to the International Working Group (IWG) revised criteria. The trial summary is registered with clinicaltrials.gov under the number NCT02976857. The trial will be conducted by Dr. Jianyong Li at the Jiangsu Provincial People’s Hospital in Nanjing China. The Jiangsu Provincial People’s Hospital (also known as the First Affiliated Hospital of Nanjing Medical University, Jiangsu Clinical Medicine Research Institute and the Red Cross Hospital of Jiangsu) was founded in 1936 and performs medical treatment, provides education, and conducts advanced research. The hospital has 3,000 beds and over 4,000 employees with total floor space of 3 million square feet covering 50 acres. The Department of Clinical Medicine of Nanjing Medical University is located inside the hospital, offering clinical medicine doctoral degree and postdoctoral research programs, with 45 teaching and research sections and more than 200 professors. The hospital maintains cooperative relationships with other research hospitals and laboratories in countries such as the US, Japan, Canada, Australia and Italy. About C-CAR011 CBMG’s proprietary anti-CD19 chimeric antigen receptor T-cell (CAR-T) construct represents advancement over CBMG’s prior CBM-C19.1 construct. C-CAR011 is entirely engineered and manufactured in CBMG’s own GMP manufacturing facility in China. About Diffuse Large B-Cell Lymphoma (DLBCL) Diffuse Large B-Cell Lymphoma (DLBCL) is the most common form of Non-Hodgkin Lymphoma (NHL) with DLBCL representing approximately 30% of newly diagnosed NHL cases in the United States and an even higher percentage of newly diagnosed NHL cases in China. DLBCL is an aggressive form of lymphoma that advances quickly and occurs in both men and women although slightly more common in men. The incidence of DLBCL increases with age with most patients over the age of 60. The current treatment options include chemotherapy, anti-CD20 targeted therapy, radiation and stem cell transplantation. However, for patients with refractory DLBCL (failed to respond to treatment) the poor clinical response rates of 20%-30% with median overall survival of approximately 6 months represents a significant unmet medical need. About Cellular Biomedicine Group (CBMG) Cellular Biomedicine Group, Inc. develops proprietary cell therapies for the treatment of cancer and degenerative diseases. Our immuno-oncology and stem cell projects are the result of research and development by CBMG’s scientists and clinicians from both China and the United States. Our GMP facilities in China, consisting of twelve independent cell production lines, are designed and managed according to both China and U.S. GMP standards. To learn more about CBMG, please visit: www.cellbiomedgroup.com Forward-Looking Statements Statements in this press release relating to plans, strategies, trends, specific activities or investments, and other statements that are not descriptions of historical facts may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking information is inherently subject to risks and uncertainties, and actual results could differ materially from those currently anticipated due to a number of factors, which include risks inherent in doing business, trends affecting the global economy, including the devaluation of the RMB by China in August 2015 and other risks detailed from time to time in CBMG’s reports filed with the Securities and Exchange Commission, quarterly reports on form 10-Q, current reports on form 8-K and annual reports on form 10-K. Forward-looking statements may be identified by terms such as "may," "will," "expects," "plans," "intends," "estimates," "potential," or "continue," or similar terms or the negative of these terms. Although CBMG believes the expectations reflected in the forward-looking statements are reasonable, they cannot guarantee that future results, levels of activity, performance or achievements will be obtained. CBMG does not have any obligation to update these forward-looking statements other than as required by law.


SHANGHAI, China and CUPERTINO, Calif., Nov. 29, 2016 (GLOBE NEWSWIRE) -- Cellular Biomedicine Group Inc. (NASDAQ:CBMG) (“CBMG” or the “Company”), a clinical-stage biomedicine firm engaged in the development of effective immunotherapies for cancer and stem cell therapies for degenerative diseases, is pleased to announce the approval and commencement of patient enrollment in China for its CARD-1 (“CAR-T Against DLBCL”) Phase I clinical trial utilizing its optimized proprietary C-CAR011 construct of CD19 chimeric antigen receptor T-cell (CAR-T) therapy for the treatment of patients with refractory Diffuse Large B-cell Lymphoma (DLBCL). The CARD-1 trial has begun enrollment with final data expected to be available in the second half of 2017. Based on the CARD-1 results, CBMG expects to initiate a larger Phase II clinical trial as soon as practicable. “Our CARD-1 trial represents the first CBMG-sponsored clinical trial after CBMG’s acquisition of its CAR-T technology and data from the PLA General Hospital (PLAGH, also known as 301 Hospital) in Beijing. We are proud of this major corporate milestone where CBMG has taken existing technology and improved it with proprietary optimization and initiated new clinical trials in China,” said Tony (Bizuo) Liu, Chief Executive Officer of CBMG. “We believe we are one of the very few companies that uniquely possesses internal viral vector production and transduction capabilities within our own integrated GMP facility. This allows CBMG to move quickly and efficiently from R&D to manufacturing CAR-T cells for clinical use.” According to a recent large, multi-cohort dataset analysis, patients with refractory DLBCL have clinical response rates of only 20%-30% with a median overall survival of approximately six months. These poor refractory DLBCL patient outcomes represent a significant unmet medical need. CBMG’s CARD-1 Phase I dose-escalation trial will use the traditional 3x3 design to evaluate the safety, efficacy and persistence of C-CAR011 in refractory DLBCL patients. “DLBCL is the largest subtype of Non-Hodgkin Lymphoma (NHL), and those refractory patients whose treatment has failed have limited options and a very poor prognosis compared to relapsed patients who had previously responded to treatment,” said Dr. Jianyong Li from Jiangsu Provincial People’s Hospital in Nanjing China, the Principal Investigator for the CARD-1 trial. “I am excited to be able to participate in the trial of C-CAR011 which may someday provide a treatment option for these refractory patients.” “We are very excited as CARD-1 represents the first of a planned series of clinical trials utilizing CBMG’s optimized CAR-T drug candidates,” said Dr. Yihong Yao, Chief Scientific Officer of CBMG. “We look forward to announcing additional trials and CAR-T candidates in the future.” About the CARD-1 Clinical Trial CARD-1 is a Phase I single-site, single-arm dose-escalating trial consisting of three patient cohorts using escalating C-CAR011 cell dosing levels with three patients in each cohort. The primary end points are Dose-Limiting Toxicity (DLT) and Treatment Emergent Adverse Events (TEAE). Secondary endpoints will measure Overall Response Rate (Complete plus Partial Responses) at 4 weeks and 12 weeks and Disease Control Rate (Complete plus Partial Responses plus Stable Disease) at 12 weeks according to the International Working Group (IWG) revised criteria. The trial summary is registered with clinicaltrials.gov under the number NCT02976857. The trial will be conducted by Dr. Jianyong Li at the Jiangsu Provincial People’s Hospital in Nanjing China. The Jiangsu Provincial People’s Hospital (also known as the First Affiliated Hospital of Nanjing Medical University, Jiangsu Clinical Medicine Research Institute and the Red Cross Hospital of Jiangsu) was founded in 1936 and performs medical treatment, provides education, and conducts advanced research. The hospital has 3,000 beds and over 4,000 employees with total floor space of 3 million square feet covering 50 acres. The Department of Clinical Medicine of Nanjing Medical University is located inside the hospital, offering clinical medicine doctoral degree and postdoctoral research programs, with 45 teaching and research sections and more than 200 professors. The hospital maintains cooperative relationships with other research hospitals and laboratories in countries such as the US, Japan, Canada, Australia and Italy. About C-CAR011 CBMG’s proprietary anti-CD19 chimeric antigen receptor T-cell (CAR-T) construct represents advancement over CBMG’s prior CBM-C19.1 construct. C-CAR011 is entirely engineered and manufactured in CBMG’s own GMP manufacturing facility in China. About Diffuse Large B-Cell Lymphoma (DLBCL) Diffuse Large B-Cell Lymphoma (DLBCL) is the most common form of Non-Hodgkin Lymphoma (NHL) with DLBCL representing approximately 30% of newly diagnosed NHL cases in the United States and an even higher percentage of newly diagnosed NHL cases in China. DLBCL is an aggressive form of lymphoma that advances quickly and occurs in both men and women although slightly more common in men. The incidence of DLBCL increases with age with most patients over the age of 60. The current treatment options include chemotherapy, anti-CD20 targeted therapy, radiation and stem cell transplantation. However, for patients with refractory DLBCL (failed to respond to treatment) the poor clinical response rates of 20%-30% with median overall survival of approximately 6 months represents a significant unmet medical need. About Cellular Biomedicine Group (CBMG) Cellular Biomedicine Group, Inc. develops proprietary cell therapies for the treatment of cancer and degenerative diseases. Our immuno-oncology and stem cell projects are the result of research and development by CBMG’s scientists and clinicians from both China and the United States. Our GMP facilities in China, consisting of twelve independent cell production lines, are designed and managed according to both China and U.S. GMP standards. To learn more about CBMG, please visit: www.cellbiomedgroup.com Forward-Looking Statements Statements in this press release relating to plans, strategies, trends, specific activities or investments, and other statements that are not descriptions of historical facts may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking information is inherently subject to risks and uncertainties, and actual results could differ materially from those currently anticipated due to a number of factors, which include risks inherent in doing business, trends affecting the global economy, including the devaluation of the RMB by China in August 2015 and other risks detailed from time to time in CBMG’s reports filed with the Securities and Exchange Commission, quarterly reports on form 10-Q, current reports on form 8-K and annual reports on form 10-K. Forward-looking statements may be identified by terms such as "may," "will," "expects," "plans," "intends," "estimates," "potential," or "continue," or similar terms or the negative of these terms. Although CBMG believes the expectations reflected in the forward-looking statements are reasonable, they cannot guarantee that future results, levels of activity, performance or achievements will be obtained. CBMG does not have any obligation to update these forward-looking statements other than as required by law.


He J.,Soochow University of China | Qiao J.-B.,Nanjing Chest Hospital | Zhu H.,Nanjing Medical University
Medical Oncology | Year: 2011

Methylation in the promoter region is one of the mechanisms through which tumor suppressors are inactivated, resulting in tumorigenesis and/or tumor progression. Herein, we studied the methylation status in the promoter region of the p14 ARF tumor suppressor gene in 33 brain tissues isolated from glioma patients (astrocytomas) and compared to 12 brain tissues isolated from autopsy donors using methylation-specific polymerase chain reaction (MSP). The correlation between the expression of P14 and P53 was investigated using immunohistochemistry (IHC). The average percentage of methylation in the promoter region of p14 ARF gene in brain samples from glioma patients is 39.4%, while 0 from autopsy donors. No difference in the methylation level between low-grade and high-grade gliomas was detected. The methylation status has no correlation with the prognosis in glioma patients. A significant correlation between the expression of mutant form of TP53 and the grade of the glioma was established. Furthermore, there was a negative correlation between methylation of the p14 ARF promoter and the expression of the mutant form of TP53. Therefore, our data suggest that methylation in the promoter region of the p14 ARF gene may be used as a biomarker for the diagnosis of gliomas. © 2010 Springer Science+Business Media, LLC.


Chen Z.,Nanjing Medical University | Cao M.,Nanjing Medical University | Plana M.N.,CIBER ISCIII | Liang J.,Nanjing Medical University | And 3 more authors.
Arthritis Care and Research | Year: 2013

Objective To assess the utility of anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody measurement for predicting a risk for developing rapidly progressive interstitial lung disease (RP-ILD) in patients with polymyositis/dermatomyositis (PM/DM). Methods A single-center cohort of 64 consecutive Chinese patients with PM/DM was examined. Serum anti-MDA5 antibody was measured by enzyme-linked immunosorbent assay. For meta-analysis, we searched PubMed and the Institute for Scientific Information Web of Knowledge for original studies that measured anti-MDA5 antibodies in patients with PM/DM. We calculated pooled sensitivity, specificity, diagnostic odds ratio (DOR), and the summary receiver operating characteristic (sROC) curve. Results In Chinese patients, anti-MDA5 antibodies were detected in 26 patients with classic DM or clinically amyopathic DM (CADM). Compared with anti-MDA5-negative patients, anti-MDA5-positive patients showed a higher prevalence of RP-ILD (P = 0.001). In a total of 233 patients with anti-MDA5 antibody, derived from 16 studies, a higher frequency of CADM was found in Japanese than in non-Japanese patients (74.7% versus 39.2%; P = 1.2 × 10-7). Meta-analysis revealed that the pooled sensitivity and specificity of anti-MDA5 antibody for RP-ILD was 77% (95% confidence interval [95% CI] 64-87%) and 86% (95% CI 79-90%), respectively. The pooled DOR was 20.41 (95% CI 9.02-46.20) with a favorable area under the sROC curve of 0.89 (95% CI 0.63-0.98). Conclusion Detection of anti-MDA5 antibody is a valuable tool for identifying DM patients with a high risk for developing RP-ILD, but the distribution of classic DM and CADM in patients with this antibody varies among ethnic groups. Copyright © 2013 by the American College of Rheumatology.


Zheng F.,St Jude Childrens Research Hospital | Zhou X.,Nanjing Medical University | Moon C.,Chonnam National University | Wang H.,Michigan State University
International Journal of Physiology, Pathophysiology and Pharmacology | Year: 2012

Brain-derived neurotrophic factor (BDNF) plays critical roles in many aspects of brain functions, including cell survival, differentiation, development, learning and memory. Aberrant BDNF expression has also been implicated in numerous neurological disorders. Thus, significant effort has been made to understand how BDNF transcription as well as translation is regulated. Interestingly, the BDNF gene structure suggests that multiple promoters control its transcription, leading to the existence of distinct mRNA species. Further, the long-and short-tail of the 3′ un-translated region may dictate different sub-cellular BDNF mRNA targeting and translational responses following neuronal stimulation. This review aims to summarize the main findings that demonstrate how neuronal activities specifically up-regulate the transcription and translation of unique BDNF transcripts. We also discuss some of the recent reports that emphasize the epigenetic regulation of BDNF transcription.


Pu D.,Nanjing Medical University | Shen Y.,Shanghai JiaoTong University | Shen Y.,Harvard University | Wu J.,Nanjing Medical University
Autism Research | Year: 2013

Methylenetetrahydrofolate reductase (MTHFR) is essential for DNA biosynthesis and the epigenetic process of DNA methylation, and its gene polymorphisms have been implicated as risk factors for birth defects, neurological disorders, and cancers. However, reports on the association of MTHFR polymorphisms with autism spectrum disorders (ASD) are inconclusive. Therefore, we investigated the relationship of the MTHFR polymorphisms (C677T and A1298C) and the risk of ASD by meta-analysis. Up to December 2012, eight case-control studies involving 1672 patients with ASD and 6760 controls were included for meta-analysis. The results showed that the C677T polymorphism was associated with significantly increased ASD risk in all the comparison models [T vs. C allele (frequency of allele): odds ratio (OR)=1.42, 95% confidence interval (CI): 1.09-1.85; CT vs. CC (heterozygote): OR=1.48, 95% CI: 1.09-2.00; TT vs. CC (homozygote): OR=1.86, 95% CI: 1.08-3.20; CT+TT vs. CC (dominant model): OR=1.56, 95% CI: 1.12-2.18; and TT vs. CC+CT (recessive model): OR=1.51, 95% CI: 1.02-2.22], whereas the A1298C polymorphism was found to be significantly associated with reduced ASD risk but only in a recessive model (CC vs. AA+AC: OR=0.73, 95% CI: 0.56-0.97). In addition, we stratified the patient population based on whether they were from a country with food fortification of folic acid or not. The meta-analysis showed that the C677T polymorphism was found to be associated with ASD only in children from countries without food fortification. Our study indicated that the MTHFR C677T polymorphism contributes to increased ASD risk, and periconceptional folic acid may reduce ASD risk in those with MTHFR 677C>T polymorphism. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.


Zhou S.G.,Jinling Hospital | Lu J.L.,Nanjing Medical University | Hui J.H.,Nanjing Medical University
World Journal of Urology | Year: 2011

Purpose: To compare the efficacy of α 1D-receptor antagonist Naftopidil and α 1A/D-receptor antagonist Tamsulosin in management of distal ureteral stones. Materials and methods: A total of 131 patients with distal ureteral stones were included in the study from December 2008 to September 2010. The patients were randomized to 3 groups: group 1 (43 patients), those receiving 10 mg naftopidil once daily; group 2 (45 patients), those receiving 0.4 mg tamsulosin once daily; and group 3 (43 patients) were given a watchful waiting and served as control group. All patients were followed up for 2 weeks. Ultrasonography and kidney-ureters-bladder (KUB) were performed on day 7 and 14. At the end of the follow-up period, patients who failed to expel the stone were scheduled to undergo ESWL or ureteroscopy. Results: Stone expulsion was observed in 31 patients in group 1 (72.1%), 37 patients in group 2 (82.2%), and 13 patients in group 3 (30.2%). A statistically significant difference was noted with Chi-square testing between groups 1 and 3, and groups 2 and 3 (P = 0.000 and P = 0.000, respectively). Average time to expulsion was 7.6 ± 2.26 days (range 1-12 days) in group 1, 7.7 ± 1.94 days (range 2-11 days) in group 2, and 9.4 ± 2.48 days (range 6-14 days) in group 3. A statistically significant difference was observed in time to expulsion between groups 1 and 3, and groups 2 and 3 (P = 0.000, P = 0.001, respectively) by ANOVA testing. The side effects encountered in the study groups were generally mild and did not require cessation of therapy in any patient. Conclusions: Naftopidil could significantly increase spontaneous passage of distal ureteral stones with low side effects. The stone expulsion rate is similar for the tamsulosin. © 2011 Springer-Verlag.


Zhao H.,Shanghai JiaoTong University | Xu Z.,Shanghai JiaoTong University | Qin H.,Shanghai JiaoTong University | Gao Z.,Nanjing Medical University | And 3 more authors.
Biochemical Journal | Year: 2014

CRC (colorectal cancer) is one of the most malignant tumours in both developing and developed countries. It is estimated that 60% of CRC patients have liver metastasis. In the present study, we show that miR-30b is an important regulator in human CRC migration and invasion, which are vital steps in CRC liver metastasis. miR-30b was significantly down-regulated in primary CRC specimens compared with normal tissues. Furthermore, miR-30b was much lower in liver metastasis tissues than in CRCs. We validated SIX1 (SIX homeobox 1), a member of the SIX homeodomain family of transcription factors and an EMT (epithelial-mesenchymal transition)-promoting gene, as the directtarget of miR-30b. Forced expression of miR-30b inhibited CRCcell migration and invasion in vitro via its target gene SIX1. Furthermore, an inverse correlation between expression of SIX1 and miR-30b has been observed both in primary CRC specimens and liver metastasis. Taken together, miR-30b plays an important role in mediating metastatic related behaviour in CRC. miR-30b may serve as a potential diagnostic marker and therapeutic target for patients with CRC in the future. © 2014 Biochemical Society.


Che D.,Shanghai JiaoTong University | Zhou H.,Nanjing Medical University | He J.,Shanghai JiaoTong University | Wu B.,Shanghai JiaoTong University
BMC Health Services Research | Year: 2014

Background: The purpose of this study was to compare, from a Chinese societal perspective, the projected health benefits, costs, and cost-effectiveness of adding pneumococcal conjugate heptavalent vaccine (PCV-7) to the routine compulsory child immunization schedule. Methods. A decision-tree model, with data and assumptions adapted for relevance to China, was developed to project the health outcomes of PCV-7 vaccination (compared with no vaccination) over a 5-year period as well as a lifetime. The vaccinated birth cohort included 16,000,000 children in China. A 2 + 1 dose schedule at US$136.51 per vaccine dose was used in the base-case analysis. One-way sensitivity analysis was used to test the robustness of the model. The impact of a net indirect effect (herd immunity) was evaluated. Outcomes are presented in terms of the saved disease burden, costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio. Results: In a Chinese birth cohort, a PCV-7 vaccination program would reduce the number of pneumococcus-related infections by at least 32% and would prevent 2,682 deaths in the first 5 years of life, saving $1,190 million in total costs and gaining an additional 9,895 QALYs (discounted by 3%). The incremental cost per QALY was estimated to be $530,354. When herd immunity was taken into account, the cost per QALY was estimated to be $95,319. The robustness of the model was influenced mainly by the PCV-7 cost per dose, effectiveness herd immunity and incidence of pneumococcal diseases. With and without herd immunity, the break-even costs in China were $29.05 and $25.87, respectively. Conclusions: Compulsory routine infant vaccination with PCV-7 is projected to substantially reduce pneumococcal disease morbidity, mortality, and related costs in China. However, a universal vaccination program with PCV-7 is not cost-effective at the willingness-to-pay threshold that is currently recommended for China by the World Health Organization. © 2014 Che et al.; licensee BioMed Central Ltd.


Zhang L.,Capital Medical University | Cheng L.,Nanjing Medical University | Hong J.,Shanghai JiaoTong University
Pharmacology | Year: 2013

Background: Cetirizine is among the first second-generation H1 antihistamines (SGAHs) developed to provide selective H1 receptor inhibition without central nervous system depression. Objective: The aim of this review is to summarize the amount of data collected over 25 years of clinical use of cetirizine and compare this with data available for other SGAHs in the management of patients with allergic rhinitis (AR). Methods: A comprehensive literature search for publications relating to cetirizine was performed using the Pubmed database, and relevant papers published in English were selected for detailed review. Results: Compared with the majority of other SGAHs, cetirizine was generally shown to have a more favourable pharmacological profile, to be well tolerated, be at least equally or more efficacious in attenuating/ inhibiting nasal and ocular symptoms and to improve the quality of life in AR patients. The majority of clinical trials investigating the effect of SGAHs in AR patients further indicated that cetirizine was often employed as the main comparator active drug. Conclusion: Based on the evidence that cetirizine is a commonly employed active comparator drug in AR, it is tempting to suggest that cetirizine may be a suitable benchmark in the development of novel pharmacotherapies for AR. Copyright © 2013 S. Karger AG, Basel.


Gu L.,Nanjing Agricultural University | Liu H.,Nanjing Agricultural University | Gu X.,Rudong Third Hospital | Boots C.,University of Washington | And 2 more authors.
Cellular and Molecular Life Sciences | Year: 2015

Obesity, diabetes, and related metabolic disorders are major health issues worldwide. As the epidemic of metabolic disorders continues, the associated medical co-morbidities, including the detrimental impact on reproduction, increase as well. Emerging evidence suggests that the effects of maternal nutrition on reproductive outcomes are likely to be mediated, at least in part, by oocyte metabolism. Well-balanced and timed energy metabolism is critical for optimal development of oocytes. To date, much of our understanding of oocyte metabolism comes from the effects of extrinsic nutrients on oocyte maturation. In contrast, intrinsic regulation of oocyte development by metabolic enzymes, intracellular mediators, and transport systems is less characterized. Specifically, decreased acid transport proteins levels, increased glucose/lipid content and elevated reactive oxygen species in oocytes have been implicated in meiotic defects, organelle dysfunction and epigenetic alteration. Therefore, metabolic disturbances in oocytes may contribute to the diminished reproductive potential experienced by women with metabolic disorders. In-depth research is needed to further explore the underlying mechanisms. This review also discusses several approaches for metabolic analysis. Metabolomic profiling of oocytes, the surrounding granulosa cells, and follicular fluid will uncover the metabolic networks regulating oocyte development, potentially leading to the identification of oocyte quality markers and prevention of reproductive disease and poor outcomes in offspring. © 2014 Springer Basel.


Qin J.-J.,Texas Tech University Health Sciences Center | Nag S.,Texas Tech University Health Sciences Center | Wang W.,Texas Tech University Health Sciences Center | Zhou J.,Nanjing Medical University | And 4 more authors.
Biochimica et Biophysica Acta - Reviews on Cancer | Year: 2014

The NFAT signaling pathway regulates various aspects of cellular functions; NFAT acts as a calcium sensor, integrating calcium signaling with other pathways involved in development and growth, immune response, and inflammatory response. The NFAT family of transcription factors regulates diverse cellular functions such as cell survival, proliferation, migration, invasion, and angiogenesis. The NFAT isoforms are constitutively activated and overexpressed in several cancer types wherein they transactivate downstream targets that play important roles in cancer development and progression. Though the NFAT family has been conclusively proved to be pivotal in cancer progression, the different isoforms play distinct roles in different cellular contexts. In this review, our discussion is focused on the mechanisms that drive the activation of various NFAT isoforms in cancer. Additionally, we analyze the potential of NFAT as a valid target for cancer prevention and therapy. © 2014 Elsevier B.V.


Font-Burgada J.,Moores Cancer Center | Sun B.,Nanjing Medical University | Karin M.,Moores Cancer Center
Cell Metabolism | Year: 2016

Although discussion of the obesity epidemic had become a cocktail party cliché, its impact on public health cannot be dismissed. In the past decade, cancer had joined the list of chronic debilitating diseases whose risk is substantially increased by hypernutrition. Here we discuss recent advances in understanding how obesity increases cancer risk and propose a unifying hypothesis according to which the major tumor-promoting mechanism triggered by hypernutrition is the indolent inflammation that takes place at particular organ sites, including liver, pancreas, and gastrointestinal tract. The mechanisms by which excessive fat deposition feeds this tumor-promoting inflammatory flame are diverse and tissue specific. © 2016 Elsevier Inc.


Chen Y.,Nanjing Medical University | Chen Y.,University of California at San Francisco | Won S.J.,University of California at San Francisco | Xu Y.,Nanjing Medical University | Swanson R.A.,University of California at San Francisco
Current Medicinal Chemistry | Year: 2014

Ischemic stroke is caused by critical reductions in blood flow to brain or spinal cord. Microglia are the resident immune cells of the central nervous system, and they respond to stroke by assuming an activated phenotype that releases cytotoxic cytokines, reactive oxygen species, proteases, and other factors. This acute, innate immune response may be teleologically adapted to limit infection, but in stroke this response can exacerbate injury by further damaging or killing nearby neurons and other cell types, and by recruiting infiltration of circulating cytotoxic immune cells. The microglial response requires hours to days to fully develop, and this time interval presents a clinically accessible time window for initiating therapy. Because of redundancy in cytotoxic microglial responses, the most effective therapeutic approach may be to target the global gene expression changes involved in microglial activation. Several classes of drugs can do this, including histone deacetylase inhibitors, minocycline and other PARP inhibitors, corticosteroids, and inhibitors of TNFβ and scavenger receptor signaling. Here we review the pre-clinical studies in which these drugs have been used to suppress microglial activation after stroke. We also review recent advances in the understanding of sex differences in the CNS inflammatory response, as these differences are likely to influence the efficacy of drugs targeting post-stroke brain inflammation. © 2014 Bentham Science Publishers.


Yan L.,Nanjing Medical University | Chen P.,Nanjing Medical University | Chen E.-Z.,Shanghai JiaoTong University | Gu A.,Nanjing Medical University | Jiang Z.-Y.,Shanghai JiaoTong University
British Journal of Cancer | Year: 2014

Background:Renal transplantation has been associated with a significantly increased risk of developing cancers during long-term follow-up, but for bladder cancer, this risk is less clear. We therefore performed a meta-analysis to determine whether bladder cancer risk in renal transplant recipients was increased.Methods:Eligible studies were identified through searches of PubMed and other public resources. Random-effects meta-analyses were used to pool overall estimates for standardised incidence ratios (SIRs). Heterogeneity test, sensitivity analysis, and assessment of publishing bias were also performed.Results:We identified a 3.18-fold higher SIR (95% confidence intervals (CI): 1.34-7.53, P=0.008) of bladder cancer in patients following renal transplantation compared with the general population, based on data from 79 988 patients with a total follow-up of 308 458 patient-years. When stratified by ethnicity, the SIRs for bladder cancer were 2.00 (95% CI: 1.51-2.65, P=0.001) and 14.74 (95% CI: 3.66-59.35, P<0.001) between European and Asian renal transplant recipients, respectively.Conclusions:Our study demonstrated that the risk of developing bladder cancer in transplant populations was increased. Such association suggests that physicians should be more vigilant in checking for bladder cancer in transplantation recipient population. © 2014 Cancer Research UK.


Ge H.-W.,Nanjing Medical University | Hu W.-W.,Zhejiang University | Ma L.-L.,People's Care | Kong F.-J.,Nanjing Medical University
Physiology and Behavior | Year: 2015

Postoperative cognitive dysfunction (POCD) is increasingly being recognized as an important clinical syndrome. Although it has been documented that volatile anesthetics induce neuronal apoptosis and cognitive deficits in several aged animal models, the underlying mechanisms are not well understood. Endoplasmic reticulum stress (ERS) is considered as an initial or early response of cells under stress and linked to neuronal death in various neurodegenerative diseases. The study was designed to explore the possible role of ERS pathway in isoflurane-induced neuroapoptosis and cognitive impairments. In the present study, twenty-month-old rats were exposed to 1.3% isoflurane for 4. h. Two weeks later, the rats were subjected to behavioral study. Protein and mRNA expressions of ERS markers were evaluated. Meanwhile, hippocampal neuronal apoptosis was also detected. We found that isoflurane triggered ERS as evidenced by increased phosphorylation of eukaryotic initiation factor (EIF) 2α, and increased expression of 78-kDa glucose-regulated protein (GRP78), activating transcription factor (ATF) 4 and C/EBP homologous protein (CHOP). Furthermore, the level of apoptosis in the hippocampus was significantly up-regulated after isoflurane exposure, and salubrinal (ERS inhibitor) treatment attenuated the increase. More importantly, cognitive impairments caused by isoflurane were also effectively alleviated by salubrinal pretreatment. These results indicate that ERS-mediated apoptotic pathway is involved in isoflurane neurotoxicity in aged rats. Inhibition of ERS overactivation contributes to the relief of isoflurane-induced neurohistopathologic changes. © 2015 Elsevier Inc.


Li W.,Luoyang Orthopedic Traumatological Hospital | Cai L.,Luoyang Orthopedic Traumatological Hospital | Zhang Y.,Chinese Academy of Sciences | Cui L.,Shanghai JiaoTong University | Shen G.,Nanjing Medical University
Journal of Orthopaedic Research | Year: 2015

We investigated the feasibility of the intra-articular injection of resveratrol for preventing the progression of existing cartilage degeneration in a mouse model of osteoarthritis (OA). The effects of resveratrol on the expression of silent information regulator 2 type 1 (SIRT1), hypoxia-inducible factor-2α (HIF-2α) and catabolic factors in OA cartilage was explored. OA was induced in the mouse knee via destabilization of the medial meniscus (DMM). Resveratrol was injected weekly into the operated knee beginning 4 weeks after surgery. The OA phenotype was evaluated via histological and immunohistochemical analyses at 8 weeks after DMM. Western blot analysis was performed to identify whether resveratrol modulated the interleukin (IL)-1β-induced expression of HIF-2α in human chondrocytes. Histologically, resveratrol treatment preserved the structural homeostasis of the articular cartilage and the subchondral bone. Following resveratrol injection, the expression of collagen type II was retained, but the expression of inducible nitric oxide synthase and matrix metalloproteinase-13 was reduced in OA cartilage. Moreover, the administration of resveratrol significantly induced the activation of SIRT1 and the inhibition of HIF-2α expression in mouse OA cartilage and in IL-1β-treated human chondrocytes. These findings indicate that the intra-articular injection of resveratrol significantly prevents the destruction of OA cartilage by activating SIRT1 and thereby suppressing the expression of HIF-2α and catabolic factors. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.


Yang L.,Hubei Maternal and Child Health Hospital | Han S.,Jinling Hospital | Sun Y.,Nanjing Medical University
Biochemical and Biophysical Research Communications | Year: 2014

Recently, a new generation of PI3K-specific inhibitors, such as GDC0941 and BKM120, are being investigated in clinical trials for treatment against tumors harboring PIK3CA mutations. Nevertheless, not all patients benefit from such treatment, suggesting that their tumors may be resistant to PI3K inhibitors. The investigation of the underlying mechanisms and efficacious personalized treatment remain a large unmet need. In this study, we revealed an IL6-STAT3 positive feedback loop that mediated the resistance to PI3K inhibitors. We found that breast cancer cells with acquired resistance to PI3K inhibitors displayed epithelial-mesenchymal transition (EMT) features and an highly enriched cancer stem cells (CSCs), secreting ∼1000-fold more IL6 than parental cells. Further studies elucidated that activation of the IL6-STAT3 signaling effectively triggered EMT action, expanded the CSCs population, and reduced sensitivity to PI3K inhibitors. Pharmacological inhibition of STAT3 disrupted the IL6-STAT3 signaling and overcome resistance to PI3K inhibitors partially due to increased apoptosis induction. Taken together, our results demonstrated that feedback activation of the IL6-STAT3 loop lead to acquired resistance to PI3K inhibitors by promoting EMT and CSC-like features, and suggested that targeting this loop may be an efficient strategy to overcome resistance to PI3K inhibitors. © 2014 Elsevier Inc. All rights reserved.


Li X.,Shanghai JiaoTong University | Liao Q.,Nanjing Medical University | Zhang S.,Shanghai JiaoTong University | Chen M.,Shanghai JiaoTong University
European Journal of Medical Research | Year: 2014

Background: The aim of this study was to investigate the relationship between the polymorphisms of the methylenetetrahytrofolate reductase (MTHFR) gene and susceptibility to childhood acute lymphoblastic leukemia (ALL). Methods. A case-control study was conducted among 98 children with ALL and 93 age- and sex- matched non-ALL controls. Genotyping of MTHFR C677T and A1298C polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The odds ratios (ORs) of MTHFR genotypes were used to assess the associations of these polymorphisms with childhood ALL susceptibility. Results: No significant differences were observed for frequencies of the 677CC, 677CT and 677TT genotypes between patients and controls. Frequencies of the 1298AA, 1298 AC and 1298CC genotypes between the two groups were significantly different. The risk of ALL with the 1298C allele carriers (AC + CC) was elevated by 1.1 times compared with the AA genotype [OR = 2.100; 95% CI (1.149; 3.837); P = 0.015]. Conclusions: The MTHFR A1298C polymorphism is associated with susceptibility to childhood ALL in the Chinese population. © 2014 Li et al.; licensee BioMed Central Ltd.


News Article | February 23, 2017
Site: www.eurekalert.org

Discovery of a dual role played by the enzyme phosphoglycerate kinase 1 (PGK1) may indicate a new therapeutic target for glioblastoma, an often fatal form of brain cancer, according to researchers at The University of Texas MD Anderson Cancer Center. Findings published in the Feb. 23 online issue of Molecular Cell determined PGK1 as instrumental in regulating both cell metabolism and autophagy, a cellular process crucial to tumor development and maintenance. In previous studies, PGK1 was shown to play a role in coordinating cellular activities tied to cancer metabolism and brain tumor formation, and is associated with tumor metastasis and drug resistance. "Our finding that PGK1 acts as both a glycolytic enzyme and a protein kinase in cell metabolism, autophagy, and cell proliferation greatly enhances our understanding of protein enzymes controlling cellular function," said Zhimin Lu, M.D., Ph.D., professor of Neuro-Oncology. "Because it regulates both autophagy and cell metabolism, PGK1 proves its significance in maintaining cellular activities, thus offering a potential new approach for cancer treatment." Lu's team found that PGK1 unexpectedly impacts the protein Beclin1 through phosphorylation, which modulates protein function. Beclin1 plays a central role in autophagy, a "recycling" process allowing cells to thrive even when starved of nutrients and/or oxygen. Autophagy has been increasingly linked to cancer since it permits tumors to access vital energy sources and cellular building blocks necessary to grow and spread. The researchers observed that lack of oxygen and the essential amino acid glutamine resulted in a complex protein-related chain of events where PGK1 phosphorylates Beclin1, which is required for autophagy and brain tumor development. The process is thought to be one reason why glioblastoma patients generally have poor prognoses. "Upregulated tumor-protective autophagy is one of the reasons for cancer treatment resistance," said Lu. "These findings suggest that approaches inhibiting PGK1-regulated autophagy are likely to increase cancer treatment efficacy. Further investigations into this area of research are underway." MD Anderson team participants included Xu Qian, Ph.D., Xinjian Li, Ph.D., Qingsong Cai, Ph.D., Yuhui Jiang, Ph.D., Jong-Ho Lee, Ph.D., Yugang Wang, Ph.D.,Yan Xia, Ph.D., and Yanhua Zheng, Ph.D., Neuro-Oncology; and David Hawke, Ph.D., Systems Biology. Other participating institutions included Capital Medical University, Beijing; Shanghai Jiotaong University School of Medicine, Shanghai; Nanjing Medical University, Nanjing, China; Washington State University College of Pharmacy, Spokane, Wash.; and The University of Texas Graduate School of Biomedical Sciences at Houston. The study was funded by the National Institutes of Health (CA109035, CA169603, CA016672, CA127001 and NS08975); the James S. McDonnell Foundation 21st Century Initiative in Brain Cancer Research Award (220020318); and a Sister Institution Network Fund and Institutional Research Grant from MD Anderson.


Tran C.M.,University of Pennsylvania | Mukherjee S.,University of Pennsylvania | Ye L.,Nanjing Medical University | Frederick D.W.,University of Pennsylvania | And 5 more authors.
Diabetes | Year: 2016

Rapamycin extends life span in mice, yet paradoxically causes lipid dysregulation and glucose intolerance through mechanisms that remain incompletely understood. Whole-body energy balance can be influenced by beige/brite adipocytes, which are inducible by cold and other stimuli via β-adrenergic signaling in white adipose depots. Induction of beige adipocytes is considered a promising strategy to combat obesity because of their ability to metabolize glucose and lipids, dissipating the resulting energy as heat through uncoupling protein 1. Here, we report that rapamycin blocks the ability of β-adrenergic signaling to induce beige adipocytes and expression of thermogenic genes in white adipose depots. Rapamycin enhanced transcriptional negative feedback on the β3-adrenergic receptor. However, ther-mogenic gene expression remained impaired even when the receptor was bypassed with a cell-permeable cAMP analog, revealing the existence of a second inhibitory mechanism. Accordingly, rapamycin-treated mice are cold intolerant, failing to maintain body temperature and weight when shifted to 4°C. Adipocyte-specific deletion of the mTORC1 subunit Raptor recapitulated the block in β-adrenergic signaling. Our findings demonstrate a positive role for mTORC1 in the recruitment of beige adipocytes and suggest that inhibition of β-adrenergic signaling by rapamycin may contribute to its physiological effects. © 2016 by the American Diabetes Association.


Zhou B.,Nanjing Southeast University | Li Z.,Nanjing Southeast University | Li Z.,Nanjing Medical University | Yang H.,Nanjing Southeast University | He N.,Nanjing Southeast University
Journal of Biomedical Nanotechnology | Year: 2014

MicroRNAs (miRNAs), a class of 19-24 nucleotides non-coding RNAs, regulate gene expression by inhibiting both translation and stability of specific mRNAs at the post-transcriptional level. The existence of miRNAs in a series of mammalian body fluids as extracellular nuclease-resistant entities, together with the aberrant expression of miRNAs during the occurrence and development of a wide range of diseases, triggers the possibility that miRNAs as promising noninvasive diagnostic biomarkers are applied to predict the pathological status of the body. However, the origin and biological function of extracellular miRNAs have not been systematically elucidated. In this review, we summarize the current literature on the biogenesis and post-transcriptional regulation of miRNAs, discuss available evidence regarding the possible origin and release of extracellular miRNAs, and collect novel views on their potentials as key mediators in cell-cell communication processes. Finally, we shed light on the accumulating knowledge about their utilities as diagnostic biomarkers in hepatic diseases. Copyright © 2014 American Scientific Publishers All rights reserved.


Wu K.H.,Nanjing Medical University | Wu K.H.,Peking Union Medical College | Han Z.C.,Peking Union Medical College | Mo X.M.,Nanjing Medical University | Zhou B.,CAS Shanghai Institutes for Biological Sciences
Ageing Research Reviews | Year: 2012

There is a growing interest in the clinical application of stem cells as a novel therapeutic approach for treatment of myocardial infarction and prevention of subsequent heart failure. Transplanted stem cells improve cardiac functions through multiple mechanisms, which include but are not limited to promoting angiogenesis, replacing dead cardiomyocytes, modulating cardiac remodeling. Most of the results obtained so far are exciting and very promising, spawning an increasing number of clinical trials recently. However, many problems still remain to be resolved such as the best delivery method for transplantation of cells to the injured myocardium and the issue of how to optimize the delivery of targeted cells is of exceptional clinical relevance. In this review, we focus on the different delivery strategies in cardiac regenerative therapy, as well as provide a brief overview of current clinical trials utilizing cell-based therapy in patients with ischemic heart disease. © 2011 Elsevier B.V.


Wang F.,Nanjing Medical University | Ying H.-Q.,Nanjing Southeast University | He B.-S.,Nanjing Medical University | Pan Y.-Q.,Nanjing Medical University | And 5 more authors.
Oncotarget | Year: 2015

The long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been recently shown to be dysregulated, which plays an important role in the progression of several cancers. However, the biological role and clinical significance of UCA1 in the carcinogenesis of hepatocellular carcinoma (HCC) remain unclear. Herein, we found that UCA1 was aberrantly upregulated in HCC tissues and associated with TNM stage, metastasis and postoperative survival. UCA1 depletion inhibited the growth and metastasis of HCC cell lines in vitro and in vivo. Furthermore, UCA1 could act as an endogenous sponge by directly binding to miR-216b and downregulation miR-216b expression. In addition, UCA1 could reverse the inhibitory effect of miR-216b on the growth and metastasis of HCC cells, which might be involved in the derepression of fibroblast growth factor receptor 1 (FGFR1) expression, a target gene of miR-216b, and the activation of ERK signaling pathway. Taken together, our data highlights the pivotal role of UCA1 in the tumorigenesis of HCC. Moreover, the present study elucidates a novel lncRNA- miRNA-mRNA regulatory network that is UCA1-miR-216b-FGFR1-ERK signaling pathway in HCC, which may help to lead a better understanding the pathogenesis of HCC and probe the feasibility of lncRNA-directed diagnosis and therapy for this deadly disease.


Tian T.,Nanjing Southeast University | Tian T.,Nanjing Medical University | Zhu Y.-L.,Nanjing Southeast University | Hu F.-H.,Nanjing Southeast University | And 3 more authors.
Journal of Cellular Physiology | Year: 2013

Cells release exosomes into extracellular medium. Although the important roles of exosomes in many physiological and pathological processes are being revealed, the mechanism of exosome-cell interaction remains unclear. In this article, employing real-time fluorescence microscopy, the motion of exosomes on the plasma membrane or in the cytoplasm of recipient PC12 cells was observed directly. In addition, several motion modes of exosomes were revealed by single particle tracking (SPT). The changes between motion modes were also detected, presenting the dynamic courses of exosome attachment onto plasma membrane and exosome uptake. Octadecyl rhodamine B chloride (R18) was found to be useful to distinguish endocytosis from fusion during exosome uptake. Colocalization with organelle markers showed exosomes were sorted to acidic vesicles after internalization. The results provide new sight into the exosome-cell interaction mode and the intercellular trafficking of exosomes. This study will help to understand the roles of exosomes at cell level. © 2012 Wiley Periodicals, Inc.


Qiu X.,Nanjing Southeast University | Dong S.,University of Hong Kong | Qiao F.,Nanjing Southeast University | Lu S.,Nanjing Medical University | And 8 more authors.
Oncogene | Year: 2013

The hepatitis B virus (HBV) X protein (HBx) has a key role in the molecular pathogenesis of HBV-related hepatocellular carcinoma (HCC). However, the mechanism of HBx-mediated hepatocarcinogenesis remains to be elucidated. In this study, we aimed to better understand the effects of HBx on gene-expression profiles that participate in hepatocarcinogenesis and the mechanism by which HBx regulates these genes. Differentially expressed genes between L02-HBx and L02-Vector control cells were identified by microarray and validated using quantitative real-time PCR. HBx upregulates 456 genes and downregulates 843 genes, including programmed cell death 4 (PDCD4). PDCD4 was downregulated in clinical HCC specimens and the downregulation of PDCD4 in HCC is correlated with HBx. Furthermore, overexpression experiments in HCC cells proved that PDCD4 has strong tumor-suppressive effects both in vitro and in vivo, and may induce cell apoptosis to suppress the development of HCC. HBx induces expression of DNA methyltransferases (DNMTs), but failed to change the methylation status of the PDCD4 promoter. HBx downregulates PDCD4 expression at least partially through miR-21. Taken together, this study reported for the first time that HBx downregulates PDCD4 and upregulates miR-21 expression. The overexpression of PDCD4 could suppress tumorigenicity. The deregulation of PDCD4 by HBx through miR-21 represents a potential novel mechanism of the downregulation of PDCD4 in HBV-related HCC and provides new insights into HCC development. © 2013 Macmillan Publishers Limited.


Jiang H.,Nanjing Southeast University | Tang R.-N.,Nanjing Southeast University | Wang J.,Nanjing Medical University
European Journal of Clinical Microbiology and Infectious Diseases | Year: 2013

Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of nosocomial pneumonia. Compared with glycopeptide antibiotics, linezolid achieves higher lung epithelial lining fluid concentrations, which may have an advantage in treating nosocomial pneumonia patients. The objective of this study was to evaluate the efficacy and safety of linezolid versus vancomycin or teicoplanin for the treatment of nosocomial pneumonia. Data were obtained from the Cochrane Central Register of Controlled Trials and the EMBASE and MEDLINE databases. Randomised controlled studies involving the use of linezolid versus vancomycin or teicoplanin in nosocomial pneumonia patients were included in the study. Twelve linezolid trials were included. There was no statistically significant difference between the two groups in the treatment of nosocomial pneumonia regarding the clinical cure rate [relative risk (RR) = 1.08, 95 % confidence interval (CI) = 1.00-1.17, p = 0.06]. Linezolid was associated with better microbiological eradication rate in nosocomial pneumonia patients compared with glycopeptide antibiotics (RR = 1.16, 95 % CI = 1.03-1.31, p = 0.01). There were no differences in the all-cause mortality (RR = 0.95, 95 % CI = 0.83-1.09, p = 0.46) between the two groups. However, the risks of rash (RR = 0.41, 95 % CI = 0.24-0.71, p = 0.001) and renal dysfunction (RR = 0.41, 95 % CI = 0.27-0.64, p < 0.0001) were higher with glycopeptide antibiotics. Although linezolid was more effective in eradicating microbiology than glycopeptide antibiotics for nosocomial pneumonia patients, it did not demonstrate superiority in clinical cure. The incidences of renal dysfunction and rash are higher in the glycopeptide antibiotics group. © 2013 Springer-Verlag Berlin Heidelberg.


Tan C.,Jiangsu Provincial Hospital of Traditional Chinese Medicine | Liu Y.,Jiangsu Provincial Hospital of Traditional Chinese Medicine | Min Z.-S.,Jiangsu Provincial Hospital of Traditional Chinese Medicine | Zhu W.-Y.,Nanjing Medical University
Journal of the European Academy of Dermatology and Venereology | Year: 2014

Background Pigmented fungiform papillae of the tongue (PFPT) is a disorder in which the fungiform papillae of the tongue have abnormal coloration. However, Chinese-specific clinical data for PFPT are lacking. Objective To determine the prevalence and characteristics of PFPT among the Chinese population. Methods A survey was carried out using a clinical examination and a questionnaire on 14,346 first-time outpatients in our dermatology department, and 58 cases of PFPT were subsequently diagnosed. Results The prevalence of PFPT was 0.4% among dermatological outpatients. All patients had pin-sized, brownish fungiform papillae on the tip, lateral or dorsal parts of the tongue. Of the three subtypes, type I was the most common (87.93%). PFPT generally coexisted with Hori's nevus (48.28%), melasma (20.69%), hysteromyoma (24.14%) and breast cystic hyperplasia (20.69%). Conclusion Our study confirms that PFPT is a relatively common disorder among Chinese outpatients, and it was presumed to be closely coupled with Hori's nevus, melasma and other disorders. © 2012 The Authors.


Jiang H.,Nanjing Southeast University | Wang J.,Nanjing Medical University | Zhao W.,Nanjing Southeast University
European Journal of Clinical Microbiology and Infectious Diseases | Year: 2013

The purpose of this study was to evaluate the efficacy of lamivudine (LAM) versus telbivudine (LdT) in the treatment of chronic hepatitis B (CHB). Randomized controlled studies (RCTs) involving the use of LAM versus LdT in CHB patients were included in the study. Data were obtained from the Cochrane-controlled trials register, EMBASE and MEDLINE databases (1/1990 to 12/2011). Two reviewers performed quality assessment and extracted data independently. Eight RCTs were included in the main analysis. Eight eligible trials were included in the analysis. At the end of one-year treatment, LdT was better than LAM at the virological response (RR = 1.43, 95 % CI = 1.12-1.84, P = 0.005), while less than LAM at the viral breakthrough (RR = 0.34,95 % CI = 0.25-0.48, P < 0.00001), viral resistance (RR = 0.41,95 % CI = 0.28-0.58, P < 0.00001), but there was no statistically significant difference in the biochemical response (RR = 1.13,95 % CI = 0.99-1.29, P = 0.06), HBeAg seroconversion (RR = 1.13,95 % CI = 0.92-1.39, P = 0.25), therapeutic response (RR = 1.22,95 % CI = 1.00-1.50, P = 0.05) and adverse events (RR = 1.07,95 % CI = 1.00-1.14, P = 0.05). The creatine kinase (CK) elevation occurred more frequently in the LdT group than in LAM group (RR = 2.43,95 % CI = 1.57-3.75, P < 0.0001). When treatment prolonged to 2 years, LdT was better than LAM at the HBeAg seroconversion (RR = 1.29,95 % CI = 1.12-1.50, P = 0.0007) and therapeutic response (RR = 1.34,95 % CI = 1.21-1.49, P < 0.00001). LdT was more effective in inhibiting HBV replication and promoting HBeAg seroconversion than LAM for CHB patients, whereby adverse effects such as CK elevation must be paid attention to. © 2012 Springer-Verlag.


Vourekas A.,University of Pennsylvania | Zheng K.,Nanjing Medical University | Fu Q.,University of Pennsylvania | Maragkakis M.,University of Pennsylvania | And 5 more authors.
Genes and Development | Year: 2015

Piwi–piRNA (Piwi-interacting RNA) ribonucleoproteins (piRNPs) enforce retrotransposon silencing, a function critical for preserving the genome integrity of germ cells. The molecular functions of most of the factors that have been genetically implicated in primary piRNA biogenesis are still elusive. Here we show that MOV10L1 exhibits 5′-to-3′ directional RNA-unwinding activity in vitro and that a point mutation that abolishes this activity causes a failure in primary piRNA biogenesis in vivo. We demonstrate that MOV10L1 selectively binds piRNA precursor transcripts and is essential for the generation of intermediate piRNA processing fragments that are subsequently loaded to Piwi proteins. Multiple analyses suggest an intimate coupling of piRNA precursor processing with elements of local secondary structures such as G quadruplexes. Our results support a model in which MOV10L1 RNA helicase activity promotes unwinding and funneling of the single-stranded piRNA precursor transcripts to the endonuclease that catalyzes the first cleavage step of piRNA processing. © 2015 Tycowski et al.


Wang X.-C.,Tongji University | Wang X.-C.,Nanjing Medical University | Gusdon A.M.,New York Medical College | Liu H.,Nanjing Medical University | And 2 more authors.
World Journal of Gastroenterology | Year: 2014

Glucagon-like peptide1 (GLP-1) is secreted from Langerhans cells in response to oral nutrient intake. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a new class of incretin-based anti-diabetic drugs. They function to stimulate insulin secretion while suppressing glucagon secretion. GLP-1-based therapies are now well established in the management of type 2 diabetes mellitus (T2DM), and recent literature has suggested potential applications of these drugs in the treatment of obesity and for protection against cardiovascular and neurological diseases. As we know, along with change in lifestyles, the prevalence of non-alcoholic fatty liver disease (NAFLD) in China is rising more than that of viral hepatitis and alcoholic fatty liver disease, and NAFLD has become the most common chronic liver disease in recent years. Recent studies further suggest that GLP-1RAs can reduce transaminase levels to improve NAFLD by improving blood lipid levels, cutting down the fat content to promote fat redistribution, directly decreasing fatty degeneration of the liver, reducing the degree of liver fibrosis and improving inflammation. This review shows the NAFLD-associated effects of GLP-1RAs in animal models and in patients with T2DM or obesity who are participants in clinical trials. © 2014 Baishideng Publishing Group Inc. All rights reserved.


Jin L.,Nanjing Southeast University | Zeng X.,Nanjing Medical University | Liu M.,Nanjing Southeast University | He N.,Nanjing Southeast University
Science of Advanced Materials | Year: 2013

Much attention has been paid to chitosan-based nanoparticles for drug and gene delivery. In this study, chitosan/polylactic acid/tripolyphosphate (CS/PLA/TPP) nanoparticles were successfully prepared for encapsulation of insoluble drugs, which was confirmed by Fourier transform infrared spectroscopy (FTIR). The nanoparticles were regular, spherical and had a uniform diameter of around 300 nm. The entrapment efficiency of the obtained CS/PLA/TPP nanoparticles for azithromycin (AZI) varied with both the ratio of CS to PLA and the ratio of CS to AZI. The highest entrapment efficiency above 85% was realized, with 4:1 ratio for CS:PLA and 10:13 ratio for CS:AZI. A sustained and controlled in vitro drug release was also observed. Moreover, the CS/PLA/TPP nanoparticles showed little cytotoxicity when co-cultured with Hela and HEK293T cells. Though the CS/PLA/TPP nanoparticles are suitable for most water-insoluble drugs, the entrapment capacity for different drugs varies. © 2013 by American Scientific Publishers.


Tang L.-Y.,U.S. National Cancer Institute | Yamashita M.,U.S. National Cancer Institute | Yamashita M.,Osaka University | Coussens N.P.,U.S. National Cancer Institute | And 7 more authors.
EMBO Journal | Year: 2011

TGF-β signalling is regulated by post-translational modifications of Smad proteins to translate quantitative difference in ligand concentration into proportional transcriptional output. Previous studies in cell culture systems suggested that Smad ubiquitination regulatory factors (Smurfs) act in this regulation by targeting Smads for proteasomal degradation, but whether this mechanism operates under physiological conditions is not clear. Here, we generated mice harbouring a target-disrupted Smurf2 allele. Using primary mouse embryonic fibroblasts and dermal fibroblasts, we show that TGF-β-mediated, Smad-dependent transcriptional responses are elevated in the absence of Smurf2. Instead of promoting poly-ubiquitination and degradation, we show that Smurf2 actually induces multiple mono-ubiquitination of Smad3 in vivo. Phosphorylation of T179, immediately upstream of the Smad3 PY motif, enhances Smurf2 and Smad3 interaction and Smad3 ubiquitination. We have mapped Smurf2-induced Smad3 ubiquitination sites to lysine residues at the MH2 domain, and demonstrate that Smad3 ubiquitination inhibits the formation of Smad3 complexes. Thus, our data support a model in which Smurf2 negatively regulates TGF-β signalling by attenuating the activity of Smad3 rather than promoting its degradation. © 2011 European Molecular Biology Organization.


Yang F.,Nanjing Southeast University | Hu S.,Nanjing Southeast University | Zhang Y.,Nanjing Southeast University | Cai X.,Nanjing Southeast University | And 5 more authors.
Advanced Materials | Year: 2012

It is found that Prussian Blue nanoparticles (PBNPs) possess a catalase-like activity to catalyse the breakdown of H2O2 into oxygen (O2) molecules under the neutral conditions (pH = 7.4). Based on this finding, we have developed a new strategy in which PBNPs can be excellent ultrasound (US) and magnetic-resonance (MR) dual modality imaging contrast agents for H2O2 diagnostics in vitro and in vivo. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Han L.,Nanjing Medical University | Zhang E.-B.,Nanjing Medical University | Yin D.-D.,Cancer Therapy and Research Center | Kong R.,Subei Peoples Hospital | And 5 more authors.
Cell Death and Disease | Year: 2015

Recently, a novel class of transcripts, long noncoding RNAs (lncRNAs), is involved in diseases including cancer. Here, we investigated the the role of lncRNA PANDAR in the progression of non-small cell lung carcinoma (NSCLC). PANDAR, interacting with NF-YA, was generally downregulated in NSCLC tissues. In a cohort of 140 NSCLC patients, decreased PANDAR expression was negatively correlated with greater tumor size (Po0.001) and advanced TNM stage (P=0.002). Moreover, PANDAR could serve as an independent predictor for overall survival in NSCLC (P=0.015). Further experiments demonstrated that PANDAR expression was induced by p53, and chromatin immunoprecipitation (ChIP) assays confirmed that PANDAR was a direct transcriptional target of p53 in NSCLC cells. PANDAR overexpression significantly repressed the proliferation in vitro and in vivo. We also showed that PANDAR-mediated growth regulation is in part due to the transcriptional modulation of Bcl-2 by interacting with NF-YA, thus affecting NSCLC cell apoptosis. To our knowledge, this is the first report which showed the role of PANDAR in the progression of NSCLC. The p53/PANDAR/NF-YA/Bcl-2 interaction might serve as targets for NSCLC diagnosis and therapy. © 2015 Macmillan Publishers Limited. All rights reserved.


Jin L.,Nanjing Southeast University | Zeng X.,Nanjing Medical University | Liu M.,Nanjing Southeast University | Deng Y.,Nanjing Southeast University | And 3 more authors.
Theranostics | Year: 2014

Gene transfer methods are promising in the field of gene therapy. Current methods for gene transfer include three major groups: viral, physical and chemical methods. This review mainly summarizes development of several types of chemical methods for gene transfer in vitro and in vivo by means of nano-carriers like; calcium phosphates, lipids, and cationic polymers including chitosan, polyethylenimine, polyamidoamine dendrimers, and poly(lactide-co-glycolide). This review also briefly introduces applications of these chemical methods for gene delivery. © Ivyspring International Publisher.


Wan Y.,Nanjing Southeast University | Guo Z.,Nanjing Medical University | Jiang X.,Nanjing Southeast University | Fang K.,Nanjing Southeast University | And 3 more authors.
Journal of Colloid and Interface Science | Year: 2013

Silver nanoparticles (AgNPs) are attracting tremendous attention in biomedicine, and their related performances are shape and size-dependent. For biomedical applications, water-soluble AgNPs are necessary. However, aqueous syntheses of AgNPs with controlled shape and size are relatively difficult as the balance between nucleation and growth is hard to regulate. This paper describes a robust method for controllable synthesis of quasi-spherical AgNPs based on the combination of the seed-mediated growth and the Lee-Meisel method by thermal reduction of AgNO3 with citrate. In the presented method, citrate-stabilized AgNPs with tunable sizes up to 80nm were achieved through one-step or stepwise growth process using qualified spherical 4nm AgNPs as starter seeds. Specially, the two main difficulties (formation of nanorods and secondary nucleation during the growth stage) in the previous studies have been effectively overcome by tailoring the experimental parameters such as the reaction temperature and the seed amount, without extra additives, pH adjustment, and laser treatment. The crucial factors that affect the uniformity of the resulting AgNPs are discussed. © 2012 Elsevier Inc.


Zhang E.-B.,Nanjing Medical University | Kong R.,Nanjing Medical University | Yin D.-D.,Nanjing Southeast University | You L.-H.,Nanjing Medical University | And 7 more authors.
Oncotarget | Year: 2014

Long noncoding RNAs are involved in diseases including cancer. Here, we reported that ANRIL (CDKN2B-AS1), a 3.8-kb long noncoding RNA, recruiting and binding to PRC2, was generally upregulated in human gastric cancer (GC) tissues. In a cohort of 120 GC patients, the higher expression of ANRIL was significantly correlated with a higher TNM stage (P=0.041) and tumor size (P=0.001). Multivariate analyses revealed that ANRIL expression served as an independent predictor for overall survival (P=0.036). Further experiments revealed that ANRIL knockdown significantly repressed the proliferation both in vitro and in vivo. We also showed that E2F1 could induce ANRIL and ANRIL-mediated growth promotion is in part due to epigenetic repression of miR-99a/miR-449a in Trans (controlling the targets-mTOR and CDK6/E2F1 pathway) by binding to PRC2, thus forming a positive feedback loop, continuing to promote GC cell proliferation. To our knowledge, this is the first report showed that the role of ANRIL in the progression of GC and ANRIL could crosstalk with microRNAs in epigenetic level. Our results suggest that ANRIL, as a growth regulator, may serve as a candidate prognostic biomarker and target for new therapies in human gastric cancer.


Li J.,Nanjing Medical University | Ren J.,Nanjing Medical University | Liu X.,Nanjing Medical University | Jiang L.,Nanjing Medical University | And 4 more authors.
Kidney International | Year: 2015

The mammalian target of rapamycin (mTOR) was recently identified in two structurally distinct multiprotein complexes: mTORC1 and mTORC2. Previously, we found that Rictor/mTORC2 protects against cisplatin-induced acute kidney injury, but the role and mechanisms for Rictor/mTORC2 in TGFβ1-induced fibroblast activation and kidney fibrosis remains unknown. To study this, we initially treated NRK-49F cells with TGFβ1 and found that TGFβ1 could activate Rictor/mTORC2 signaling in cultured cells. Blocking Rictor/mTORC2 signaling with Rictor or Akt1 small interfering RNAs markedly inhibited TGFβ1-induced fibronection and α-smooth muscle actin expression. Ensuing western blotting or immunostaining results showed that Rictor/mTORC2 signaling was activated in kidney interstitial myofibroblasts from mice with unilateral ureteral obstruction. Next, a mouse model with fibroblast-specific deletion of Rictor was generated. These knockout mice were normal at birth and had no obvious kidney dysfunction or kidney morphological abnormality within 2 months of birth. Compared with control littermates, the kidneys of Rictor knockout mice developed less interstitial extracellular matrix deposition and inflammatory cell infiltration at 1 or 2 weeks after ureteral obstruction. Thus our study suggests that Rictor/mTORC2 signaling activation mediates TGFβ1-induced fibroblast activation and contributes to the development of kidney fibrosis. This may provide a therapeutic target for chronic kidney diseases. © 2015 International Society of Nephrology.


Zhang R.-L.,Nanjing Medical University | Zhang J.-P.,Peking Union Medical College | Wang Q.-Q.,Peking Union Medical College
PLoS ONE | Year: 2014

The recombinant Treponema pallidum protein Tp0965 (rTp0965), one of the many proteins derived from the genome of T. pallidum subsp. pallidum, shows strong immunogenicity and immunoreactivity. In this study, we investigated the effects of rTp0965 on the endothelial barrier. Treatment of human umbilical vein endothelial cells (HUVECs) with rTp0965 resulted in increased levels of ICAM-1, E-selectin, and MCP-1 mRNA and protein expression. These increases contributed to the adhesion and chemataxis of monocytes (THP-1 cells) to HUVECs preincubated with rTp0965. In addition, rTp0965 induced reorganization of F-actin and decreased expression of claudin-1 in HUVECs. Interestingly, inhibition of the RhoA/ROCK signal pathway protected against rTp0965-induced higher endothelial permeability as well as transendothelial migration of monocytes. These data indicate that Tp0965 protein may play an important role in the immunopathogenesis of syphilis. © 2014 Zhang et al.


Yan L.,Nanjing Medical University | Wu S.,Nanjing Institute of Environmental Sciences | Zhang S.,Nanjing Institute of Environmental Sciences | Ji G.,Nanjing Institute of Environmental Sciences | Gu A.,Nanjing Medical University
Gene | Year: 2014

Telomeres are critical in maintaining genomic stability and integrity, and telomerase expression in spermatogonial stem cells is responsible for the maintenance of telomere length in the human male germline. Genetic variants in telomere-associated pathway genes might affect telomere length and chromosomal stability, and subsequently disease susceptibility. Thus, we hypothesize that single nucleotide polymorphisms (SNPs) in this pathway could contribute to male infertility risk. In a case-control study of 580 male infertility cases and 580 matched controls, 8 common SNPs in telomerase reverse transcriptase (TERT) and telomerase-associated protein 1 (TEP1) were genotyped. Overall, we found that TERT rs2736100 was inversely associated with male infertility risk (adjusted odds ratio (OR)=0.66, 95% confidence interval (CI): 0.47-0.92; Ptrend=0.011), whereas TEP1 rs1713449 was positively associated with risk of male infertility (adjusted OR=1.39, 95% CI: 1.20-1.62; Ptrend<0.001). In addition, subjects carrying risk genotypes of these both loci had a two-fold (95% CI: 1.34-3.15) increase in the risk of male infertility, indicating a significant gene-gene interaction between these two loci (P for multiplicative interaction=0.009). Moreover, linear regression analysis showed that individuals carrying the TEP1 rs1713419 variants have significantly higher levels of sperm DNA fragmentation (β=2.243, P=0.016). In conclusion, our results give the first evidence that genetic variations of TERT rs2736100 and TEP1 rs1713449 were associated with susceptibility to male infertility. © 2013 Elsevier B.V.


Yin H.-T.,Nanjing Southeast University | Zhang D.-G.,Jiangsu Taizhou Peoples Hospital | Wu X.-L.,Nanjing Medical University | Huang X.-E.,JiangSu Cancer Hospital and Research Institute | Chen G.,Nanjing Medical University
Asian Pacific Journal of Cancer Prevention | Year: 2013

Curcumin (Cum) has been reported to have potential chemo-preventive and chemotherapeutic activity through influencing various processes, inducing cell cycle arrest, differentiation and apoptosis in a series of cancers. However, the poor solubility of Cum limits its further applications in the treatment of cancer. We have previously reported Cum-loaded nanoparticles (Cum-NPs) prepared with amphilic methoxy poly(ethylene glycol)-polycaprolactone (mPEG-PCL) block copolymers. The current study demonstrated superior antitumor efficacy of Cum-NPs over free Cum in the treatment of lung cancer. In vivo evaluation further demonstrated superior anticancer effects of Cum-NPs by delaying tumor growth compared to free Cum in an established A549 transplanted mice model. Moreover, Cum-NPs showed little toxicity to normal tissues including bone marrow, liver and kidney at a therapeutic dose. These results suggest that Cum-NPs are effective to inhibit the growth of human lung cancer with little toxicity to normal tissues, and could provide a clinically useful therapeutic regimen. They thus merit more research to evaluate the feasibility of clinical application.


Gusdon A.M.,Tongji University | Gusdon A.M.,New York Medical College | Song K.-X.,Tongji University | Qu S.,Tongji University | Qu S.,Nanjing Medical University
Oxidative Medicine and Cellular Longevity | Year: 2014

Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of disorders characterized by the accumulation of triglycerides within the liver. The global prevalence of NAFLD has been increasing as the obesity epidemic shows no sign of relenting. Mitochondria play a central role in hepatic lipid metabolism and also are affected by upstream signaling pathways involved in hepatic metabolism. This review will focus on the role of mitochondria in the pathophysiology of NAFLD and touch on some of the therapeutic approaches targeting mitochondria as well as metabolically important signaling pathways. Mitochondria are able to adapt to lipid accumulation in hepatocytes by increasing rates of beta-oxidation; however increased substrate delivery to the mitochondrial electron transport chain (ETC) leads to increased reactive oxygen species (ROS) production and eventually ETC dysfunction. Decreased ETC function combined with increased rates of fatty acid beta-oxidation leads to the accumulation of incomplete products of beta-oxidation, which combined with increased levels of ROS contribute to insulin resistance. Several related signaling pathways, nuclear receptors, and transcription factors also regulate hepatic lipid metabolism, many of which are redox sensitive and regulated by ROS. © 2014 Aaron M. Gusdon et al.


Dong C.G.,China Agricultural University | Wu W.K.K.,Chinese University of Hong Kong | Feng S.Y.,Soochow University of China | Wang X.J.,Chinese University of Hong Kong | And 2 more authors.
International Journal of Oncology | Year: 2012

MicroRNAs (miRNAs) are small non-coding RNAs that function as negative gene regulators. Alterations in the expression of miRNAs have been implicated in the pathogenesis and development of most human malignancies. Recent data indicate that microRNA-21 and microRNA-10b are significantly elevated in glioblastoma multiforme (GBM) suggesting their role in the regulation of multiple genes associated with cancer. In this study, U87MG human glioblastoma cells were treated with miRNA inhibitors targeting miR-10b and miR-21, alone or in combination. The results showed that the miR-21 inhibitor additively interacted with miR-10b inhibitor on U87MG cells. The 50% inhibitory concentration values were dramatically decreased in cells treated with the combination of miR-10b and miR-21 inhibitors. Furthermore, inhibitors synergistically combined, enhanced apoptosis significantly and reduced invasion ability assessed by flow cytometry and Transwell migration assay. Thus, the miR-21 inhibitor may interrupt the activity of EGFR pathways, increasing PDCD4 and TPM1 expression and reducing MMP activities, independently of PTEN status. Meanwhile, miR-10b inhibitor reduced by Twist proceeds to inhibit translation of the mRNA encoding HOXD10 leading to the increase of the expression of the well-characterized pro-metastatic gene RHOC. Taken together, these data strongly suggest that a combination of miR-21 inhibitor and miR-10b inhibitor could be an effective therapeutic strategy for controlling the growth of GBM by inhibiting oncogene expression and overexpressing tumor suppressor genes. Moreover, a regulatory strategy based on the combination of miRNA inhibitors may provide insights into the mechanisms of the modulation of signaling genes involved in tumor cell apoptosis and invasiveness.


Han F.,Nanjing University | Jiang H.,Nanjing Southeast University | Fang D.,Nanjing Medical University | Jiang D.,Nanjing University
Analytical Chemistry | Year: 2014

The potential-resolved electrochemiluminescence (ECL) was achieved for the determination of two antigens at the cell surface through a potential scanning on the electrode. Luminol and Ru(bpy)3 2+ groups as ECL probes were linked with the antibodies to recognize the corresponding antigens on the cell surface. A self-quenching of luminescence from the luminol group under negative potential was initialized by the introduction of concentrated aqueous luminol, which offered accurate measurements of the luminescence from luminol and Ru(bpy)3 2+ groups under positive and negative potentials, respectively. Using this strategy, carcinoembryonic (CEA) and alphafetoprotein (AFP) antigens on cells as the models were quantified serially through a potential scanning. Different patterns of luminescence were observed at MCF 7 and PC 3 cells, which exhibited that the assay can characterize the cells with a difference expression of antigens. Compared with fluorescence measurement, the potential resolved ECL for the detection of two analytes was not limited by the spectrum difference of probes. The strategy involving potential-induced signals required a simplified optical setup and eventually offered an alternative imaging method for multiply antigens in immunohistochemistry. © 2014 American Chemical Society.


Jiang H.,Nanjing Southeast University | Wang J.,Nanjing Medical University | Zhao W.,Nanjing Southeast University
Clinica Chimica Acta | Year: 2013

Background: We investigated the prognostic value of cyclooxygenase-2 (COX-2) for survival of patients with non-small cell lung cancer (NSCLC). Methods: We performed a meta-analysis of literature to aggregate the available survival results, using studies published in English until June 2012. Eligible studies dealt with COX-2 protein assessment in NSCLC patients on primary lesions and reported survival data according to COX-2 expression. Results: Nineteen trials, comprising 2651 patients, provided sufficient information for the meta-analysis. Overall combined hazard ratio (HR) was 1.86 (95% CI: 1.58-2.20); it was calculated using a random-effects model, and associates high COX-2 expression with poor survival in all NSCLC patients. Aggregate survival data showed poor survival for patients with adenocarcinoma (ADC), squamous cell cancer (SCC) and Stage I NSCLC with high COX-2 expression, at 2.00 (95% CI: 1.38-2.88), 2.29 (95% CI: 1.58-3.33) and 1.95 (95% CI: 1.31-2.91) respectively. Conclusions: Our meta-analysis shows that the COX-2 expression status is an independent prognostic factor in NSCLC, and this tendency applies to SCC, ADC and stage I NSCLC. © 2013 Elsevier B.V.


Wu D.,Nanjing Southeast University | Yuan Y.,Nanjing Southeast University | Bai F.,Nanjing Southeast University | You J.,Nanjing Medical University | And 2 more authors.
Journal of Affective Disorders | Year: 2013

Background: The functional neural network model has been a major method used to investigate mechanisms of neuropsychopathy. There is considerable evidence that late-onset depression (LOD) is the prodrome, or the early clinical manifestation, of Alzheimer's disease (AD). The default mode network (DMN) is one of the neural networks that can be used to explore the complex relationships between depressive symptoms, episodic memory deficits and other cognitive impairments. To date, no study has directly linked the DMN to LOD while focusing on episodic memory and the influence of apolipoprotein E4 (APOE4), a major genetic risk factor for AD in LOD patients. Methods: In total, 33 remitted LOD (rLOD) patients and 33 elderly controls underwent fMRI scanning using low-frequency BOLD signal imaging during the resting state and during an episodic memory task. Furthermore, function-based functional connectivities (FCs) in the region of interesting (ROI) (posterior cingulate cortex (PCC) of the DMN) were analysed to explore interactions between disease states, task states and genetic risk factors (APOE4). Results: Compared to healthy control subjects (HC), the FCs between the PCC and the right medial temporal lobe of the rLOD patients were significantly stronger during rest (p<0.005) and significantly weaker (p<0.05) during performance of the task. The mode of change from rest to task performance in the HC was in contrast to the mode of change in the rLOD patients. The FCs of the rLOD patients without APOE4 were significantly increased (p<0.05) in the resting state, but the rLOD patients who carried APOE4 showed a trend toward decreased FCs. Limitations: The sample size was small. While the study was cross-sectional, we did not differentiate between the various types of antidepressants the patients used, which may have had different effects on cognitive function, especially on episodic memory. Conclusion: Our results suggested that rLOD might be the prodrome, or the early clinical manifestation, of AD and that rLOD patients with APOE4 showed an increased risk for episodic memory decline and AD. © 2012 Elsevier B.V. All rights reserved.


Peng W.,Nanjing Medical University | Gao W.,Nanjing Southeast University | Feng J.,Nanjing Medical University
Medical Oncology | Year: 2014

Pancreatic cancer (PC) is the fourth leading cause of cancer-related mortalities in the USA and the sixth leading cause of mortality in China. Recent studies have shown that lncRNAs play important roles in carcinogenesis. The aim of this study was to explore the role of lncRNA HULC in PC. Quantitative real-time PCR was performed to investigate the expression of HULC in tumor tissues and corresponding normal tissues from 304 patients with PC. The higher expression of HULC was significantly correlated with large tumor size, advanced lymph node metastasis and vascular invasion. Multivariate analyses revealed that HULC expression served as an independent predictor for overall survival (P = 0.032). Further experiments revealed that HULC knockdown significantly repressed cell proliferation of PC in vitro. In conclusion, our results suggest that HULC may serve as a candidate prognostic biomarker through growth regulation in human PC. © 2014, Springer Science+Business Media New York.


Chen D.,Nanjing Medical University | Tang Q.,Nanjing Southeast University
BMC Cancer | Year: 2010

Background: To evaluate the killing effect of HSV-TK/GCV suicide gene therapy system combined with 60Co radiotherapy on human cervical cancer Hela cell line in vitro and in vivo, and to explore the radiosensitization by HSV-TK/GCV system.Methods: HSV-TK/GCV suicide gene therapy system and 60Co radiotherapy were used separately or in combination on human cervical cancer Hela cell line in vitro and in vivo to compare their effects. Colony formation test and the rate of radiosensitization effect (E/O) were employed to observed the radiosensitization by HSV-TK/GCV system.Results: HSV-TK/GCV suicide gene therapy system had strong therapeutic effects on Hela cells in vitro and in vivo (the inhibition rates were 45.8% and 39.5%, respectively), moreover, the combined administration of gene therapy and radiotherapy had stronger therapeutic effects in vitro and in vivo (the inhibition rate was 87.5% in vitro, and the inhibition rate was 87.9% in vivo) (P < 0.01). The inhibition rate by radiotherapy alone was 42.4% in vitro and 35.8% in vivo. The sensitivity of combined therapy to radiotherapy increased more than that of therapy alone, the ability of colony formation decreased (P < 0.01). The rate of radiosensitivity effect (E/O) was 3.17(> 1.4), indicating HSV-TK/GCV system could exert a sensitizing effect on 60Co radiotherapy of the transplanted human cervical cancer cell in nude mice.Conclusion: HSV-TK/GCV system had radiosensitization. Gene therapy combined with radiotherapy may be a good supplementary method for cervix cancer synthetic treatment. © 2010 Chen and Tang; licensee BioMed Central Ltd.


Wu Q.,Nanjing Medical University | Wu Q.,Nanjing Southeast University | Wang C.,Nanjing Medical University | Lu Z.,Nanjing Southeast University | And 2 more authors.
Clinica Chimica Acta | Year: 2012

Objective: Among methods for profiling levels of miRNAs, next-generation sequencing (NGS) has an effective one for genome-wide profiles, which not only can accurately quantify known miRNAs expression, but also discovery novel miRNAs. In this paper, we investigated that whether specific miRNAs were co-expressed in the serum and tissue of breast cancer (BC) patients as novel biomarkers by SOLiD sequencing. Methods: Different miRNA expression profiles of serum and tissue in breast cancer patients and control subjects were obtained by NGS -SOLiD sequencing. Real-time PCR was used to selected and validated candidate miRNA-biomarkers. Novel miRNAs were predicted by computational pipeline, and validated by Northern blot analysis. Results: Of genome-wide miRNA analysis using SOLiD sequencing, 7 miRNAs were found to be co-upregulated (i.e., miR-103, miR-23a, miR-29a, miR-222, miR-23b, miR-24 and miR-25). miR-222 was significantly increased in the serum of BC patients by further validation(P < 0.05), which may be a useful biomarker for differentiating BC patients from controls with receiver operating characteristic (ROC) curve area 0.67 of (95% CI = 0.5649 to 0.7775). A novel miRNA, named miR-BS1 was preliminarily identified and validated. Pre-miR-BS1 has a characteristic secondary structure. Mature miR-BS1 expression was detected in MCF-7 and MDA-MB-231 cells. Through gene ontology analysis, predicted target genes of miR-BS1, such as FOXO3 and KRAS, were involved in cancer-related signaling pathway. Conclusions: This study presented a connection between serum- and tissue- based miRNA of breast cancer which suggested that serum-miRNAs may be potential biomarkers for BC detection. And next-generation sequencing will provide a robust platform for miRNA profilings. © 2012 Elsevier B.V.


Zhang H.,Nanjing Medical University | Zeng X.,Peking Union Medical College | Sun L.,Nanjing Medical University
Expert Opinion on Biological Therapy | Year: 2010

Importance of the field: Bone-marrow-derived mesenchymal stem cells (BMMSC) are multipotent non-hematopoietic progenitor cells that are being explored as a promising new treatment for tissue regeneration. Although their immunomodulatory properties are not yet completely understood, their low immunogenic potential together with their effects on immune response make them a promising therapeutic tool for severe refractory autoimmune diseases including systemic lupus erythematosus (SLE). Area covered in this review: Our aim is to discuss recent progress in understanding the role of malfunctioning BMMSC in etiopathogenesis of SLE and to explore allogenic BMMSC transplantation as a potential therapy for SLE. What the reader will gain: Recent evidence suggests that the functions of BMMSC are disrupted in SLE pathology. This malfunction may result as a corollary of the disease, or may play a more fundamental role in its etiopathogenesis. We provide a brief characterization of BMMSC immunomodulatory effects, and describe our current understanding of the mechanisms by which it plays a part in treating SLE. We also present our clinical trial using allogenic BMMSC in this context. Take home message: Allogenic BMMSC appear to be a safe therapeutic option for treatment-resistant SLE as illustrated in our clinical trial. © 2010 Informa UK Ltd.


Huang Y.Y.,Tongji University | Gusdon A.M.,New York Medical College | Qu S.,Tongji University | Qu S.,Nanjing Medical University
Lipids in Health and Disease | Year: 2013

Along with rising numbers of patients with metabolic syndrome, the prevalence of nonalcoholic fatty liver disease (NAFLD) has increased in proportion with the obesity epidemic. While there are no established treatments for NAFLD, current research is targeting new molecular mechanisms that underlie NAFLD and associated metabolic disorders. This review discusses some of these emerging molecular mechanisms and their therapeutic implications for the treatment of NAFLD. The basic research that has identified potential molecular targets for pharmacotherapy will be outlined. © 2013Huang et al.; licensee BioMed Central Ltd.


Wu K.H.,Nanjing Medical University | Mo X.M.,Nanjing Medical University | Han Z.C.,Peking Union Medical College | Zhou B.,CAS Shanghai Institutes for Biological Sciences
Annals of Thoracic Surgery | Year: 2011

Cellular therapy has emerged as a potentially novel treatment for severe ischemic heart disease, and there is increasing evidence that stem cell transplantation may improve the perfusion and contractile function of ischemic myocardium. However, the problem of poor donor cell engraftment and survival in ischemic myocardium limits the successful use of cellular therapy for treating ischemic heart disease. This review discusses the state-of-the-art understanding of the low level of cell engraftment and cell survival after transplantation into the ischemic heart, with a focus on the approaches that have been investigated for supporting and improving the survival and engraftment of transplanted cells in this setting. © 2011 The Society of Thoracic Surgeons.


Dai Y.,Nanjing Medical University | Diao Z.,Nanjing Medical University | Sun H.,Nanjing Medical University | Li R.,Nanjing Medical University | And 2 more authors.
Human Reproduction | Year: 2011

Background: A low dose injection of lipopolysaccharides (LPS) may induce pre-eclampsia-like symptoms in rats, and microRNA-155 (miR-155) is elevated in the placentas of patients with pre-eclampsia. Our goal was to investigate the association of miR-155 with pre-eclampsia and the pathways involved using human-trophoblast-derived cell line (HTR-8/SVneo) stimulated with LPS. Methods: We measured miR-155 in HTR-8/SVneo cells treated with LPS (25800 ng/ml) using real-time PCR. Western blotting was used to study transcription factor activated protein 1 (AP-1) (JunB and FosB subunits) and nuclear factor (NF)-κB p65 in the HTR-8/SVneo cells and placentas from patients with pre-eclampsia. DNA precipitation assays and luciferase reporter analysis were used to evaluate the regulation of miR-155 by AP-1 and NF-κB. Cell migration was determined by scratch assay. Syncytialization of HTR-8/SVneo cells was analysed following transfection with miR-155. Results: miR-155 was increased together with AP-1 and NF-κB in HTR-8/SVneo cells incubated with low dose of LPS (≤100 ng/ml; P < 0.05 versus baseline). Both JunB/FosB and p65 were increased in placenta from women with severe pre-eclampsia versus a normal pregnancy, with elevated expression of miR-155 (P < 0.05). For specific DNA-binding sites upstream of BIC/miR-155 gene promoter, the AP-1 site was more important than the NF-κB site for increasing miR-155 in HTR-8/SVneo cells. The cells with enforced expression of miR-155 showed a reduced ability to migrate (P < 0.05) and an increased number of syncytiotrophoblast-like multinuclear cells (P < 0.05). Conclusions: LPS may induce remodelling of the human-trophoblast-derived HTR-8/SVneo cells by increasing miR-155, acting in part through the AP-1 and NF-κB pathways. © 2011 The Author.


Wu S.-H.,Nanjing Medical University | Chen X.-Q.,Nanjing Medical University | Liu B.,Nanjing Southeast University | Wu H.-J.,Nanjing Southeast University | Dong L.,Nanjing Medical University
British Journal of Dermatology | Year: 2013

Background Lipoxins are potential anti-inflammatory mediators and serve as an endogenous 'braking signal' in the inflammatory process. Accumulating evidence has indicated the efficacy of lipoxin A4 (LXA4) and its analogs in the treatment of many animal models of inflammatory diseases. Objectives This study investigates the efficacy and safety of 15(R/S)-methyl-lipoxin A4 in the topical treatment of infantile eczema. Patients and methods In this two-centre, double-blind, placebo-controlled, randomized, parallel-groups comparative study, 60 patients were randomly assigned to receive either the 15(R/S)-methyl-lipoxin A 4 cream, mometasone furoate (Eloson, Schering-Plough, Shanghai, China) or placebo for 10 days. The efficacy was determined using the Severity Scale Score (SSS), Eczema Area and Severity Index (EASI) and the Infants' Dermatitis Quality of Life Index (IDQOL). Safety was monitored by physical examination, laboratory investigation and documentation of clinical adverse events. Results The treatment of eczema with 15(R/S)-methyl-LXA4 cream significantly relieved the severity, induced a recovery, and improved the quality of life of the patients, as demonstrated by significantly reduced SSS, EASI and IDQOL, respectively, in a way similar to the efficacy of Eloson. All safety parameters remained within normal limits. No clinical adverse event was found in the three patient groups. Conclusions 15(R/S)-methyl-LXA4 was well tolerated, and significantly reduced the severity of eczema. The results of this small exploratory study suggest that 15(R/S)-methyl-LXA 4 warrants further investigation in the treatment of eczema. © 2012 The Authors. BJD © 2012 British Association of Dermatologists.


Jiang W.-L.,Nanjing Medical University | Jiang W.-L.,Nanjing Southeast University | He H.-W.,Nanjing Medical University | Yang Z.-J.,Nanjing Medical University
Scientific Reports | Year: 2014

The angiotensinogen (AGT) gene M235T polymorphism has been suggested to be linked to risk of heart failure (HF). However, association studies on the M235T polymorphism and HF risk have shown conflicting results. PubMed and China Biology Medicine (CBM) databases were systematically searched to identify relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. A total of 1,281 HF cases and 1,376 controls were included in the analysis. The pooled data showed that there was no significant associations between the AGT M235T polymorphism and HF risk for TT vs. MM (OR = 1.17, 95%CI = 0.62-2.19, P = 0.635), MT vs. MM (OR = 0.97, 95%CI = 0.77-1.22, P = 0.776), MT/TT vs. MM (OR = 1.07, 95%CI = 0.67-1.69, P = 0.781), and TT vs. MM/MT (OR = 1.23, 95%CI = 0.86-1.76, P = 0.259). In contrast, in the HF subgroup analysis by ethnicity, the AGT M235T polymorphism had a decreased risk of HF among Asians (MT vs. MM, OR = 0.39, 95%CI = 0.17-0.92, P = 0.032). Our results suggest that the AGT M235T polymorphism is a low-penetrant risk factor for the development of HF among Asians.


Ji G.,Nanjing Medical University | Ji G.,Nanjing Institute of Environmental Sciences | Long Y.,China Pharmaceutical University | Zhou Y.,CAS Shanghai Institutes for Biological Sciences | And 3 more authors.
BMC Medicine | Year: 2012

Background: The mismatch repair (MMR) pathway plays an important role in the maintenance of the genome integrity, meiotic recombination and gametogenesis. This study investigated whether genetic variations in MMR genes are associated with an increased risk of sperm DNA damage and male infertility.Methods: We selected and genotyped 21 tagging single nucleotide polymorphisms (SNPs) in five MMR genes (MLH1, MLH3, PMS2, MSH4 and MSH5) using the SNPstream 12-plex platform in a case-control study of 1,292 idiopathic infertility patients and 480 fertile controls in a Chinese population. Sperm DNA damage levels were detected with the Tdt-mediated dUTP nick end labelling (TUNEL) assay in 450 cases. Fluorescence resonance energy transfer (FRET) and co-immunoprecipitation techniques were employed to determine the effects of functional variants.Results: One intronic SNP in MLH1 (rs4647269) and two non-synonymous SNPs in PMS2 (rs1059060, Ser775Asn) and MSH5 (rs2075789, Pro29Ser) seem to be risk factors for the development of azoospermia or oligozoospermia. Meanwhile, we also identified a possible contribution of PMS2 rs1059060 to the risk of male infertility with normal sperm count. Among patients with normal sperm count, MLH1 rs4647269 and PMS2 rs1059060 were associated with increased sperm DNA damage. Functional analysis revealed that the PMS2 rs1059060 can affect the interactions between MLH1 and PMS2.Conclusions: Our results provide evidence supporting the involvement of genetic polymorphisms in MMR genes in the aetiology of male infertility. © 2012 Ji et al; licensee BioMed Central Ltd.


Zhu C.,Nanjing Medical University | Huang S.,Nanjing Medical University | Yuan Y.,Nanjing Medical University | Ding G.,Nanjing Medical University | And 4 more authors.
American Journal of Pathology | Year: 2011

Aldosterone (Aldo) causes podocyte damage by an unknown mechanism. We examined the role of mitochondrial dysfunction (MtD) in Aldo-treated podocytes in vitro and in vivo. Exposure of podocytes to Aldo reduced nephrin expression dose dependently, accompanied by increased production of reactive oxygen species (ROS). The ROS generation and podocyte damage were abolished by the mitochondrial (mt) respiratory chain complex I inhibitor rotenone. Pronounced MtD, including reduced mt membrane potential, ATP levels, and mtDNA copy number were seen in Aldo-treated podocytes and in the glomeruli of Aldo-infused mice. The mineralocorticoid receptor antagonist eplerenone significantly inhibited Aldo-induced MtD. The MtD was associated with higher levels of ROS, reduction in the activity of complexes I, III, and IV, and expression of the peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1α and mt transcription factor A. Both the PPARγ agonist rosiglitazone and PPARγ overexpression protected against podocyte injury by preventing MtD and oxidative stress, as evidenced by reduced ROS production, by maintenance of mt morphology, by restoration of mtDNA copy number, by decrease in mt membrane potential loss, and by recovery of mt electron transport function. The protective effect of rosiglitazone was abrogated by the specific PPARγ small interference RNA, but not a control small interference RNA. We conclude that MtD is involved in Aldo-induced podocyte injury, and that the PPARγ agonist rosiglitazone may protect podocytes from this injury by improving mitochondrial function. Copyright © 2011 American Society for Investigative Pathology.


Ren S.-Q.,Nanjing Medical University | Yan J.-Z.,Nanjing Medical University | Zhang X.-Y.,Nanjing Medical University | Bu Y.-F.,Nanjing Medical University | And 5 more authors.
EMBO Journal | Year: 2013

Direct phosphorylation of GluA1 by PKC controls α-amino-3-hydroxy-5- methyl-isoxazole-4-propionic acid (AMPA) receptor (AMPAR) incorporation into active synapses during long-term potentiation (LTP). Numerous signalling molecules that involved in AMPAR incorporation have been identified, but the specific PKC isoform(s) participating in GluA1 phosphorylation and the molecule triggering PKC activation remain largely unknown. Here, we report that the atypical isoform of PKC, PKCλ, is a critical molecule that acts downstream of phosphatidylinositol 3-kinase (PI3K) and is essential for LTP expression. PKCλ activation is required for both GluA1 phosphorylation and increased surface expression of AMPARs during LTP. Moreover, p62 interacts with both PKCλ and GluA1 during LTP and may serve as a scaffolding protein to place PKCλ in close proximity to facilitate GluA1 phosphorylation by PKCλ. Thus, we conclude that PKCλ is the critical signalling molecule responsible for GluA1-containing AMPAR phosphorylation and synaptic incorporation at activated synapses during LTP expression. © 2013 European Molecular Biology Organization.


Patent
Nanjing Southeast University, Nanjing Medical University and Zhejiang Shapuaisi Pharmacy Ltd. | Date: 2012-09-26

Organic dicarboxylic acid compounds, salts and preparation methods thereof. The said compounds have activity of resisting oxidation damage to crystalline lens of eyes. The structures of the above organic dicarboxylic acid compounds are shown as formula (1).


Xu Y.,Xiamen University | Liu Y.,Nanjing Medical University | Wu Y.,Xiamen University | Xia X.,Xiamen University | And 2 more authors.
Analytical Chemistry | Year: 2014

Here we report a rapid, low cost, and disposable dipstick-type DNA biosensor that enables multiplex detection in a single assay. The fluorescent probes labeled with different fluorophores were introduced into the lateral flow nucleic acid testing system. In combination with multiple immobilized probes arranged in an array formant on the membrane, a dual-color fluorescent lateral flow DNA biosensor was developed using a portable fluorescence reader. Up to 13 human papillomavirus types could be detected simultaneously by a single-step operation in less than 30 min after linear-after-the-exponential (LATE)-PCR. The sensitivity was determined to be 10-102 copies plasmid DNA/μL. The specificity study showed no cross-reactivity among the 31 different common HPV types. In the clinical validation, 95.3% overall agreement showed very good potential for this method in the clinical application when compared to a commercial kit. © 2014 American Chemical Society.


Zhang M.,Nanjing Medical University | Han L.,Nanjing Medical University | Xu Y.,Nanjing Medical University | Xu Y.,Nanjing University | Xu Y.,Jiangsu Key Laboratory for Molecular Medicine
Clinical and Experimental Pharmacology and Physiology | Year: 2012

1. Cocaine- and amphetamine-regulated transcript (CART), first isolated from the ovine hypothalamus, is a potential neurotransmitter widely distributed throughout the central and peripheral nervous systems, as well as in endocrine cells in the pituitary and adrenal glands, pancreatic islets and stomach. 2. Numerous studies have established the role of CART in food intake, maintenance of bodyweight, stress control, reward and pain transmission. Recently, it was demonstrated that CART, as a neurotrophic peptide, had a cerebroprotective against focal ischaemic stroke and inhibited the neurotoxicity of β-amyloid protein, which focused attention on the role of CART in the central nervous system (CNS) and neurological diseases. 3. In fact, little is known about the way in which CART peptide interacts with its receptors, initiates downstream cascades and finally exerts its neuroprotective effect under normal or pathological conditions. The literature indicates that there are many factors, such as regulation of the immunological system and protection against energy failure, that may be involved in the cerebroprotection afforded by CART. 4. The present review provides a brief summary of the current literature on CART synthesis and active fragments, its distribution in the CNS and, in particular, the role of CART peptide (and its receptors and signalling) in neurological diseases. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.


Zhang Y.,Sun Yat Sen University | Jiang L.,Nanjing Medical University
Clinics and Research in Hepatology and Gastroenterology | Year: 2014

Background and objective: Previous studies have shown that C-reactive protein (CRP) 1059G/C and 1846G/A polymorphisms may play a role in cancer risk. However, the results from the published studies are conflicting. To derive a more precise estimation of the relationship between CRP 1059G/C and 1846G/A polymorphisms and cancer risk, we conducted a meta-analysis of 21 studies involving a total of 26,634 subjects. Methods: Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. Results: No significant association was found between CRP 1846G/A polymorphism and cancer risk. However, a significant association was found between CRP 1059G/C polymorphism and cancer risk (CC vs CG+GG: OR=3.60, 95% CI=1.63-7.92, PH=0.67; CC vs GG: OR=3.53, 95% CI=1.60-7.77, PH=0.69). In the subgroup analysis by ethnicity, a significant association was found for the CRP 1846G/A polymorphism among mixed population. Interestingly, when stratifying by cancer type, marginally increased risks were observed for CRP 1846G/A polymorphism in colorectal cancer (AA vs AG+GG: OR=1.17, 95% CI=1.00-1.36, PH=0.27) and significantly decreased risks were found for CRP 1846G/A polymorphism in breast cancer (AA vs GG: OR=0.73, 95% CI=0.56-0.95, PH=0.93; A vs G: OR=0.88, 95% CI=0.79-0.99, PH=0.54). For 1059G/C polymorphism, a significant association was found in colorectal cancer. Conclusion: This meta-analysis showed the evidence that CRP 1059G/C and 1846G/A polymorphisms were risk factors for the development of colorectal cancer, and CRP 1846G/A polymorphism is also a protective factor for decreasing breast cancer. © 2014 Elsevier Masson SAS.


Xie H.-G.,Nanjing Medical University | Xie H.-G.,Nanjing First Hospital Affiliated | Zou J.-J.,Nanjing First Hospital Affiliated | Hu Z.-Y.,Nanjing First Hospital Affiliated | And 3 more authors.
Pharmacology and Therapeutics | Year: 2011

The widespread use of clopidogrel alone or in combination with aspirin has significantly benefited patients with acute coronary syndrome who are managed medically or by percutaneous coronary intervention and stent implantation, greatly improving their survival. Emerging data have documented that the clopidogrel response may vary from person to person and even from disease to disease, and that genetic and nongenetic factors contribute to that variability. Genetic polymorphisms affecting clopidogrel metabolic bioactivation and platelet function may be responsible, each exerting a small effect. CYP2C19*2,*3 and*17, CYP2C9*2 and*3, MDR1*2, and functional variants in the genes encoding platelet membrane receptors and intracellular signaling proteins are involved, and other genetic factors remain to be identified. In addition, nongenetic factors may be influential covariates, such as ethnicity, gender, age, body weight, co-existing diseases, drug-drug interactions, and other factors to be determined. Each piece of the puzzle would be useful to bridge and delineate identified knowledge gaps and to determine future research needs for the risk prediction of fatal complications associated with inadequate clopidogrel therapy in patient care. © 2010 Elsevier Inc. All rights reserved.


Zheng Q.-Y.,The Military General Hospital of Beijing PLA | Jin F.-S.,Chongqing Medical University | Yao C.,Nanjing Medical University | Zhang T.,The Military General Hospital of Beijing PLA | And 2 more authors.
Biochemical and Biophysical Research Communications | Year: 2012

Ursolic acid (UA) has shown the anti-tumor properties against a number of human cancers both in vivo and in vitro, however, its effect in bladder cancer and the corresponding mechanisms of action remain largely unknown. Here we found that UA dose-dependently induced growth inhibition and apoptosis in human bladder cancer T24 cells, and activation of AMP-activated protein kinase (AMPK) may contribute to the process. Our Western-blot results demonstrated a significant AMPK activation after UA treatment in T24 cells. Notably, knockdown of AMPKα by the targeted shRNA largely inhibited UA-induced T24 cell growth inhibition and apoptosis, while an AMPK activator 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) or a constitutively active form of AMPK mimic UA's effect. We found the ceramide level was increased after UA treatment in T24 cells, and UA-induced AMPK activation and T24 cell apoptosis were inhibited by ceramide synthase inhibitor fumonisin B1, and was enhanced by exogenously adding cell permeable short-chain ceramide (C6), suggesting that ceramide might serve as an upstream signal for AMPK activation. Further, activation of AMPK by UA promoted c-Jun N-terminal kinase (JNK) activation, but inhibited mTOR complex 1 (mTORC1) signaling to cause survivin down-regulation. Our study suggests that activation of AMPK by UA contributes to growth inhibition and apoptosis in human bladder cancer cells. © 2012 Elsevier Inc.


Lei L.,Fujian Medical University | Li H.,Fujian Medical University | Yan F.,Nanjing Medical University | Xiao Y.,Queensland University of Technology
PLoS ONE | Year: 2013

A finely-tuned innate immune response plays a pivotal role in protecting host against bacterial invasion during periodontal disease progression. Hyperlipidemia has been suggested to exacerbate periodontal health condition. However, the underlying mechanism has not been addressed. In the present study, we investigated the effect of hyperlipidemia on innate immune responses to periodontal pathogen Porphyromonas gingivalis infection. Apolipoprotein E-deficient and wild-type mice at the age of 20 weeks were used for the study. Peritoneal macrophages were isolated and subsequently used for the study of viable P. gingivalis infection. ApoE-/- mice demonstrated inhibited iNOS production and impaired clearance of P. gingivalis in vitro and in vivo; furthermore, ApoE-/- mice displayed disrupted cytokine production pattern in response to P. gingivalis, with a decreased production of tumor necrosis factor-α, interleukin-6 (IL-6), IL-1β and monocyte chemotactic protein-1. Microarray data demonstrated that Toll-like receptor (TLR) and NOD-like receptor (NLR) pathway were altered in ApoE-/- mice macrophages; further analysis of pattern recognition receptors (PRRs) demonstrated that expression of triggering receptors on myeloid cells-1 (TREM-1), an amplifier of the TLR and NLR pathway, was decreased in ApoE-/- mice macrophages, leading to decreased recruitment of NF-κB onto the promoters of the TNF-α and IL-6. Our data suggest that in ApoE-/- mice hyperlipidemia disrupts the expression of PRRs, and cripples the host's capability to generate sufficient innate immune response to P. gingivalis, which may facilitate immune evasion, subgingival colonization and establishment of P. gingivalis in the periodontal niche. © 2013 Lei et al.


Wu Q.-L.,Nanjing Medical University | Shen T.,First Hospital Affiliated to Liaoning Medical College | Shao L.-L.,First Peoples Hospital in Jining | Ma H.,Nanjing Medical University | Wang J.-K.,Nanjing Medical University
Shock | Year: 2012

Previous studies have shown that PI3K/GSK-3β/β-catenin signaling pathway plays a vital role in ischemic preconditioning. The present study attempts to evaluate whether PI3K/GSK-3β/β-catenin signaling pathway might be responsible for the cardioprotection in ischemic postconditioning. Male Sprague-Dawley rats underwent 30 min of left anterior descending coronary artery occlusion and 2 h of reperfusion. One hundred twenty rats were randomized into six groups: sham, ischemia/reperfusion (I/R), ischemic postconditioning (Post), 15 μg • kg -1 wortmannin (PI3K inhibitor) plus ischemic postconditioning (Wort + Post), wortmannin plus I/R (Wort + I/R), and 0.6 mg • kg -1 SB216763 (GSK-3β inhibitor) plus I/R (SB + I/R). Wortmannin and SB216763 were administered, respectively, 10 and 5 min before reperfusion. Myocardial infarct size; number of apoptotic cardiomyocytes; total Akt, GSK-3β; phosphorylated Akt, GSK-3β; β-catenin in cytosol and nucleus; and Bcl-2 protein were assessed. It was found that Post and SB + I/R reduced infarct size (32.3% [SD, 2.8%], 32.7% [SD, 2.1%], vs. 53.4% [SD, 3.2%], respectively, P < 0.05) and apoptotic index of cardiomyocytes (23.2% [SD, 1.8%], 23.8% [SD, 1.8%], vs. 47.3% [SD, 5.8%], respectively, P < 0.05); compared with I/R, wortmannin abolished the cardioprotection of ischemic postconditioning. Post and SB + I/R increased phosphorylated Akt, phosphorylated GSK3β, β-catenin in cytosol and nucleus, and Bcl-2 expression versus I/R. These results indicate that ischemic postconditioning could induce myocardial protection via PI3K/GSK-3β/β-catenin signaling pathway, activation of which results in accumulation of β-catenin and upregulation of its target genes Bcl-2. © 2012 by the Shock Society.


Gasque G.,Rockefeller University | Conway S.,Rockefeller University | Huang J.,Nanjing Medical University | Rao Y.,Tsinghua University | And 2 more authors.
Scientific Reports | Year: 2013

Dysregulation of eating behavior can lead to obesity, which affects 10% of the adult population worldwide and accounts for nearly 3 million deaths every year. Despite this burden on society, we currently lack effective pharmacological treatment options to regulate appetite. We used Drosophila melanogaster larvae to develop a high-throughput whole organism screen for drugs that modulate food intake. In a screen of 3630 small molecules, we identified the serotonin (5-hydroxytryptamine or 5-HT) receptor antagonist metitepine as a potent anorectic drug. Using cell-based assays we show that metitepine is an antagonist of all five Drosophila 5-HT receptors. We screened fly mutants for each of these receptors and found that serotonin receptor 5-HT2A is the sole molecular target for feeding inhibition by metitepine. These results highlight the conservation of molecular mechanisms controlling appetite and provide a method for unbiased whole-organism drug screens to identify novel drugs and molecular pathways modulating food intake.


Rao J.,University of California at Los Angeles | Rao J.,Nanjing Medical University | Lu L.,University of California at Los Angeles | Lu L.,Nanjing Medical University | Zhai Y.,University of California at Los Angeles
Current Opinion in Organ Transplantation | Year: 2014

PURPOSE OF REVIEW: Ischemia and reperfusion injuries occur in multiple clinical settings and contribute to organ dysfunction/failures. Despite the innate inflammatory immune nature, T cells that are critically involved in the pathogenesis of ischemia reperfusion injury (IRI), include not only CD4 T cells, but also CD8 and γδT cells. This review focuses on questions of how putative Ag-specific T cells are involved, which include whether they function in an Ag-dependent manner; how they function, cytokine-mediated or costimulatory molecule-mediated mechanisms; and whether different T-cell subsets, Th1, Th17, regulatory T cell (Treg), are all involved and play distinctive roles? RECENT FINDINGS: Specific T-cell populations, such as effector memory CD4 T cells, promote inflammatory immune activation by ischemia reperfusion independent of their adaptive properties, that is Ag-independently. They function by secreting cytokines and expressing costimulatory molecules to either promote or inhibit innate immune activation, or facilitate tissue repair/homeostasis, as exemplified by Th1, Th17 or Th2, Treg cells, respectively. SUMMARY: T-cell-targeted therapies need to be refined with strategies to maximally eliminate the proinflammatory but spare the anti-inflammatory/immune regulatory properties of T cells, for future clinical application to ameliorate IRI.


Ji H.,University of Houston | Ding Z.,University of Houston | Hawke D.,University of Houston | Xing D.,Tsinghua University | And 3 more authors.
EMBO Reports | Year: 2012

Although Niban is highly expressed in human cancer cells, the cellular functions of Niban remain largely unknown. We demonstrate here that ultraviolet irradiation induces phosphorylation of Niban at S602 by AKT, which increases the association of Niban with nucleophosmin and disassociation of nucleophosmin from the MDM2 complex. This leads to the promotion of MDM2-p53 interaction and subsequent p53 degradation, thereby providing an antiapoptotic effect. Conversely, depletion of or deficiency in Niban expression promotes stabilization of p53 with increased cell apoptosis. Our findings illustrate a pivotal role for AKT-mediated phosphorylation of Niban in protecting cells from genotoxic stress-induced cell apoptosis. ©2012 European Molecular Biology Organization.


Xu Q.,Nanjing Medical University | Liu L.-Z.,Thomas Jefferson University | Qian X.,Nanjing Medical University | Chen Q.,Nanjing Medical University | And 5 more authors.
Nucleic Acids Research | Year: 2012

MiR-145 can regulate cell apoptosis, proliferation, neural development and stem cell differentiation. Previous studies indicate that miR-145 is downregulated in human colon cancer cells. However, the molecular mechanisms of miR-145 used to regulate colon carcinogenesis and angiogenesis remain to be clarified. Here, we show that the expression of miR-145 is downregulated in colon and ovarian cancer tissues and cell lines. MiR-145 inhibits p70S6K1 post-transcriptional expression by binding to its 3′-UTR. The angiogenic factors hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF), which are downstream molecules of p70S6K1, are decreased by miR-145 overexpression. P70S6K1 rescues miR-145-suppressed HIF-1 and VEGF levels, tumorigenesis and tumor angiogenesis. Furthermore, the miR-145 level is inversely correlated with the amount of p70S6K1 protein in colon cancer tissues. Taken together, these studies suggest that miR-145 serves as a tumor suppressor which downregulates HIF-1 and VEGF expression by targeting p70S6K1, leading to the inhibition of tumor growth and angiogenesis. The miR-145 rescue could be a rationale for therapeutic applications in colon cancer in the future. © The Author(s) 2011. Published by Oxford University Press.


Tian Y.,Nanjing Medical University | Wang K.,Nanjing Medical University | Wang Z.,Nanjing Medical University | Li N.,Third Peoples Hospital of Shenzhen | Ji G.,Nanjing Medical University
Carcinogenesis | Year: 2013

Chronic colonic inflammation is a known risk factor for colorectalcancer (CRC). Glutamine (GLN) supplementation has shownits anti-inflammation benefit in experimental colitis. WhetherGLN is effective in preventing colon carcinogenesis remains tobe investigated. The chemopreventive activity of GLN was evaluatedin the mouse model of dextran sulfate sodium (DSS)/azoxymethane(AOM)-induced colitis-associated CRC in this study. Mice were treated with DSS/AOM and randomized to receiveeither a control diet or GLN-enriched diet intermittently of thestudy. The disease activity index was evaluated weekly. On day80 of the experiment, the entire colon and rectum were processedfor histopathologic examination and further evaluation. Pro-inflammatory mediators and cytokines were measured byenzyme-linked immunosorbent assay, real-time-PCR and westernblot analysis. Here, we show that after GLN-enriched diet, the colitis presented a statistical improvement and tumors burdendecreased significantly. This was accompanied by lower activityof nuclear factor-κB (NF-κB), decreased expression of cyclooxygenase-2 and inducible nitric oxide synthase, lower expression ofcytokines and chemokines as well as reduced proliferation andinduced apoptosis in the colons of colitis-associated CRC mice. Our data demonstrate the protective/preventive effect of GLN inthe progression of colitis-associated CRC, which was correlatedwith a dampening of inflammation and NF-κB activity and with adecrease of inflammatory protein overexpression. © The Author 2013. Published by Oxford University Press. All rights reserved.


Mao X.,Yixing Peoples Hospital | Sun Y.,Nanjing Medical University | Tang J.,Yixing Peoples Hospital
Neurological Sciences | Year: 2014

The standard of care for primary central nervous system lymphoma (PCNSL) is systemic chemotherapy with or without whole brain radiotherapy or intrathecal chemotherapy. In contrast to treatment for other brain tumors, efforts at resection are discouraged. However, it is difficult to distinguish PCNSL from other central nervous system tumors which need aggressive surgery in both CT and MRI images. In this study, we assessed whether measurement of miR-21 in the serum could improve diagnostic accuracy for PCNSL. We found that serum miR-21 significantly increased in PCNSL when compared with other brain tumors and normal controls in both test and validation cohort. Further, serum miR-21 could discriminate PCNSL from all controls with an area under the curve of 0.930 for the test cohort and 0.916 for the validation cohort in ROC analysis. Similar results were also obtained in the validation cohort. Besides, raised concentrations of miR-21 in serum could differentiate PCNSL from glioblastoma under the curve of 0.883 for the test cohort and 0.851 for the validation cohort in ROC analysis. Furthermore, Kaplan-Meier curve analysis (p = 0.03 for test cohort and 0.02 for validation cohort) and Multivariable Cox regression (p = 0.03 for test cohort and 0.01 for validation cohort) revealed serum miR-21 as an independent and powerful predictor of overall survival. Taken together, our results demonstrate that serum miR-21 may represent a diagnostic and prognostic marker for PCNSL. © 2013 Springer-Verlag Italia.


Lu R.-N.,University of Alabama at Birmingham | Lu R.-N.,Nanjing Medical University | Yang S.,Ohio State University | Wu H.M.,Ohio State University | Zheng X.L.,University of Alabama at Birmingham
Journal of Thrombosis and Haemostasis | Year: 2015

Background: Bilirubin is a yellow breakdown product of heme catabolism. Increased serum levels of unconjugated bilirubin are conditions commonly seen in premature neonates and adults with acute hemolysis including thrombotic microangiopathy. Previous studies have shown that unconjugated bilirubin lowers plasma ADAMTS13 activity, but the mechanism is not fully understood. Objectives: The study is to determine whether unconjugated bilirubin directly inhibits the cleavage of von Willebrand factor (VWF) and its analogs by ADAMTS13. Methods: Fluorogenic, surface-enhanced laser desorption/ionization time-of-flight mass spectrometric assay, and Western blotting analyses were used to address this question. Results: Unconjugated bilirubin inhibits the cleavage of F485-rVWF73-H, D633-rVWF73-H, and GST-rVWF71-11K by ADAMTS13 in a concentration-dependent manner with a half-maximal inhibitory concentration of ~13, ~70, and ~17 μmol L-1, respectively. Unconjugated bilirubin also dose-dependently inhibits the cleavage of multimeric VWF by ADAMTS13 under denaturing conditions. The inhibitory activity of bilirubin on the cleavage of D633-rVWF73-H and multimeric VWF, but not F485-rVWF73-H, was eliminated after incubation with bilirubin oxidase that converts bilirubin to biliverdin. Furthermore, plasma ADAMTS13 activity in patients with hyperbilirubinemia increased after treatment with bilirubin oxidase. Conclusions: Unconjugated bilirubin directly inhibits ADAMTS13's ability to cleave both peptidyl and native VWF substrates in addition to its interference with certain fluorogenic assays. Our findings may help proper interpretation of ADAMTS13 results under pathological conditions. Whether elevated serum unconjugated bilirubin has prothrombotic effect in vivo remains to be determined in our future study. © 2015 International Society on Thrombosis and Haemostasis.


Xie J.,Nanjing Medical University | Gu J.,Sun Yat Sen University
Journal of Cellular and Molecular Medicine | Year: 2015

In patients with inflammatory arthritis, tumour necrosis factor (TNF)-α are overproduced in inflamed joints. This leads to local erosion of cartilage and bone, periarticular osteopenia, as well as osteoporosis. But less is known regarding the molecular mechanisms that mediate the effect of TNF-α on osteoblast function. The purpose of this study was to test that C terminus of Hsc70-interacting protein (CHIP) has a specific role in suppressing the osteogenic activity of osteoblasts under inflammatory conditions. C2C12, MC3T3-E1 and HEK293T cell lines were cultured and cotransfected with related plasmids. After transfection, the cells were cultured further in the presence or absence of murine TNF-α and subjected to real time RT-PCR, Western blot, Ubiquitination assay, Co-immunoprecipitation, Luciferase reporter assay, Small interfering RNAs and Mineralization assay. The expression levels of TNF-α-induced CHIP and Osx were examined by RT-PCR and Western blot analysis. Co-immunoprecipitation and ubiquitination assays revealed ubiquitinated Osx, confirmed that CHIP indeed interacted with Osx and identified K55 and K386 residues as the ubiquitination sites in Osx, Luciferase reporter assay and Small interfering RNAs examined whether TNF-α target the bone morphogenetic protein signalling through CHIP. We established stable cell lines with the overexpression of HA-CHIP, Mineralization assay and CHIP siRNA demonstrated the important roles of CHIP on osteoblast function in conditions in which TNF-α is overexpressed. We found that the K55 and K386 residues are ubiquitination site(s) in Osx, and that TNF-α inhibits osteoblast differentiation by promoting Osx degradation through up-regulation of E3 ubiquitin ligase CHIP in osteoblast. Thus, CHIP targets Osx for ubiquitination and degradation in osteoblasts after chronic exposure to TNF-α, and inhibition of CHIP expression in osteoblasts may be a new mechanism to limit inflammation-mediated osteoporosis by promoting their differentiation into osteoblasts. © 2015 John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.


Zheng Q.-Y.,The Military General Hospital of Beijing PLA | Li P.-P.,Southern Medical University | Jin F.-S.,Chongqing Medical University | Yao C.,Nanjing Medical University | And 3 more authors.
Cellular Signalling | Year: 2013

Here we studied the cellular mechanisms of ursolic acid's anti-bladder cancer ability by focusing on endoplasmic reticulum stress (ER stress) signaling. We show that ursolic acid induces a significant ER stress response in cultured human bladder cancer T24 cells. ER stress inhibitor salubrinal, or PERK silencing, diminishes ursolic acid-induced anti-T24 cell effects. Salubrinal inhibits ursolic acid-induced CHOP expression, Bim ER accumulation and caspase-3 activation in T24 cells. Ursolic acid induces IRE1-TRAF2-ASK1 signaling complex formation to activate pro-apoptotic ASK1-JNK signaling. We suggest that ER stress contributes to ursolic acid's effects against bladder cancer cells. © 2012 Elsevier Inc.


Zhang S.,Nanjing Medical University | Zheng X.,Zhejiang Academy of Medical science | Huang H.,Nanjing Medical University | Wu K.,Nanjing Medical University | And 3 more authors.
Oncotarget | Year: 2015

Afatinib is a second-generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and has shown a significant clinical benefit in non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations. However, the potential therapeutic effects of afatinib combining with other modalities, including ionizing radiation (IR), are not well understood. In this study, we developed a gefitinib-resistant cell subline (PC-9-GR) with a secondary EGFR mutation (T790M) from NSCLC PC-9 cells after chronic exposures to increasing doses of gefitinib. The presence of afatinib significantly increases the cell killing effect of radiation in PC-9-GR cells harboring acquired T790M, but not in H1975 cells with de novo T790M or in H460 cells that express wild-type EGFR. In PC-9-GR cells, afatinib remarkable blocks baseline of EGFR and ERK phosphorylations, and causes delay of IR-induced AKT phosphorylation. Afatinib treatment also leads to increased apoptosis and suppressed DNA damage repair in irradiated PC-9-GR cells, and enhanced tumor growth inhibition when combined with IR in PC-9-GR xenografts. Our findings suggest a potential therapeutic impact of afatinib as a radiation sensitizer in lung cancer cells harboring acquired T790M mutation, providing a rationale for a clinical trial with combination of afatinib and radiation in NSCLCs with EGFR T790M mutation.


Li R.,Nanjing Medical University | Yan G.,Nanjing Medical University | Li Q.,Nanjing Medical University | Sun H.,Nanjing Medical University | And 3 more authors.
PLoS ONE | Year: 2012

MicroRNAs, a class of small and non-encoding RNAs that transcriptionally or post-transcriptionally modulate the expression of their target genes, has been implicated as critical regulatory molecules in many cardiovascular diseases, including ischemia/reperfusion induced cardiac injury. Here, we report microRNA-145, a tumor suppressor miRNA, can protect cardiomyocytes from hydrogen peroxide (H2O2)-induced apoptosis through targeting the mitochondrial pathway. Quantitative real-time PCR (qPCR) demonstrated that the expression of miR-145 in either ischemia/reperfused mice myocardial tissues or H2O2-treated neonatal rat ventricle myocytes (NRVMs) was markedly down-regulated. Over-expression of miR-145 significantly inhibited the H2O2-induced cellular apoptosis, ROS production, mitochondrial structure disruption as well as the activation of key signaling proteins in mitochondrial apoptotic pathway. These protective effects of miR-145 were abrogated by over-expression of Bnip3, an initiation factor of the mitochondrial apoptotic pathway in cardiomyocytes. Finally, we utilized both luciferase reporter assay and western blot analysis to identify Bnip3 as a direct target of miR-145. Our results suggest miR-145 plays an important role in regulating mitochondrial apoptotic pathway in heart challenged with oxidative stress. MiR-145 may represent a potential therapeutic target for treatment of oxidative stress-associated cardiovascular diseases, such as myocardial ischemia/reperfusion injury. © 2012 Li et al.


Xu B.,Fu Wai Hospital | Gao R.,Fu Wai Hospital | Wang J.,Zhejiang University | Yang Y.,Fu Wai Hospital | And 8 more authors.
JACC: Cardiovascular Interventions | Year: 2014

Objectives The intention of the PEPCAD China ISR (A Prospective, Multicenter, Randomized Trial of Paclitaxel-Coated versus Paclitaxel-Eluting Stent for the Treatment of Drug-Eluting Stent In-Stent Restenosis) was to demonstrate the efficacy of paclitaxel-coated balloon (PCB) angioplasty in a non-European patient population with coronary drug-eluting stent in-stent restenosis (DES-ISR). Background The treatment of DES-ISR is still challenging with no established best strategy. Moreover, there is no study on the effect of PCB in the treatment of ISR in the Chinese population. Methods PEPCAD China ISR was a 220-patient randomized (1:1), single-blind prospective multicenter trial conducted in China. Patients with coronary DES-ISR received either PCB (SeQuent Please, B. Braun Melsungen AG, Melsungen, Germany) or paclitaxel-eluting stent (Taxus Liberté, Boston Scientific, Natick, Massachusetts) treatment. The primary endpoint was in-segment late lumen loss at 9 months. Results There were no significant baseline differences between both treatment groups in terms of patient, lesion, or procedural characteristics. At 9 months, in-segment late lumen loss in the PCB group was noninferior to that of the paclitaxel-eluting stent group (0.46 ± 0.51 mm vs. 0.55 ± 0.61 mm; difference: -0.06 mm with 95% confidence interval: -0.23 to 0.10; p for noninferiority = 0.0005). The 9-month rate of binary restenosis and 12-month composite clinical event rates were not significantly different between groups. Conclusions In a randomized trial of 220 patients, angioplasty with a PCB was noninferior to paclitaxel-eluting stent implantation when used to treat DES-ISR. On the basis of these, as well as previous randomized trial data, PCB angioplasty offers an effective treatment for DES-ISR without the necessity of implanting additional metal layers for drug release. © 2014 by the American College of Cardiology Foundation.


Wang W.,Texas Tech University Health Sciences Center | Nag S.,Texas Tech University Health Sciences Center | Zhang X.,Texas Tech University Health Sciences Center | Wang M.-H.,Texas Tech University Health Sciences Center | And 3 more authors.
Medicinal Research Reviews | Year: 2015

Ribosomes are essential components of the protein synthesis machinery. The process of ribosome biogenesis is well organized and tightly regulated. Recent studies have shown that ribosomal proteins (RPs) have extraribosomal functions that are involved in cell proliferation, differentiation, apoptosis, DNA repair, and other cellular processes. The dysfunction of RPs has been linked to the development and progression of hematological, metabolic, and cardiovascular diseases and cancer. Perturbation of ribosome biogenesis results in ribosomal stress, which triggers activation of the p53 signaling pathway through RPs-MDM2 interactions, resulting in p53-dependent cell cycle arrest and apoptosis. RPs also regulate cellular functions through p53-independent mechanisms. We herein review the recent advances in several forefronts of RP research, including the understanding of their biological features and roles in regulating cellular functions, maintaining cell homeostasis, and their involvement in the pathogenesis of human diseases. We also highlight the translational potential of this research for the identification of molecular biomarkers, and in the discovery and development of novel treatments for human diseases. © 2014 Wiley Periodicals, Inc.


Zhu Y.,Nanjing Medical University | You W.,Nanjing Medical University | Wang H.,Nanjing Medical University | Li Y.,Nanjing Medical University | And 5 more authors.
Diabetes | Year: 2013

Overnutrition and genetics both contribute separately to pancreatic β-cell dysfunction, but how these factors interact is unclear. This study was aimed at determining whether microRNAs (miRNAs) provide a link between these factors. In this study, miRNA-24 (miR-24) was highly expressed in pancreatic β-cells and further upregulated in islets from genetic fatty (db/db) or mice fed a high-fat diet, and islets subject to oxidative stress. Overexpression of miR-24 inhibited insulin secretion and β-cell proliferation, potentially involving 351 downregulated genes. By using bioinformatic analysis combined with luciferase-based promoter activity assays and quantitative real-time PCR assays, we identified two maturity-onset diabetes of the young (MODY) genes as direct targets of miR-24. Silencing either of these MODY genes (Hnf1a and Neurod1) mimicked the cellular phenotype caused by miR-24 overexpression, whereas restoring their expression rescued β-cell function. Our findings functionally link the miR-24/MODY gene regulatory pathway to the onset of type 2 diabetes and create a novel network between nutrient overload and genetic diabetes via miR-24. © 2013 by the American Diabetes Association.


Tan X.,Nanjing Medical University | Tan X.,Zhongshan Ophthalmic Center | Tan X.,Jiangsu Institute of Nuclear Medicine | Tan X.,University of Sydney
Eye (London, England) | Year: 2014

PURPOSE: To determine the levels of Th17-associated cytokines, particularly interleukin (IL)-17 and IL-22 in tears of patients with dry eye syndrome.METHODS: Tear samples were collected from 20 healthy volunteers, 20 dry eye (DE) patients with non-Sjögren's syndrome (NSSDE) and 20 DE patients with Sjögren's syndrome (SSDE). Symptom questionnaire was self-administered and multiple dry eye disease (DED)-related clinical tests were performed. The levels of IL-17 and IL-22 in tears were measured by enzyme-linked immunosorbent assay.RESULTS: The levels of IL-17 and IL-22 were significantly increased in tears of DE patients compared with those of controls and also higher in SSDE patients compared with those of NSSDE patients (P<0.05). Moreover, the levels of IL-17 and IL-22 were positively correlated with questionnaire score and keratopathy score but negatively correlated with tear film break-up time and Schirmer I test in both NSSDE and SSDE patients (P<0.05).CONCLUSIONS: The levels of IL-17 and IL-22 in tears were significantly increased in DE patients, which were associated with the disease severity. Therefore, Th17 cell-associated cytokines, particularly IL-17 and IL-22, may have important roles in the immunopathogenesis of the DED.


Yang L.-J.,Nanjing Medical University | Wang J.,Xuzhou Medical University | Tian Z.-F.,Nanjing Medical University | Yuan Y.-F.,Nanjing Medical University
Neurological Sciences | Year: 2013

Perinatal hypoxia-ischemia remains the most important cause of brain injury in the newborn. However, there is still no effective cure for neonatal hypoxic-ischemic brain damage (HIBD). In the present study, we aimed to examine the neuroprotective effects of Shenfu injection (SFI) on HIBD of neonatal rat. Sprague-Dawley rats were divided randomly into three groups (n = 8): S group: the rats were sham operated; C group: the rats were operated for HIBD modeling and received intraperitoneal injection of saline; SFI group: the rats were operated for HIBD modeling and received intraperitoneal injection of SFI (10 ml/kg days) for 7 days. Flow cytometry analysis showed that apoptosis rate of neuron in hippocampal CAI region in SFI group was significantly less than in NC group at 3 and 7 days after HI insult (P < 0.05). Immunohistochemical staining demonstrated that Bcl-2 expression was markedly higher while Bax expression was significantly lower in SFI group than in the C group at 24, 72 h and 7 days after HI insult (P < 0.05). Our findings suggest that SFI exhibits neuroprotective effects for neonatal hypoxic-ischemic brain injury by preventing neuron apoptosis and has potential to be used in the clinical for the treatment of perinatal hypoxia-ischemia. © 2013 Springer-Verlag Italia.


Zhuang M.,Nanjing Medical University | Zhuang M.,First Peoples Hospital of Lianyungang | Gao W.,Nanjing Medical University | Xu J.,Nanjing Medical University | And 2 more authors.
Biochemical and Biophysical Research Communications | Year: 2014

The lncRNA H19 has been recently shown to be upregulated and play important roles in gastric cancer tumorigenesis. However, the precise molecular mechanism of H19 and its mature product miR-675 in the carcinogenesis of gastric cancer remains unclear. In this study, we found that miR-675 was positively expressed with H19 and was a pivotal mediator in H19-induced gastric cancer cell growth promotion. Subsequently, the tumor suppressor Runt Domain Transcription Factor1 (RUNX1) was confirmed to be a direct target of miR-675 using a luciferase reporter assay and Western blotting analyses. A series of rescue assays indicated that RUNX1 mediated H19/miR-67-induced gastric cancer cell phenotypic changes. Moreover, the inverse relationship between the expression of RUNX1 and H19/miR-675 was also revealed in gastric cancer tissues and gastric cancer cell lines. Taken together, our study demonstrated that the novel pathway H19/miR-675/RUNX1 regulates gastric cancer development and may serve as a potential target for gastric cancer therapy. © 2014 Published by Elsevier Inc.


Yang C.S.,Rutgers University | Fengb Q.,Nanjing Medical University
Journal of Biomedical Research | Year: 2014

Cancer is a major disease worldwide and different approaches are needed for its prevention. Previous laboratory and clinical studies suggest that cancer can be prevented by chemicals, including those from the diet. Furthermore, epidemiological studies have suggested that deficiencies in certain nutrients can increase the risk of some cancers. In this article on chemo/dietary prevention, examples will be given to illustrate the effectiveness of chemopreventive agents in the prevention of breast, colon and prostate cancers in high-risk populations and the possible side effects of these agents. The potential usefulness of dietary approaches in cancer prevention and the reasons for some of the failed trials will be discussed. Lessons learned from these studies can be used to design more relevant research projects and develop effective measures for cancer prevention in the future. The development of effective chemopreventive agents, the use of nutrient supplements in deficient or carcinogen-exposed populations, and the importance of cohort studies will be discussed in the context of the current socioeconomic situation in China. More discussions are needed on how we can influence society to pay more attention to cancer prevention research and measures. © 2014 by the Journal of Biomedical Research.


He W.,Nanjing University of Aeronautics and Astronautics | Jiang H.,Nanjing Medical University | Zhou Y.,CAS Shanghai Advanced Research Institute | Yang S.,Nanjing University of Aeronautics and Astronautics | And 5 more authors.
Carbon | Year: 2012

Pt and Pd-Pt nanoparticles were anchored on reduced graphene oxide (RGO) with the aid of poly(diallyldimethylammonium chloride) (PDDA), where Pt and Pd ions were first attached to PDDA-functionalized graphene oxide sheets and the encased metal ions and graphene oxide were then reduced simultaneously by ethylene glycol. As supported by transmission electron microscopy, metal nanoparticles, of small particle size even at a high metal loading, were chemically attached to PDDA-RGO. X-ray diffraction indicates that the as-prepared Pd-Pt nanoparticles have a single-phase fcc structure and are principally alloys of Pd and Pt. Among the RGO-supported Pt and Pd-Pt catalysts, Pt nanoparticles anchored on PDDA-RGO exhibit the highest activity for the oxygen reduction reaction (ORR), and the ORR activity of the Pd-Pt alloy electrocatalysts increases with Pt content. All the catalysts demonstrate an enhanced ORR durability when PDDA is present; strongly suggesting that PDDA plays a crucial role in the dispersion and stabilization of the metal nanoparticles on RGO. The ORR activities of the Pd-Pt catalysts remain enhanced even after accelerated durability testing. The formation of a Pt-rich shell, as confirmed by X-ray photoelectron spectroscopy and CO stripping voltammetry, may account for the increased activity. © 2011 Elsevier Ltd. All rights reserved.


Feng Y.,Nanjing Medical University | Liu S.,Nanjing Medical University | Wang Q.,U.S. Center for Disease Control and Prevention | Wang L.,East Tennessee State University | And 3 more authors.
PLoS ONE | Year: 2013

Background: There are urgent needs for rapid and accurate drug susceptibility testing of M. tuberculosis. GenoType MTBDRsl is a new molecular kit designed for rapid identification of the resistance to the second-line antituberculosis drugs with a single strip. In recent years, it has been evaluated in many settings, but with varied results. The aim of this meta-analysis was to synthesize the latest data on the diagnostic accuracy of GenoType MTBDRsl in detecting drug resistance to fluoroquinolones, amikacin, capreomycin, kanamycin and ethambutol, in comparison with the phenotypic drug susceptibility test. Methods: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. The search terms of "MTBDRsl" and "tuberculosis" were used on PubMed, EMBASE, and Web of Science. QUADAS-2 was used to assess the quality of included studies. Data were analyzed by Meta-Disc 1.4. We calculated the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and corresponding 95% confidence interval (CI) for each study. From these calculations, forest plots and summary receiver operating characteristic (SROC) curves were produced. Results: Patient selection bias as well as flow and timing bias were observed in most studies. The summarized sensitivity (95% CI) was 0.874(0.845-0.899), 0.826(0.777-0.869), 0.820(0.772-0.862), 0.444(0.396-0.492), and 0.679(0.652-0.706) for fluoroquinolones, amikacin, capreomycin, kanamycin, and ethambutol, respectively. The specificity (95% CI) was 0.971(0.961-0.980), 0.995(0.987-0.998), 0.973(0.963-0.981), 0.993(0.985-0.997), and 0.799(0.773-0.823), respectively. The AUC (standard error) were 0.9754(0.0203), 0.9300(0.0598), 0.9885(0.0038), 0.9689(0.0359), and 0.6846(0.0550), respectively. Conclusion: Genotype MTBDRsl showed good accuracy for detecting drug resistance to fluoroquinolones, amikacin and capreomycin, but it may not be an appropriate choice for kanamycin and ethambutol. The lack of data did not allow for proper evaluation of the test on clinical specimens. Further systematic assessment of diagnostic performance should be carried out on direct clinical samples. © 2013 Feng et al.


Xu H.,Nanjing Medical University | Wu X.,Nanjing Medical University | Qin H.,Nanjing Medical University | Tian W.,Nanjing Medical University | And 7 more authors.
Journal of the American Society of Nephrology | Year: 2015

Diabetic nephropathy (DN) is one of the most common complications associated with diabetes and characterized by renal microvascular injury along with accelerated synthesis of extracellular matrix proteins causing tubulointerstitial fibrosis. Production of type I collagen, the major component of extracellularmatrix, is augmented during renal fibrosis after chronic exposure to hyperglycemia.However, the transcriptional modulator responsible for the epigenetic manipulation leading to induction of type I collagen genes is not clearly defined. We show here that tubulointerstitial fibrosis as a result of DN was diminished in myocardin-related transcription factor A (MRTF-A) -deficient mice. In cultured renal tubular epithelial cells and the kidneys of mice withDN,MRTF-Awas induced by glucose and synergizedwith glucose to activate collagen transcription. Notably, MRTF-A silencing led to the disappearance of prominent histone modifications indicative of transcriptional activation, including acetylated histone H3K18/K27 and trimethylated histone H3K4. Detailed analysis revealed thatMRTF-A recruited p300, a histone acetyltransferase, and WD repeat-containing protein 5 (WDR5), a key component of the histone H3K4 methyltransferase complex, to the collagen promoters and engaged these proteins in transcriptional activation. Estradiol suppressed collagen production by dampening the expression and binding activity of MRTF-A and interfering with the interaction between p300 and WDR5 in renal epithelial cells. Therefore, targeting the MRTF-A-associated epigenetic machinery might yield interventional strategies against DN-associated renal fibrosis. Copyright © 2015 by the American Society of Nephrology.


Wang S.,Nanjing Medical University | Tang J.,Nanjing Medical University | Wang M.,Nanjing Medical University | Yuan L.,Nanjing Medical University | And 2 more authors.
Carcinogenesis | Year: 2010

Recently, two genome-wide association studies identified a significant association between the prostate stem cell antigen (PSCA) rs2294008 (C>T) polymorphism and risk of diffuse-type of gastric cancer in Asians and bladder cancer in Caucasians, respectively. PSCA has been reported highly expressed in bladder cancer and been considered as a useful marker for diagnosis and progression of bladder cancer. To determine whether rs2294008 polymorphism is associated with risk of bladder cancer in Chinese populations, we conducted a hospital-based case-control study of 581 cases and 580 controls. Sixteen normal bladder tissues adjacent to tumors were used to evaluate the functionality of this polymorphism. We genotyped the rs2294008 polymorphism and assessed its association with risk of bladder cancer and messenger RNA (mRNA) expression in normal bladder tissues. A significant increased risk of bladder cancer was found for rs2294008 CT/TT genotypes (adjusted odds ratio, 1.38; 95% confidence interval, 1.09-1.75) compared with the CC genotype. Furthermore, analysis of PSCA mRNA expression identified a clear correlation of rs2294008 with expression levels of PSCA mRNA. These results indicated that the rs2294008 polymorphism of PSCA gene may play a role in bladder cancer carcinogenesis and it could be served as a biomarker for genetic susceptibility to bladder cancer in Chinese populations. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.


Hu L.,Nanjing Medical University | Zhai X.,U.S. Center for Disease Control and Prevention | Liu J.,Nantong Tumor Hospital | Chu M.,Nanjing Medical University | And 7 more authors.
Hepatology | Year: 2012

Recent genome-wide association studies showed that four single-nucleotide polymorphisms (SNPs) in human leukocyte antigen (HLA)-DP (rs3077and rs9277535) and HLA-DQ (rs2856718 and rs7453920) were associated with chronic hepatitis B virus (HBV) infection in Japanese populations. More than 75% of hepatocellular carcinoma (HCC) patients are attributable to persistent infection of hepatitis B virus (HBV), especially in China. We genotyped these four SNPs in 1,300 HBV-positive HCC patients, 1,344 persistent HBV carriers, and 1,344 persons with HBV natural clearance from Southeast China to further test the associations of HLA-DP/DQ variants and with risk of both HBV clearance and HCC development. Logistic regression analyses showed that HLA-DQ rs2856718 significantly decreased host HCC risk, whereas three SNPs were associated with HBV clearance (HLA-DP rs9277535 as well as HLA-DQ rs7453920 and rs2856718). In addition, HLA-DP rs3077 showed an approaching significant effect on susceptibility to HBV persistent infection and HCC development when considering multiple testing adjustments. Taken together, we report, for the first time, that genetic variants in the HLA-DP and HLA-DQ loci may be marker SNPs for risk of both HBV clearance and HCC development. © 2011 American Association for the Study of Liver Diseases.


Pan W.,Nanjing Medical University | Pan W.,The Second Hospital of Nanjing Jiangning | Yang Y.,Nanjing Medical University | Zhu H.,Nanjing Medical University | And 3 more authors.
Oncotarget | Year: 2016

Mutation of oncogene KRAS is common in non-small cell lung cancer (NSCLC), however, its clinical significance is still controversial. Independent studies evaluating its prognostic and predictive value usually drew inconsistent conclusions. Hence, We performed a meta-analysis with 41 relative publications, retrieved from multi-databases, to reconcile these controversial results and to give an overall impression of KRAS mutation in NSCLC. According to our findings, KRAS mutation was significantly associated with worse overall survival (OS) and disease-free survival (DFS) in early stage resected NSCLC (hazard ratio or HR=1.56 and 1.57, 95% CI 1.39-1.76 and 1.17-2.09 respectively), and with inferior outcomes of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) treatment and chemotherapy (relative risk or RR=0.21 and 0.66 for objective response rate or ORR, 95% CI 0.12-0.39 and 0.54-0.81 respectively; HR=1.46 and 1.30 for progression-free survival or PFS, 95%CI 1.23-1.74 and 1.14-1.50 respectively) in advanced NSCLC. When EGFR mutant patients were excluded, KRAS mutation was still significantly associated with worse OS and PFS of EGFR-TKIs (HR=1.40 and 1.35, 95 % CI 1.21-1.61 and 1.11-1.64). Although KRAS mutant patients presented worse DFS and PFS of chemotherapy (HR=1.33 and 1.11, 95% CI 0.97-1.84 and 0.95-1.30), and lower response rate to EGFR-TKIs or chemotherapy (RR=0.55 and 0.88, 95 % CI 0.27-1.11 and 0.76-1.02), statistical differences were not met. In conclusion, KRAS mutation is a weak, but valid predictor for poor prognosis and treatment outcomes in NSCLC. There's a need for developing target therapies for KRAS mutant lung cancer and other tumors.


Li R.F.,Johns Hopkins University | Li R.F.,Nanjing Medical University | Gupta M.,Johns Hopkins University | Gupta M.,Beth Israel Deaconess Medical Center | And 3 more authors.
American Journal of Surgical Pathology | Year: 2013

In its classical form, embryonal rhabdomyosarcoma (ERMS, botryoid type) is a vaginal neoplasm occurring in infants and young girls and is often not considered in the differential diagnosis of uterine corpus and cervical spindle cell tumors in adult women. Clinicopathologic and immunohistochemical features of 25 cases of ERMS in women 20 years of age or older were analyzed. Patient age ranged from 20 to 89 years (mean, 44.4 y; median, 46 y), with 8 patients aged 20 to 39 years, 14 patients aged 40 to 59 years, and 3 patients older than 60 years of age. Tumors originated in the cervix in 20 cases and in the uterine corpus in 5. They were characterized by an edematous hypocellular spindle cell proliferation, typically with cellular condensation beneath epithelial surfaces (cambium layer), in which tightly packed hypercellular foci were scattered. Neoplastic cells had hyperchromatic nuclei and minimal cytoplasm, usually with delicate cytoplasmic processes. Occasionally, elongated or globular cells with eosinophilic cytoplasm (rhabdomyoblasts) were evident, but cytoplasmic cross-striations were only rarely identified. Apoptotic bodies and mitotic figures were usually identified in the hypercellular foci. Hemorrhage was common, often making recognition of the hypercellular foci difficult. Desmin and myogenin were coexpressed in 22 of 23 (95.6%) tumors evaluated. Proliferative activity, as assessed by Ki-67 expression, was notably elevated in all tumors evaluated, typically concentrated in the hypercellular foci. Estrogen and progesterone receptors were expressed focally in only 3 of 12 (25%) and 1 of 8 (12.5%) tumors evaluated, respectively. Follow-up was available in 7 cases. Five patients were alive without evidence of disease with follow-up of 3 to 8 years, and 1 patient was alive with disease at 5 months. One patient died at 5 months with pulmonary nodules, but it was not determined whether this was due to metastatic ERMS or the patient's known ductal breast carcinoma. ERMS has a broader clinical profile than classically expected and should be considered in the differential diagnosis of a uterine corpus or cervical spindle cell tumor, regardless of patient age. Recognition can be rendered difficult by the hypocellular background, which can suggest a benign polyp or low-grade tumor, and hemorrhage, which can obscure the characteristic hypercellular foci. Identification of hypercellular foci in which mitotic activity and apoptotic bodies are found, desmin and myogenin are coexpressed, proliferative activity is notably elevated, and hormone receptor expression is usually absent is very useful for establishing the diagnosis. Copyright © 2013 by Lippincott Williams & Wilkins.


Wu Q.-L.,Nanjing Medical University | Shen T.,First Hospital Affiliated with Liaoning Medical College | Ma H.,Nanjing Medical University | Wang J.-K.,Nanjing Medical University
Journal of Surgical Research | Year: 2012

Background: Previous studies have shown that opioid postconditioning reduces apoptosis through antiapoptotic signaling. The present study evaluated whether sufentanil could induce cardioprotection after ischemia-reperfusion (I/R) and whether the PI3K/Akt-GSK-3β pathway modulates antiapoptotic proteins in sufentanil postconditioning. Methods: We subjected male Sprague-Dawley rats to 30 min of myocardial ischemia and 2 h of reperfusion. We randomized rats into seven groups: sham, I/R, sufentanil postconditioning (I/R+sufen), sham plus sufentanil (sham+sufen), sham plus 15 μg·kg-1 intravenous wortmannin (PI3K inhibitor), I/R plus wortmannin, and sufentanil plus wortmannin. We induced sufentanil postconditioning with 3 μg·kg-1 sufentanil for 3 min in the beginning of reperfusion after 30 min ischemia. We assessed hemodynamics, myocardial infarct size, number of apoptotic cardiomyocytes, total Akt and GSK-3β, phosphorylated Akt and GSK-3β, caspase-3, Bax, and Bcl-2 protein expression. Results: The I/R+sufen group had significantly reduced infarct size compared with the I/R group (23.3% ± 9.0% versus 50.1% ± 7.4%; P < 0.05). The apoptotic index of cardiomyocytes was significantly reduced with sufentanil treatment (20.0% ± 3.5%) compared with the I/R group (47.0% ± 6.3%; P < 0.05). The I/R+sufen group reduced the expression of protein-cleaved caspase-3 and Bax, and increased Bcl-2, phosphorylated Akt, and GSK3β compared with the I/R group. Wortmannin eliminated the cardioprotection produced with sufentanil treatment. Conclusions: Sufentanil postconditioning can induce myocardial protection by activating the PI3K/Akt-GSK-3β pathway and modulating Bax and Bcl-2 expression. © 2012 Elsevier Inc. All rights reserved.


Hu M.,Nanjing Medical University | Zhao L.,Kunshan Agency for Public Health Inspection | Hu S.,Nanjing Medical University | Yang J.,Nanjing Medical University
PLoS ONE | Year: 2013

Background: Emerging evidence has shown that microRNAs (miRNAs) participate in human carcinogenesis as tumor suppressors or oncogenes. Single nucleotide polymorphism (SNP) located in the miRNAs may influence the function of mature miRNAs and then affect the processing of carcinogenesis. It has been suggested that two common SNPs rs2910164 in miR-146a and rs3746444 in miR-499 are associated with susceptibility to hepatocellular carcinoma (HCC). However, published results are inconsistent and inconclusive. To acquire a more precise effect of the association between these polymorphisms and HCC risk, we performed this meta-analysis. Methodology/Principal Findings: We have conducted a search of case-control studies on the associations of SNPs rs2910164 and/or rs3746444 with susceptibility to HCC in PubMed, ScienceDirect, Cochrane Central Register of Controlled Trials, and Chinese National Knowledge Infrastructure databases for the period up to Sep 10th, 2012. A total of 6 studies were identified with 2071 cases and 2350 controls for miR-146a rs2910164 polymorphism, 667 cases and 1006 controls for miR-499 rs3746444 polymorphism. It was found that neither allele frequency nor genotype distribution of the two polymorphisms was associated with risk of HCC in all genetic models. Similarly, subgroup analysis in Asian population showed no associations between the two SNPs and the susceptibility to HCC. Conclusions/Significance: This meta-analysis suggests that miR-146a rs2910164 and miR-499 rs3746444 polymorphisms may not be associated with the risk of HCC, especially for Asian population. However, well-designed studies with larger sample size and more detailed data are needed to confirm these conclusions. © 2013 Hu et al.


Zhou Y.-B.,Nanjing Medical University | Sun H.-J.,Nanjing Medical University | Chen D.,Nanjing Medical University | Liu T.-Y.,Nanjing Medical University | And 5 more authors.
Hypertension | Year: 2014

Intermedin (IMD) is a member of calcitonin/calcitonin gene-related peptide family, which shares the receptor system consisting of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs). This study investigated the effects of IMD in paraventricular nucleus (PVN) on renal sympathetic nerve activity and mean arterial pressure and its downstream mechanism in hypertension. Rats were subjected to 2-kidney 1-clip (2K1C) surgery to induce renovascular hypertension or sham operation. Acute experiments were performed 4 weeks later under anesthesia. IMD mRNA and protein were downregulated in 2K1C rats. Bilateral PVN microinjection of IMD caused greater decreases in renal sympathetic nerve activity and mean arterial pressure in 2K1C rats than in sham-operated rats, which were prevented by pretreatment with adrenomedullin receptor antagonist AM22-52 or nonselective nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester, and attenuated by selective neuronal NO synthase inhibitor N-propyl-l-arginine hydrochloride or endothelial NO synthase inhibitor N(5)-(1-iminoethyl)-l-ornithine dihydrochloride. AM22-52 increased renal sympathetic nerve activity and mean arterial pressure in 2K1C rats but not in sham-operated rats, whereas calcitonin/calcitonin gene-related peptide receptor antagonist calcitonin/calcitonin gene-related peptide 8-37 had no significant effect. CRLR and RAMP3 mRNA, as well as CRLR, RAMP2, and RAMP3 protein expressions, in the PVN were increased in 2K1C rats. Microinjection of IMD into the PVN increased the NO metabolites (NOx) level in the PVN in 2K1C rats, which was prevented by AM22-52. Chronic PVN infusion of IMD reduced, but AM22-52 increased, blood pressure in conscious 2K1C rats. These results indicate that IMD in the PVN inhibits sympathetic activity and attenuates hypertension in 2K1C rats, which are mediated by adrenomedullin receptors (CRLR/RAMP2 or CRLR/RAMP3) and its downstream NO. © 2013 American Heart Association, Inc.


Redmond A.D.,University of Manchester | Li J.,Nanjing Medical University
Emergency Medicine Journal | Year: 2011

Background: At 14:48 on 12 May 2008 an earthquake of magnitude 8.0 struck the Wenchuan area of Sichuan province, China. A decision to offer/receive UK medical assistance was agreed at a Sino/British political level and a medical team was despatched to the earthquake area. Methods: This study describes the team's experience during the immediate aftermath of the earthquake and the following 18 months, during which there have been joint developments in emergency medicine, disaster planning/preparedness and the management of spinal cord injury. Results: The long-term disability following sudden onset natural disaster and the wider impact on healthcare delivery may prove to be a greater burden to the country than the immediate medical needs, and, accordingly, emergency international aid may need to widen its focus. Although international teams usually arrive too late to support resuscitative measures, they can respond to specific requests for specialised assistance, for example plastic and reconstructive surgery to assist with the ongoing management of complex injury, relieve those who have worked continuously through the disaster, and when required maintain routine day-to-day services while local staff continue to manage the disaster. The timing of this does not necessarily need to be immediate. Conclusions: To maximise its impact, the team planned from the outset to build a relationship with Chinese colleagues that would lead to a sharing of knowledge and experience that would benefit major incident responses in both countries in the future. This has been established, and the linkage of emergency humanitarian assistance to longer term development should be considered by others the next time international emergency humanitarian assistance is contemplated.


Deng G.-M.,Nanjing Medical University | Tsokos G.C.,Beth Israel Deaconess Medical Center
Nature Reviews Rheumatology | Year: 2015

Skin is the second most common organ (after the kidney) to be affected in patients with systemic lupus erythematosus (SLE), yet the aetiology of skin injury and the mechanisms involved in the development of dermal manifestations of SLE remain unclear. Ultraviolet light (UV), immune cells, cytokines and deposition of immunoglobulins all seem to have a role in the development of skin inflammation and damage in SLE. UV represents the most important environmental factor, and exposure to UV triggers the development of skin lesions in areas where immunoglobulin has been deposited and various other components of the immune system have accumulated. In addition, a number of intracellular kinases and transcription factors have also been demonstrated to be involved in the generation of skin lesions in lupus-prone mice. These molecules can be targeted by small-molecule inhibitors, leading to the prospect that treatments suitable for topical application, and with limited adverse effects, could be developed. Further studies to eliminate the burden of skin inflammation in patients with SLE are clearly required. © 2015 Macmillan Publishers Limited. All rights reserved.


Tan Z.-M.,Nanjing Medical University | Tan Z.-M.,The Key Laboratory of Living Donor Liver Transplantation | Sun B.-C.,Nanjing Medical University | Sun B.-C.,The Key Laboratory of Living Donor Liver Transplantation
World Journal of Gastroenterology | Year: 2013

Chronic hepatitis B virus (HBV) infection is the key driving force of liver disease progression, resulting in the development of hepatic dysfunction, cirrhosis and hepatocellular carcinoma (HCC). The primary aim of therapy is to suppress or eliminate HBV replication to reduce the activity of hepatitis, thus reducing the risk of, or slowing the progression of, liver disease. Nucleos(t)ide analogues (Nucs) may result in rapid suppression of HBV replication with normalization of serum transaminases and restore liver function, thus increasing survival in patients with hepatic decompensation. Long-term Nuc therapy may result in histologi-cal improvement or reversal of advanced fibrosis and reduction in disease progression, including the development of HCC. The long-term benefits of a finite course of interferon (IFN)-α therapy also include a sustained and cumulative response, as well as hepatitis B surface antigen seroclearance and reduction in the development of cirrhosis and/or HCC. Pegylated IFN and newer Nucs may achieve better long-term outcomes because of improved efficacy and a low risk of drug resistance. However, treatment outcomes are still far from satisfactory. Understanding the effects of anti-HBV treatment against HCC incidence and recurrence after hepatec-tomy or liver transplantation is required for further improvement of outcome. © 2013 Baishideng Publishing Group Co., Limited. All rights reserved.


Zou W.,Nanjing Medical University | Wu Z.,Nanjing Medical University | Xiang X.,Changshu Second Peoples Hospital | Sun S.,Nanjing Medical University | Zhang J.,Nanjing Medical University
Graefe's Archive for Clinical and Experimental Ophthalmology | Year: 2014

Background: Human leukocyte antigen B27 (HLA-B27)-Associated uveitis is the most common reason for non-infectious uveitis. This purpose of the research was to study the expression and significance of T lymphocyte subsets and CD 4 + CD25 + T regulatory (Treg) cells in peripheral blood of patients with Human leukocyte antigen B27-positive acute anterior uveitis (HLA-B27-positive AAU). Methods: The concentrations of Th1, Th2, Th17, CD4 + CD25 +, and CD 4 +CD25 +FOXP3+ Treg cells in peripheral blood were tested by flow cytometry. C-reactive protein (CRP) in peripheral blood was detected by immunoturbidimetry (ITM). Spearman's rank correlation was used to analyze the relationships between the concentration of Th1, Th2, Th17, CD4 + CD25 +, and CD4 +CD25 +FOXP3+ Treg cells in peripheral blood and disease activity score and CRP content. Results: The ratio of both γ [interferon (IFN)-γ] +CD4+Th1 cells and CD4+IL-17+Th17 cells in peripheral blood of patients with HLA-B27-positive AAU (P∈=∈0.041) was higher than that of the control group (P∈=∈0.002). The concentration of CD4+CD25 +FOXP3+ T cells in peripheral blood of patients with AAU was lower than that of the control group (P∈=∈0.026). The concentration of Th1 cells in peripheral blood of the patients had no correlation with disease activity score (P∈=∈0.50) or CRP content (P∈=∈0.383). This was also true of the concentration of Th2 cells (Disease activity score: R∈=∈0.068, P∈=∈0.817; CRP content: R∈=∈0.439, P∈=∈0.116). Th17 cell concentration positively correlated with disease activity score (R∈=∈0.805, P∈=∈0.001). The concentration of CD4+CD25+ T cells showed no correlation with disease activity score (R∈=-0.209, P∈=∈0.472) or CRP content (R∈=-0.169, P∈=∈0.563), whereas the concentration of CD4+CD25+FOXP3+ T cells negatively correlated with disease activity score but did not correlate with CRP (R∈=-0.248, P∈=∈0.392). Conclusions: The peripheral blood of patients with HLA-B27-positive AAU showed a higher expression of interferon-γ and interleukin-17 cells in CD4+T cells, whereas CD4+CD25+FOXP3+ T cells displayed a lower expression of the cytokines. The balance between Th17 cells and CD4∈+∈CD25∈+∈FOXP3+ T cells may contribute to the activity of HLA-B27-positive AAU. © 2014 Springer-Verlag Berlin Heidelberg.


Ma G.,Nanjing Medical University | Dai W.,Nanjing Medical University | Sang A.,Lianshui Third Peoples Hospital | Yang X.,Nanjing Medical University | Gao C.,Nanjing Medical University
International Journal of Clinical and Experimental Pathology | Year: 2014

Background and purpose: To investigate the clinical significance of microRNA (miR)-23a and miR-23b expression in human gastric cancer (GC). Methods: Quantitative RT-PCR was performed to detect the expression changes of miR-23a and miR-23b in 160 human GC tissues and paired normal mucosa. The associations between miR-23a and miR-23b expression, and the selected clinicopathological characteristics and patients' prognosis were also evaluated. Results: MiR-23a (GC vs. Normal: 3.98 ± 1.23 vs. 2.29 ± 1.12, P < 0.001) and miR-23b (GC vs. Normal: 3.70 ± 1.24 vs. 1.58 ± 1.18, P < 0.001) expression were both increased dramatically when compared with paired normal mucosa. Notably, the expression levels of miR-23a in GC tissues were positively correlated with those of miR-23b (Spearman correlation coefficient r = 0.77, P < 0.001). Then, the coexpression of miR-23a and miR-23b (miR-23a-high/miR-23b-high) in GC tissues was significantly associated with the advanced TNM stage (P < 0.001), the presence of lymph node metastasis (P = 0.008) and the great depth of invasion (P = 0.02). Furthermore, both univariate and multivariate analyses showed that miR-23a/miR-23b co-expression was an independent predictor for unfavorable overall survival. Conclusions: These results suggest that the dysregulation of miR-23a and miR-23b may be implicated in the progression of human GC. Combined expression of miR-23a and miR-23b appears to be a valuable marker for prognosis of this disease.


Bian Z.,Nanjing University | Bian Z.,Georgia State University | Li L.,Nanjing University | Cui J.,Nanjing University | And 4 more authors.
Journal of Pathology | Year: 2011

Chronic inflammatory bowel diseases (IBDs) are associated with differential expression of genes involved in inflammation and tissue remodelling. We surveyed the expression profile of apoptosis-related microRNAs by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) in a dextran sulphate sodium (DSS) murine model of colitis. We found that miR-150 was strongly elevated, whereas c-Myb, a transcription factor and a target gene of miR-150, was significantly reduced in colon tissue after DSS treatment. Interestingly, elevation of miR-150 and down-regulation of c-Myb were also observed in human colon with active ulcerative colitis compared to the normal colon. Supporting the observation of DSS treatment inducing colonic cell apoptosis, Bcl-2, an anti-apoptotic protein known to be regulated by c-Myb, was reduced in colon tissue of DSS-treated mice. Furthermore, forced expression of pre-miR-150 in colonic epithelial HT29 cells strongly elevated miR-150 levels and decreased c-Myb and Bcl-2 levels, thus enhancing cell apoptosis induced by serum deprivation. Together, the present study presents the first evidence that miR-150 and its targeting of c-Myb may serve as a new mechanism underlying the colonic epithelial disruption in DSS-induced murine experimental colitis and in active human IBD. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Wang X.,East Tennessee State University | Ha T.,East Tennessee State University | Liu L.,Nanjing Medical University | Zou J.,Nanjing University | And 5 more authors.
Cardiovascular Research | Year: 2013

AimsWe have reported that either toll-like receptor 4 deficiency (TLR4 -/-) or TLR2 modulation protects against myocardial ischaemia/reperfusion (I/R) injury. The mechanisms involve attenuation of I/R-induced nuclear factor KappaB (NF-κB) activation. MicroRNA-146a (miR-146a) has been reported to target interleukin-1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6), resulting in inhibiting NF-κB activation. This study examined the role of microRNA-146a in myocardial I/R injury.Methods and resultsWe constructed lentivirus expressing miR-146a (LmiR-146a). LmiR-146a was transfected into mouse hearts through the right common carotid artery. The lentivirus vector (LmiR-Con) served as vector control. Untransfected mice served as I/R control. Sham operation served as sham control. Seven days after transfection, the hearts were subjected to ischaemia (60 min) followed by reperfusion (4 h). Myocardial infarct size was analysed by triphenyltetrazolium chloride (TTC) staining. In separate experiments, the hearts were subjected to ischaemia (60 min) followed by reperfusion for up to 7 days. Cardiac function was measured by echocardiography prior to I/R, 3 and 7 days after myocardial I/R. LmiR-146a transfection significantly decreased I/R-induced myocardial infarct size by 55% and prevented I/R-induced decreases in ejection fraction (EF%) and fractional shortening (%FS). LmiR-146a transfection attenuated I/R-induced myocardial apoptosis and caspase-3/7 and-8 activities. LmiR-146a transfection suppresses IRAK1 and TRAF6 expression in the myocardium. In addition, transfection of LmiR-146a prevented I/R-induced NF-κB activation and inflammatory cytokine production.ConclusionsMicroRNA-146a protects the myocardium from I/R injury. The mechanisms may involve attenuation of NF-κB activation and inflammatory cytokine production by suppressing IRAK1 and TRAF6. © 2012 The Author.


Guo J.,Nanjing Medical University | Sachs F.,State University of New York at Buffalo | Meng F.,State University of New York at Buffalo
Antioxidants and Redox Signaling | Year: 2014

Significance: Three signaling systems, chemical, electrical, and mechanical, ubiquitously contribute to cellular activities. There is limited information on the mechanical signaling system because of a lack of tools to measure stress in specific proteins. Although significant advances in methodologies such as atomic force microscopy and laser tweezers have achieved great success in single molecules and measuring the mean properties of cells and tissues, they cannot deal with specific proteins in live cells. Recent Advances: To remedy the situation, we developed a family of genetically encoded optical force sensors to measure the stress in structural proteins in living cells. The sensors can be incorporated into specific proteins and are not harmful in transgenic animals. The chimeric proteins distribute and function as their wild-type counterparts, and local stress can be read out from changes in Förster resonance energy transfer (FRET). Critical Issues: Our original sensor used two mutant green fluorescence proteins linked by an alpha helix that served as a linking spring. Ever since, we have improved the probe design in a number of ways. For example, we replaced the helical linker with more common elastic protein domains to better match the compliance of the wild-type hosts. We greatly improved sensitivity by using the angular dependence of FRET rather than the distance dependence as the transduction mechanism, because that has nearly 100% efficiency at rest and nearly zero when stretched. Future Directions: These probes enable researchers to investigate the roles of mechanical force in cellular activities at the level of single molecules, cells, tissues, and whole animals. Antioxid. Redox Signal. 20, 986-999. © 2014 Mary Ann Liebert, Inc.


Pan F.,Johns Hopkins University | Fan H.,Tongji University | Lu L.,Nanjing Medical University | Liu Z.,Tongji University | Jiang S.,Tongji University
Science Signaling | Year: 2011

Substantial advances in our understanding of the developmental and functional relationship between regulatory T cells (Tregs) and T helper 17 (TH17) cells and their potential clinical applications have been made. In response to these break-throughs, the second international conference entitled "China Tregs/Th17 2010 Shanghai Conference," held in Shanghai, China, was dedicated to this topic. Various types of T regs and TH17 cells, as well as their relevant cytokines, were discussed. Here, we summarize some of the findings shared at the conference, specifically focusing on the biology of TH17 cells, including interleukin-17 (IL-17)-producing innate cells, Tregs, and the factors that control the critical balance between Tregs and cells of the TH17 lineage.


Guo J.,Nanjing Medical University | Wang Y.,Capital Medical University | Sachs F.,State University of New York at Buffalo | Meng F.,State University of New York at Buffalo
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

Cell mechanics plays a role in stem cell reprogramming and differentiation. To understand this process better, we created a genetically encoded optical probe, named actin-cpstFRET-actin (AcpA), to report forces in actin in living cells in real time. We showed that stemness was associated with increased force in actin. We reprogrammed HEK-293 cells into stem-like cells using no transcription factors but simply by softening the substrate. However, Madin-Darby canine kidney (MDCK) cell reprogramming required, in addition to a soft substrate, Harvey rat sarcoma viral oncogene homolog expression. Replating the stem-like cells on glass led to redifferentiation and reduced force in actin. The actin force probe was a FRET sensor, called cpstFRET (circularly permuted stretch sensitive FRET), flanked by g-actin subunits. The labeled actin expressed efficiently in HEK, MDCK, 3T3, and bovine aortic endothelial cells and in multiple stable cell lines created from those cells. The viability of the cell lines demonstrated that labeled actin did not significantly affect cell physiology. The labeled actin distribution was similar to that observed with GFPtagged actin. We also examined the stress in the actin cross-linker actinin. Actinin force was not always correlated with actin force, emphasizing the need for addressing protein specificity when discussing forces. Because actin is a primary structural protein in animal cells, understanding its force distribution is central to understanding animal cell physiology and the many linked reactions such as stress-induced gene expression. This new probe permits measuring actin forces in a wide range of experiments on preparations ranging from isolated proteins to transgenic animals.


Hao L.,Nanjing Medical University | Huang H.,Nanjing Medical University | Gao J.,Nanjing Medical University | Marshall C.,University of Kentucky | And 2 more authors.
Neuroscience Letters | Year: 2014

Chronic exposure to d-galactose (d-gal) serves as a model for age-related oxidative damage and cognitive dysfunction. However, methods used, including the dose and treatment time of d-gal as well as the gender, age and strain of animals used, vary greatly among published articles. In this study, we investigate the effect of gender, age and treatment time on brain oxidative stress and spatial memory deficits induced by d-gal in mice, respectively. Eight-week-old female mice injected with 100. mg/kg d-gal per day, for 6 weeks, did not show spatial memory impairment or high levels of hydroxyl radical, protein carbonyl and malondialdehyde in brain homogenates, although brain reactive oxygen species were increased when compared with saline control mice. In contrast, both 8-week-old male mice and 24-week-old female mice receiving 100. mg/kg d-gal for 6 weeks, or 8-week-old female mice receiving 100. mg/kg d-gal for 10 weeks showed spatial memory deficits and significant increases in the above oxidative markers, compared with their corresponding controls. These results demonstrate that d-gal-induced brain oxidative stress and spatial memory impairment are dependent upon exposure time of d-gal, plus gender and age of the animals used. The findings can serve as a useful guide for successfully establishing d-gal induced age-related oxidative damage models. © 2014 Elsevier Ireland Ltd.


Huang H.,Hitachi Ltd. | Huang H.,Nanjing Medical University | Goto M.,Hitachi Ltd. | Tsunoda H.,Hitachi Ltd. | And 4 more authors.
Nucleic Acids Research | Year: 2014

Analysis of single-cell gene expression promises a more precise understanding of molecular mechanisms of a living system. Most techniques only allow studies of the expressions for limited numbers of gene species. When amplification of cDNA was carried out for analysing more genes, amplification biases were frequently reported. A non-biased and efficient global-amplification method, which uses a single-cell cDNA library immobilized on beads, was developed for analysing entire gene expressions for single cells. Every step in this analysis from reverse transcription to cDNA amplification was optimized. By removing degrading excess primers, the bias due to the digestion of cDNA was prevented. Since the residual reagents, which affect the efficiency of each subsequent reaction, could be removed by washing beads, the conditions for uniform and maximized amplification of cDNAs were achieved. The differences in the amplification rates for randomly selected eight genes were within 1.5-folds, which could be negligible for most of the applications of single-cell analysis. The global amplification gives a large amount of amplified cDNA (>100 μg) from a single cell (2-pg mRNA), and that amount is enough for downstream analysis. The proposed global-amplification method was used to analyse transcript ratios of multiple cDNA targets (from several copies to several thousand copies) quantitatively. © 2013 The Author(s).


Yang R.,University of Pittsburgh | Yang R.,University of Tampere | Zou X.,Nanjing Medical University | Koskinen M.-L.,University of Tampere | Tenhunen J.,University of Tampere
Critical Care | Year: 2012

Introduction: Inflammation may critically affect mechanisms of liver injury in acetaminophen (APAP) hepatotoxicity. Kupffer cells (KC) play important roles in inflammation, and KC depletion confers protection at early time points after APAP treatment but can lead to more severe injury at a later time point. It is possible that some inflammatory factors might contribute to liver damage at an early injurious phase but facilitate liver regeneration at a late time point. Therefore, we tested this hypothesis by using ethyl pyruvate (EP), an anti-inflammatory agent, to treat APAP overdose for 24-48 hours.Methods: C57BL/6 male mice were intraperitoneally injected with a single dose of APAP (350 mg/kg dissolved in 1 mL sterile saline). Following 2 hours of APAP challenge, the mice were given 0.5 mL EP (40 mg/kg) or saline treatment every 8 hours for a total of 24 or 48 hours.Results: Twenty-four hours after APAP challenge, compared to the saline-treated group, EP treatment significantly lowered serum transaminases (ALT/AST) and reduced liver injury seen in histopathology; however, at the 48-hour time point, compared to the saline therapy, EP therapy impaired hepatocyte regeneration and increased serum AST; this late detrimental effect was associated with reduced serum TNF-α concentration and decreased expression of cell cycle protein cyclin D1, two important factors in liver regeneration.Conclusions: Inflammation likely contributes to liver damage at an early injurious phase but improves hepatocyte regeneration at a late time point, and prolonged anti-inflammation therapy at a late phase is not beneficial. © 2012 Yang et al.; licensee BioMed Central Ltd.


Yu H.,Yancheng First Peoples Hospital | Yang W.,Nanjing Medical University
Biochemical and Biophysical Research Communications | Year: 2016

MiR-211 has strong inhibitive effects on melanoma cell growth, invasion and metastasis. However, how it is downregulated and whether other genes are involved its downstream regulation in melanoma are not clear. In this study, we firstly verified the expression of miR-211 in melanoma cell lines and observed that its downregulation is associated with increased DNMT1 expression. By performing qRT-PCR and MSP analysis, we confirmed that DNMT1 is negatively correlated with miR-211 expression and can modulate DNA methylation in the promoter region of miR-211. By performing bioinformatics analysis, we found that RAB22A is a possible target of miR-211, which has two broadly conversed binding sites with miR-211 in the 3'UTR. Following dual luciferase assay, qRT-PCR and western blot analysis confirmed the direct binding between miR-211 and RAB22A and the suppressive effect of miR-211 on RAB22A expression. Knockdown of RAB22A increased epithelial properties and impaired mesenchymal properties of the melanoma cells, suggesting that miR-211 modulates epithelial mesenchymal transition (EMT) of melanoma cells via downregulating RAB22A. In summary, the present study firstly demonstrated that DNMT1 mediated promoter methylation is a mechanism of miRNA suppression in melanoma and revealed a new tumor suppressor role of the miR-211 by targeting RAB22A in melanoma. The DNMT1/miR-211/RAB22A axis provides a novel insight into the pathogenesis of melanoma, particularly in the EMT process. © 2016 Elsevier Inc.


Shu T.,Nanjing Medical University | Zhu Y.,Nanjing Medical University | Wang H.,Nanjing Medical University | Lin Y.,Nanjing Medical University | And 2 more authors.
PLoS ONE | Year: 2011

Advanced glycation end products (AGEs) have been implicated in diverse pathological settings of many diabetic complications, and the possible mechanisms have been widely reported. However, the relationship between AGEs and pancreatic β-cell dysfunction is still poorly understood. Recent studies have shown that AGEs can impair β-cell function by inducing apoptosis or decreasing insulin secretion. Our previous research revealed that AGEs could significantly down-regulate insulin transcription and reduce β-cell glucose-stimulated insulin secretion (GSIS). Here, we investigated the possible mechanisms underlying AGE-related suppression of insulin synthesis. In the rat pancreatic β-cell line INS-1, we found that AGEs induced dephosphorylation of Foxo1 and increased its accumulation in the nucleus. The translocation of Foxo1 subsequently inhibited pancreatic-duodenal homeobox factor-1 (Pdx-1) levels in both nuclear and cytoplasmic compartments. We observed that with AGEs treatment, Pdx-1 protein levels decreased after 4 h, but there was no change in the Pdx-1 mRNA level or promoter activity at the same time point; this demonstrated that the decrease in Pdx-1 expression was not regulated at the transcriptional level. In our study, the decrease in Pdx-1 protein level was related to its reduced stability, overexpression of DN-Foxo1 could partially reverse the inhibition of Pdx-1 expression. Pretreatment with AGEs receptor (RAGE) antibody also prevented the AGE-induced diminution of Pdx-1 protein and insulin mRNA expression. In summary, AGEs induced nuclear accumulation of Foxo1; this in turn reduced Pdx-1 expression by decreasing its protein stability, ultimately affecting insulin synthesis. © 2011 Shu et al.


Lu M.,Nanjing Medical University | Sun L.,Shenyang University | Zhou J.,Nanjing Medical University | Yang J.,Nanjing Medical University
Tumor Biology | Year: 2014

Dihydroartemisinin (DHA), a semisynthetic derivative of artemisinin isolated from the traditional Chinese herb Artemisia annua, has been shown to exhibit antitumor activity in various cancer cells, including colorectal cancer. However, the detailed mechanisms underlying its antitumor activity in colorectal cancer remain to be elucidated. In the present study, we investigated DHA-induced apoptosis in human colorectal cancer HCT-116 cells in vitro. The results showed that DHA treatment significantly reduced cell viability in a concentration- and time-dependent manner. Furthermore, DHA induced G1 cell cycle arrest, apoptotic cell death, and accumulation of reactive oxygen species (ROS). We also found that DHA decreased the mitochondrial membrane potential; activated the caspase-3, caspase-8, and caspase-9; and increased the ratio of Bax/Bcl-2. Meanwhile, the translocation of apoptotic inducing factor (AIF) and the release of cytochrome c from the mitochondria were observed. Strikingly, the free radical scavenger N-acetylcysteine or the caspase-3 inhibitor Ac-DEVD-CHO significantly prevented DHA-induced apoptotic cell death. Taken together, we concluded that DHA-triggered apoptosis in HCT-116 cells occurs through the ROS-mediated mitochondria-dependent pathway. Our data suggest that DHA has great potential to be developed as a novel therapeutic agent for the treatment of human colorectal cancer. © 2014 International Society of Oncology and BioMarkers (ISOBM).


Tang W.,Nanjing Medical University | Tang W.,Jiangsu Province Hospital on Integration of Chinese and Western Medicine | Jiang Y.,Nanjing Medical University | Mu X.,Nanjing Medical University | And 4 more authors.
Cellular Signalling | Year: 2014

The activation of homeobox A10 (HOXA10) has been proved to be an important event in epithelial ovarian carcinogenesis, yet its regulation in epithelial ovarian cancer (EOC) is still not fully understood. Here, we aimed to reveal the mechanism that a predicted target miRNA regulates HOXA10 expression and the association of its expression with progression of EOC. Here, by using computer-assisted algorithms from PicTar, TargetScan, and miRBase, we identified that the predicted target miRNA of HOXA10 was miR-135a. MiR-135a expression in EOC tissues and controls was measured with quantitative RT-PCR. The role of miR-135a and HOXA10 in the growth and survival of several EOC cell lines was determined with several in vitro approaches. We found that miR-135a expression was downregulated in an EOC patient cohort. Also, patients with low miR-135a expression had shorter overall survival and progression-free survival durations than those with high expression. Functional analysis of three EOC-derived cell lines (SKOV-3, HEY, and OVCAR-3) demonstrated that miR-135a directly regulated HOXA10 expression by targeting its 3'-UTR. Inhibition of HOXA10 expression with miR-135a mimics and HOXA10 siRNA consistently resulted in cell apoptosis with concomitant enhancement of caspase-3, increase of p53 expression and reduction of Bcl-2 expression, and also suppressed cell growth and adhesion. These findings suggest that ubiquitous loss of miR-135a expression is a critical mechanism for the overexpression of HOXA10 in EOC cells, which is implicated in epithelial ovarian carcinogenesis. Furthermore, miR-135a may be predictive of EOC prognosis. © 2014.


Zhang L.,Nanjing Medical University | Xu H.-G.,Guangzhou University | Lu C.,Nanjing Medical University
Leukemia and Lymphoma | Year: 2014

T-cell acute lymphoblastic leukemia (T-ALL) is a hematologic malignancy with a poor prognosis. It has been shown that long non-coding RNA (lncRNA) plays an important role in tumorigenesis. Here, we characterized a novel lncRNA, T-ALL-R-LncR1, with whole-transcriptome deep sequencing from the Jurkat leukemic T-cell line. T-ALL-R-LncR1 was not observed in human normal tissues. However, an obvious expression was observed in some tumor tissues. T-ALL-R-LncR1 was markedly expressed in neoplastic T lymphocytes of 11 cases out of 21 children with T-ALL, indicating that T-ALL-R-LncR1 might be associated with T-ALL. T-ALL-R-LncR1 knockdown predisposed Jurkat cells to undergo pro-apoptotic factor Par-4-induced apoptosis. Further studies revealed that T-ALL-R-LncR1 knockdown facilitated the formation of a Par-4/THAP1 protein complex, resulting in the activation of caspase-3 and an increase of pro-apoptotic Smac protein in T-ALL cells. Our studies indicate a potential role of suppressing the novel long non-coding RNA T-ALL-R-LncR1 in the therapy of human T-ALL. © 2014 Informa UK, Ltd.


Xiao M.,Southern Medical University | Xiao M.,Nanjing Medical University | Gao Y.,Southern Medical University | Wang Y.,Southern Medical University
International Journal of Clinical Practice | Year: 2014

Objective: Since the discovery of Helicobacter species in human biliary system, the association between Helicobacter species infection and cholangiocarcinoma is under debate. This meta-analysis aims to explore this issue. Methods: Literature search was carried out to identify all eligible articles. We performed overall meta-analysis of all included studies and subgroup analysis based on regional distribution. Subgroup analysis in the light of detection methods and specimens was also conducted. Results: Ten case-control studies were included. Overall meta-analysis favoured a significant association between Helicobacter species infection and cholangiocarcinoma (cumulative OR 8.88, 95% CI 3.67-21.49). Subgroup analysis based on geographic distribution indicated that Helicobacter species infection may serve as a risk factor not only in a region with high cholangiocarcinoma incidence (Asia, OR 6.68, 95% CI 2.29-19.49) but also in low incidence region (Europe, OR 14.90, 95% CI 4.79-46.35). The other subgroup analysis showed that PCR was the most effective and efficient method to detect Helicobacter species in surgically resected tissue and bile. There was significant heterogeneity among studies and obvious publication bias. Conclusion: Our meta-analysis supports the possible association between Helicobacter species infection and cholangiocarcinoma. Further investigations are required to clarify the role of Helicobacter species in this malignancy. © 2013 John Wiley & Sons Ltd.


Hou X.,Nanjing Medical University | Hu Z.,Tongji University | Huang X.,Dalian Medical University | Chen Y.,Loma Linda University | And 3 more authors.
Journal of Molecular Medicine | Year: 2014

This study aims to investigate the role of osteopontin (OPN) genetic polymorphisms in the occurrence of left ventricular hypertrophy (LVH) in Chinese patients with essential hypertension (EH). A total of 1,092 patients diagnosed with EH were recruited. Three single nucleotide polymorphisms (SNP) on the promoter region of the OPN gene, including -66T/G, -156G/GG, and -443C/T were genotyped. The serum thrombin-cleaved OPN levels were studied. Patients were divided into LVH+ (n=443) and the LVH- (n=649) groups. We found that none of the studied SNPs in the OPN gene was associated with the risk and severity of LVH. The SNPs in the OPN gene did not correlate with the serum OPN levels. However, the serum thrombin-cleaved OPN levels were found to be an independent risk factor for LVH in the EH patients. Multivariate logistic regression analysis showed that serum thrombin-cleaved OPN levels were independently associated with the development of LVH (adjusted OR=2.47, 95 % CI 1.56-4.01, adjusted P<0.001). In vitro studies showed that the thrombin-cleaved OPN treatment increased the protein content per cell, the cardiomyocyte surface size, and the expression level of atrial natriuretic peptide protein in a dose-dependent manner. The thrombin-cleaved OPN serum level, but not OPN gene polymorphism, is associated with the development of LVH in EH patients. © 2013 Springer-Verlag.


Wang T.-Y.,Nanjing Medical University | Huang Y.-P.,Shenyang University | Ma P.,Nanjing Medical University
Tumor Biology | Year: 2014

The aim of this study was to identify the correlations of a common polymorphism (rs6774494 A > G) in the EVI-1 gene targeted by micro-RNA (miRNA)-206/133b with the pathogenesis of breast cancer (BC). A total of 196 unrelated ethnic Han Chinese women diagnosed with primary BC were consecutively recruited and 200 healthy controls were randomly selected from the same population-based cohort. Direct PCR sequencing assay was used to detection of rs6774494 A > G polymorphism in the EVI-1 gene. Real-time quantitative PCR (RT-PCR) analysis was performed to verify the alterations of the EVI1 messenger RNA (mRNA) levels. Kaplan–Meier analysis was used to investigate and to estimate the survival outcomes for each endpoint. All statistical analyses were performed with SPSS software (version 18.0, SPSS, Chicago, IL). Our results demonstrated that the carriers of EVI-1 AG genotype were more likely to develop BC when compared with the EVI-1 GG genotype (P = 0.034, OR = 1.26, 95% CI = 1.02 ∼ 1.57). In addition, it was found that patients with the G (AG + GG) allele of EVI-1 genetic variants were associated with higher risk of BC compared with the EVI-1 AA genotype (OR = 1.26, 95% CI = 1.02 ∼ 1.54, P = 0.028). The results of a subgroup analysis stratified by menopause revealed that in female post-menopause subgroup patients with the EVI-1 G allele were correlated with a higher risk of BC than those with the EVI-1 AA genotype (OR = 1.31, 95% CI = 1.00 ∼ 1.72, P = 0.054). Kaplan–Meier analyses suggested that carriers of the G allele (AG + GG) were associated with poorer overall survival (OS) and progression-free survival (PFS) compared with those with AA genotype (OS P = 0.042; PFS P = 0.036, respectively). The correlation analysis showed that EVI-1 mRNA levels were negatively associated with miRNA-206/133b levels in the carriers of the G allele (AG + GG) (r = −1.274, P < 0.05). Our findings provide evidence that the EVI-1 rs6774494 G > A polymorphism targeted by miRNA-206/133b may contribute to the pathogenesis of BC. © 2014, International Society of Oncology and BioMarkers (ISOBM).


Yang M.,University of Hong Kong | Sun L.,Nanjing Medical University | Wang S.,Jiangsu University | Ko K.-H.,University of Hong Kong | And 4 more authors.
Journal of Immunology | Year: 2010

Although B cells have been shown to possess a regulatory function, microenvironmental factors or cytokines involved in the induction of regulatory B cells remain largely uncharacterized. B cell-activating factor (BAFF), a member of TNF family cytokines, is a key regulator for Bcell maturation and function. In this study, we detected significantly increased numbers of IL-10-producing B cells in BAFF-treated B cell cultures, an effect specifically abrogated by neutralization of BAFF with TACIFc. BAFF-induced IL-10-producing B cells showed a distinct CD1dhiCD5+ phenotype, which were mainly derived from marginal zone B cells. Moreover, BAFF activated transcription factor AP-1 for binding to IL-10 promoter. Notably, BAFF treatment in vivo increased the number of IL-10-producing B cells in marginal zone regions. Furthermore, BAFF-induced IL-10-producing B cells possess a regulatory function both in vitro and in vivo. Taken together, our findings identify a novel function of BAFF in the induction of IL-10-producing regulatory B cells. Copyright © 2010 by The American Association of Immunologists, Inc.


Wang Z.,Nanjing Medical University | Fu Y.,Nanjing Medical University | Tang C.,Nanjing Medical University | Lu S.,Tianjin Medical University | Chu W.-M.,Brown University
Breast Cancer Research and Treatment | Year: 2010

The SULT1A1 R213H polymorphism is suggested to be implicated in the development and progression of breast cancer. However, the published findings are inconsistent. We therefore performed a meta-analysis of 8,454 breast cancer cases and 11,800 controls from 14 published case-control studies. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association of the R213H polymorphism with breast cancer risk. Overall, our results suggested that there is no significant relationship between SULT1A1 R213H polymorphism and the risk of breast cancer. However, further ethnic population analysis revealed a significantly increased risk of breast cancer for HH allele carriers among Asians (for HH vs. RR: OR = 2.27, 95% CI = 1.11-4.63, P heterogeneity = 0.63; for the recessive model: OR = 2.03, 95% CI = 1.00-4.41, P heterogeneity = 0.62). Taken together, this meta-analysis suggests that the SULT1A1 R213H may be a low-penetrant risk factor for developing breast cancer in Asian population. © 2009 Springer Science+Business Media, LLC.


Xiao M.,Nanjing Medical University | Xiao M.,Southern Medical University | Wang Y.,Southern Medical University | Gao Y.,Southern Medical University
PLoS ONE | Year: 2013

Background:Pancreatic cancer is one of the most troublesome malignancies with dismal prognosis. H. pylori has been recognized as a type I carcinogen. Several studies have evaluated the association between H. pylori infectionand pancreatic cancer development, however, the conclusions are inconsistent.Methods:Literature search was carried out in PubMed, EMBASE, Cochrane Library and CNKI databases to identify eligible researches. We performed overall meta-analysis of all studies included and subgroup analysis based on regional distribution. Quality of the studies (assessed by Newcastle-Ottawa quality assessment scale for case-control studies) and CagA+ strains of H. pylori were taken into consideration, and we conducted additional analyses including high-quality researches and those concerning CagA+ H. pylori respectively.Results:9 studies involving 3033 subjects (1083 pancreatic cancer cases, 1950 controls) were included. Summary OR and 95%CI of the overall meta-analysis of all included studies were 1.47 and 1.22-1.77, pooled data of the 4 high-quality studies were OR 1.28, 95%CI 1.01-1.63. OR of the 5 studies examined CagA+ strains was 1.42, corresponding 95%CI was 0.79 to 2.57. Summary estimates of subgroup analysis based on regional distribution are as follows, Europe group: OR 1.56, 95%CI 1.15-2.10; East Asia group: OR 2.01, 95%CI 1.33-3.02; North America group: OR 1.17, 95%CI 0.87-1.58. There was not obvious heterogeneity across the 9 studies. No publication bias was detected.Conclusion:H. pylori infection is significantly, albeit weakly, associated with pancreatic cancer development. The association is prominent in Europe and East Asia, but not in North America. CagA+ H. pylori strains appear not to be associated with pancreatic cancer. However, more studies, especially prospective studies, are needed to validate our results. © 2013 Xiao et al.


Jia D.-M.,Nanjing Medical University | Chen Z.-B.,Nanjing Medical University | Zhang M.-J.,Nanjing Medical University | Yang W.-J.,Nanjing Medical University | And 6 more authors.
Stroke | Year: 2013

Background and Purpose-Little research regarding genotypes and clopidogrel response related to acute ischemic stroke has been published. This study was conducted to investigate whether the polymorphisms of receptors or enzymes involved in the metabolic process of clopidogrel affect clopidogrel response and prognosis related to acute stroke. Methods-A total of 259 patients with acute ischemic stroke were enrolled in this study; all received follow-up evaluations 3 and 6 months after clopidogrel treatment. CYP2C19, CYP3A4, and P2Y12 were screened. The adenosine diphosphateinduced platelet aggregation test, the National Institutes of Health Stroke Scale (NIHSS), and the modified Rankin Scale (mRS) were used, and blood vascular events were evaluated. Results-The difference before and after clopidogrel treatment on adenosine diphosphate-induced platelet aggregation was significantly smaller in patients carrying 1 or 2 CYP2C19 loss-of-function alleles (*2,*3) compared with patients carrying none. Patients with none had better outcomes than patients with CYP2C19 loss-of-function alleles, as demonstrated by NIHSS and mRS scores at 3 and 6 months after treatment. Regression analysis showed that CYP2C19 was an independent predictor of clopidogrel resistance. Conclusions-CYP2C19 genotypes had significant impact on clopidogrel response and prognosis of patients with stroke. © 2013 American Heart Association, Inc.


Hao S.,University of Pittsburgh | Hao S.,Nanjing Medical University | He W.,University of Pittsburgh | Li Y.,University of Pittsburgh | And 6 more authors.
Journal of the American Society of Nephrology | Year: 2011

Because fibrotic kidneys exhibit aberrant activation of β-catenin signaling, this pathway may be a potential target for antifibrotic therapy. In this study, we examined the effects of β-catenin activation on tubular epithelial-mesenchymal transition (EMT) in vitro and evaluated the therapeutic efficacy of the peptidomimetic small molecule ICG-001, which specifically disrupts β-catenin-mediated gene transcription, in obstructive nephropathy. In vitro, ectopic expression of stabilized β-catenin in tubular epithelial (HKC-8) cells suppressed E-cadherin and induced Snail1, fibronectin, and plasminogen activator inhibitor-1 (PAI-1) expression. ICG-001 suppressed β-catenin-driven gene transcription in a dose-dependent manner and abolished TGF-β1-induced expression of Snail1, PAI-1, collagen I, fibronectin, and α-smooth muscle actin (α-SMA). This antifibrotic effect of ICG-001 did not involve disruption of Smad signaling. In the unilateral ureteral obstruction model, ICG-001 ameliorated renal interstitial fibrosis and suppressed renal expression of fibronectin, collagen I, collagen III, α-SMA, PAI-1, fibroblast-specific protein-1, Snail1, and Snail2. Late administration of ICG-001 also effectively attenuated fibrotic lesions in obstructive nephropathy. In conclusion, inhibiting β-catenin signaling may be an effective approach to the treatment of fibrotic kidney diseases. Copyright © 2011 by the American Society of Nephrology.


Isom S.C.,University of Missouri | Li R.F.,University of Missouri | Li R.F.,Nanjing Medical University | Whitworth K.M.,University of Missouri | Prather R.S.,University of Missouri
Molecular Reproduction and Development | Year: 2012

Evidence in many species has suggested that those embryos that cleave earliest after fertilization are more developmentally competent than those that cleave relatively later after fertilization. Herein we document this phenomenon in porcine in vitro-fertilized (IVF), somatic cell nuclear transfer (SCNT), and parthenogenetic (PA) embryos. In vitro-matured pig oocytes were used to generate IVF, SCNT, and PA embryos. At 24hr post-activation (or insemination; hpa/hpi), embryos were visually assessed, and cleaved embryos were moved into a new culture well. This process was repeated at 30 and 48 hpa/hpi. All embryos were allowed to develop 7 days in culture. For IVF embryos, 39.9%, 24.6%, and 10.5% of fast-, intermediate-, or slow-cleaving embryos, respectively, developed into blastocysts by day 7. For SCNT embryos, 31.8% of fast-, 5.7% of intermediate-, and 2.9% of late-cleaving embryos achieved the blastocyst stage of development. For PA embryos, the percentages of those cleaved embryos that developed to blastocyst were 59.3%, 36.7%, and 7.5% for early-, intermediate-, and late-cleaving embryos, respectively. Using RNA collected from early-, intermediate-, and late-cleaving embryos, real-time PCR was performed to assess the transcript levels of 14 different genes of widely varied function. The qPCR results suggest that maternal mRNA degradation may not proceed in an appropriate pattern in slow-cleaving embryos. These findings (1) confirm that, as observed in other species, earlier-cleaving porcine embryos are more successful at developing in culture than are slower-cleaving embryos, and (2) implicate mechanisms of maternal transcript destruction as potential determinants of oocyte/embryo quality. © 2011 Wiley Periodicals, Inc.


Zhang L.,Nanjing Agricultural University | Zhang L.,Nanjing Medical University | Hou X.,Nanjing Medical University | Ma R.,Nanjing Agricultural University | And 4 more authors.
FASEB Journal | Year: 2014

Sirtuins have been widely reported to be involved in multiple biological processes; however, their function in oocyte meiosis has not been. Here, by confocal scanning and quantitative analysis, we show that specific depletion of Sirt2 in mouse oocytes results in spindle defects and chromosome disorganization (35.5±8.7 vs. 9.6±3.8% control; P<0.05), with impaired microtubule-kinetochore interaction. Moreover, knockdown and overexpression experiments reveal that Sirt2 modulates the acetylation status of histone H4K16 and α-tubulin in oocytes, which may in part mediate the defective phenotypes described above by influencing microtubule dynamics and kinetochore function. Finally, we find lower Sirt2 protein level in oocytes from aged mice by immunoblotting and that maternal age-associated meiotic defects can be ameliorated through overexpression of Sirt2 (33.2±5.1% old vs.12.7±5.2% old+Sirt2; P<0.05), providing support for the hypothesis that decreased Sirt2 is one of a number of factors contributing to oocyte age-dependent deficits. In summary, our data indicate a role for Sirt2 during oocyte meiosis and uncover a striking beneficial effect of increased Sirt2 expression on aged oocytes. © FASEB.


Henderson B.E.,University of Southern California | Lee N.H.,George Washington University | Seewaldt V.,Duke University | Shen H.,Nanjing Medical University
Nature Reviews Cancer | Year: 2012

It is becoming clear that some of the differences in cancer risk, incidence and survival among people of different racial and ethnic backgrounds can be attributed to biological factors. However, identifying these factors and exploiting them to help eliminate cancer disparities has proved challenging. With this in mind, we asked four scientists for their opinions on the most crucial advances, as well as the challenges and what the future holds for this important emerging area of research. © 2012 Macmillan Publishers Limited. All rights reserved.


Zhou J.,Nanjing Medical University | Xiao D.,Loma Linda University | Hu Y.,Nanjing Medical University | Wang Z.,Nanjing Medical University | And 3 more authors.
Hypertension | Year: 2013

Preeclampsia is a life-threatening pregnancy disorder. However, its pathogenesis remains unclear. We tested the hypothesis that gestational hypoxia induces preeclampsia-like symptoms via heightened endothelin-1 (ET-1) signaling. Time-dated pregnant and nonpregnant rats were divided into normoxic and hypoxic (10.5% O2 from the gestational day 6-21) groups. Chronic hypoxia had no significant effect on blood pressure or proteinuria in nonpregnant rats but significantly increased blood pressure on day 12 (systolic blood pressure, 111.7±6.1 versus 138.5±3.5 mm Hg; P=0.004) and day 20 (systolic blood pressure, 103.4±4.6 versus 125.1±6.1 mm Hg; P=0.02) in pregnant rats and urine protein (μg/μL)/creatinine (nmol/μL) ratio on day 20 (0.10±0.01 versus 0.20±0.04; P=0.04), as compared with the normoxic control group. This was accompanied with asymmetrical fetal growth restriction. Hypoxia resulted in impaired trophoblast invasion and uteroplacental vascular remodeling. In addition, plasma ET-1 levels, as well as the abundance of prepro-ET-1 mRNA, ET-1 type A receptor and angiotensin II type 1 receptor protein in the kidney and placenta were significantly increased in the chronic hypoxic group, as compared with the control animals. Treatment with the ET-1 type A receptor antagonist, BQ123, during the course of hypoxia exposure significantly attenuated the hypoxia-induced hypertension and other preeclampsia-like features. The results demonstrate that chronic hypoxia during gestation induces preeclamptic symptoms in pregnant rats via heightened ET-1 and ET-1 type A receptor-mediated signaling, providing a molecular mechanism linking gestational hypoxia and increased risk of preeclampsia. © 2013 American Heart Association, Inc.


Xiao Z.,Harvard University | Xiao Z.,Massachusetts Institute of Technology | Ji C.,Harvard University | Ji C.,Nanjing Medical University | And 8 more authors.
Angewandte Chemie - International Edition | Year: 2012

Targeted cancer therapy: Inspired by the ability of DNA hybridization, a targeted near-infrared (NIR) light-responsive delivery system has been developed through simple DNA self-assembly (see picture; PEG=polyethylene glycol). This DNA-based platform shows the ability of releasing therapeutics upon near-infrared irradiation, and remarkable targeted thermo- and chemotherapeutic efficacy invitro and invivo. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Chen S.-L.,Nanjing Medical University | Santoso T.,University of Indonesia | Zhang J.-J.,Nanjing Medical University | Ye F.,Nanjing Medical University | And 7 more authors.
Journal of the American College of Cardiology | Year: 2011

Objectives: The present study aimed to investigate the difference in major adverse cardiac events (MACE) at 12 months in patients with coronary bifurcation lesions after double kissing double crush (DK crush) or provisional stenting (PS) techniques. Background: Provisional side branch (SB) stenting is preferable to DK crush because it has been associated with fewer complications. It is unknown which strategy would provide the best results. Methods: From April 2007 to June 2009, 370 unselected patients with coronary bifurcation lesions from 7 Asian centers were randomly assigned to either the DK or the PS group. Additional SB stenting in PS was required if final results were suboptimal. The primary end point was the occurrence of MACE at 12 months, including cardiac death, myocardial infarction, or target vessel revascularization (TVR). Secondary end point was the angiographic restenosis at 8 months. Results: There were 3 procedural occlusions of SB in the PS group. At 8 months, angiographic restenosis rates in the main vessel and SB were significantly different between the DK (3.8% and 4.9%) and the PS groups (9.7% and 22.2%, p = 0.036 and p < 0.001, respectively). Additional SB stenting in the PS group was required in 28.6% of lesions. TVR was 6.5% in the DK group, occurring significantly less often than in the PS group (14.6%, p = 0.017). There were nonsignificant differences in MACE and definite stent thrombosis between the DK (10.3% and 2.2%) and PS groups (17.3%, and 0.5%, p = 0.070 and p = 0.372, respectively). Conclusions: DK crush was associated with a significant reduction of TLR and TVR in this unselected patient population. However, there was no significant difference in MACE between DK and the PS groups. (Randomized Study on DK Crush Technique Versus Provisional Stenting Technique for Coronary Artery Bifurcation Lesions; ChicTR-TRC-00000015) © 2011 American College of Cardiology Foundation.


Tao Z.,Xuzhou Central Hospital | Shi A.,Nanjing Medical University | Zhao J.,Xuzhou Central Hospital
Cell Biochemistry and Biophysics | Year: 2015

The global statistics of diabetes mellitus in year 2013 indicated, about 382 million people had this disease worldwide, with type 2 diabetes making up about 90 % of the cases. This is equal to 8.3 % of the adult population with equal rates in both women and men. In year 2012 and 2013 diabetes resulted in mortality of 1.5–5.1 million people per year, making it the 8th leading cause of death in the world. It is predicted that by year 2035 about 592 million people will die of diabetes. The economic cost of diabetes seems to have increased worldwide. An average age of onset of diabetes is 42.5 years and could be due to consumption of high sugar and high-calorie diet, low physical activity, genetic susceptibility, and lifestyle. Approximately 8 % children and about 26 % young adults have diabetes mellitus in the world. The results of epidemiological study of type 1 diabetes mellitus (T1D) are presented by demographic, geographic, biologic, cultural, and other factors in human populations. The prevalence of T1D has been increased by 2–5 % worldwide and its prevalence is approximately one in 300 in US by 18 years of age. The epidemiological studies are important to study the role, causes, clinical care, prevention, and treatment of type1 diabetes in pregnant women and their children before and after birth. In this article, causes, diagnosis, symptoms, treatment and medications, and epidemiology of diabetes will be described. © 2015, Springer Science+Business Media New York.


Tao Z.-Q.,Xuzhou Central Hospital | Shi A.-M.,Nanjing Medical University | Wang K.-X.,Xuzhou Central Hospital | Zhang W.-D.,Xuzhou Central Hospital
European Review for Medical and Pharmacological Sciences | Year: 2015

Prostate cancer is one of the most common cancers affecting men with > 1,100,000 new cases and 300,000 deaths worldwide each year. The disease is more common among older men, with a median age at diagnosis around age above 60 years. Prostate cancer is a major medical problem that needs immediate attention as the disease is indolent, shows prolonged latency in association with high morbidity and mortality. Administration of diagnostic tests including PSA test and biopsies and the advances in other diagnostic procedures have led to early detection of the disease with therapeutic steps being taken early on, there has been a steady decline in the disease-specific mortality. Global incidence and mortality rates show that the disease is more prevalent among black people, even though the differences cannot be attributed entirely to race, as the influence of socioeconomic situation and the resultant limited access to medical technologies and treatment could not be ruled out completely. Several genes have been identified that when mutated confer high risk for the disease. Besides the genetic factors, family history and nutritional factors such as lack of enough vitamin D, high intake of calcium, obesity and high fat diets have been implicated as risk factors for prostate cancer. Therapeutic measures for prostate cancer involve mostly radical prostatectomy followed by radiotherapy in combination with hormonal treatment as needed.


Tang N.-P.,Shanghai Institute of Pharmaceutical Industry | Wu Y.-M.,Peoples Hospital of Jiangsu Province | Wang B.,Nanjing Medical University | Ma J.,Shanghai Institute of Pharmaceutical Industry
European Journal of Surgical Oncology | Year: 2010

Background: A number of studies has evaluated the association between P53 codon 72 polymorphism and colorectal cancer. However, results were inconsistent. To clarify the role of this polymorphism in colorectal cancer, we conducted a meta-analysis on this topic. Methods: Two authors independently searched the PubMed and EMBASE database from 1966 to January 2010 for studies regarding the association of P53 codon 72 polymorphism with colorectal cancer. Summary odds ratios with their corresponding 95% confidence intervals were calculated by using random-effects model. Results: The combined results showed that P53 codon 72 variant genotypes were not associated with colorectal cancer risk when compared to Arg/Arg genotype (Pro/Pro: OR = 1.02, 95% CI = 0.80-1.29; Arg/Pro: OR = 1.00, 95% CI = 0.86-1.16; Pro allele: OR = 1.00, 95% CI = 0.86-1.17). When stratifying for study population, design and cancer location, no statistically significant results were observed either. Conclusion: Our data indicate that the P53 codon 72 polymorphism may be not associated with colorectal cancer risk. © 2010 Elsevier Ltd. All rights reserved.


Cai Z.,Hubei University of Medicine | Chen G.,Hubei University of Medicine | He W.,Hubei University of Medicine | Xiao M.,Nanjing Medical University | Yan L.-J.,University of North Texas Health Science Center
Neuropsychiatric Disease and Treatment | Year: 2015

Alzheimer’s disease (AD) is characterized by cognitive impairment in clinical presentation, and by β-amyloid (Aβ) production and the hyper-phosphorylation of tau in basic research. More highlights demonstrate that the activation of the mammalian target of rapamycin (mTOR) enhances Aβ generation and deposition by modulating amyloid precursor protein (APP) metabolism and upregulating β- and γ-secretases. mTOR, an inhibitor of autophagy, decreases Aβ clearance by scissoring autophagy function. mTOR regulates Aβ generation or Aβ clearance by regulating several key signaling pathways, including phosphoinositide 3-kinase (PI3-K)/protein kinase B (Akt), glycogen synthase kinase 3 [GSK-3], AMP-activated protein kinase (AMPK), and insulin/insulin-like growth factor 1 (IGF-1). The activation of mTOR is also a contributor to aberrant hyperphosphorylated tau. Rapamycin, the inhibitor of mTOR, may mitigate cognitive impairment and inhibit the pathologies associated with amyloid plaques and neurofibrillary tangles by promoting autophagy. Furthermore, the upstream and downstream components of mTOR signaling are involved in the pathogenesis and progression of AD. Hence, inhibiting the activation of mTOR may be an important therapeutic target for AD. © 2015 Cai et al.


Wang S.,Nanjing Medical University | Li P.,Peoples Hospital of Jiangsu Province | Sun X.F.,Peoples Hospital of Jiangsu Province | Ye N.Y.,Peoples Hospital of Jiangsu Province | And 2 more authors.
Obesity Surgery | Year: 2013

Bariatric surgery is now widely accepted for treatment of morbid obesity. This study compared the effects of laparoscopic sleeve gastrectomy (LSG) and laparoscopic adjustable gastric banding (LAGB) on excess weight loss (EWL) and type 2 diabetes mellitus (T2DM). PubMed and Embase were searched for publications concerning LAGB and LSG from 2000 to 2012, with the last search on August 17, 2012. EWL and T2DM improvement over 6 and 12 months were pooled and compared by meta-analysis. Odds ratios (ORs) and mean differences were calculated with 95 % confidence intervals (CIs). Eleven studies involving 1,004 patients met the inclusion criteria. Compared with LAGB, LSG achieved greater EWL. The mean percentage EWL for LAGB was 33.9 % after 6 months in six studies and 37.8 % after 12 months in four studies; for LSG, EWL was 50.6 % after 6 months and 51.8 % after 12 months in the same studies. LSG was also superior to LAGB in treating T2DM. In five studies, T2DM was improved in 42 of 68 (61.8 %) patients after LAGB and 66 of 80 (82.5 %) after LSG, representing a pooled OR of 0.34 (95 % CI 0.16-0.73) and pooled mean differences of -12.55 (95 % CI -15.66 to -9.43) and -4.97 (95 % CI -7.58 to -8.36), respectively. LSG is more effective than LAGB in morbid obesity, with higher percentage EWL and greater improvement in T2DM. © 2013 The Author(s).


Tang Y.-R.,Nanjing Medical University | Tang Y.-R.,Peoples Hospital of Jiangsu Province | Yang W.-W.,Nanjing Medical University | Wang Y.-L.,Nanjing Medical University | Lin L.,Nanjing Medical University
European Journal of Gastroenterology and Hepatology | Year: 2012

Objective: To investigate the relationship between gender and symptomatology, psychological factors, and quality of life (QOL) in irritable bowel syndrome (IBS). Methods: The diagnosis of IBS was made on the basis of the Rome III Criteria. A physician obtained demographic and symptom data, Zung Self-Rated Anxiety and Depression Scale scores (SAS/SDS), and IBS-specific quality-of-life ratings (IBS-QOL). Results: Of the 4015 patients approached, 452 patients were diagnosed with IBS. Age ranged from 14 to 79 years (44.05±14.89 years) and the male to female ratio was 1: 1.3. The gender composition between the four IBS subtypes differed significantly (P<0.01). Male and female patients differed in their rating of abdominal pain/discomfort in terms of severity and time (P<0.01). Groups did not differ with regard to attack frequency. Female patients more frequently reported headache, dizziness, backache, muscular soreness, inappetence, insomnia, and fatigue (P<0.01). In comparison with men, anxiety and depression scores were significantly higher in women (P<0.01). Severity, duration, and frequency of abdominal pain/discomfort did not correlate with IBS-QOL scores. Insomnia/fatigue was negatively correlated with IBS-QOL scores (P<0.01). SAS and SDS scores were negatively correlated with IBS-QOL (total score and each subscale; P<0.01). Conclusion: There are significant gender differences in the symptoms, psychological rating, and QOL scores in IBS. Somatic symptoms, anxiety, and depression all contribute to the negative impact of IBS. Our findings suggest that gender differences should be recognized in IBS treatment. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Chian R.-C.,Nanjing Medical University | Chian R.-C.,McGill University | Uzelac P.S.,Marin Fertility Center | Nargund G.,The London Clinic
Fertility and Sterility | Year: 2013

Cryopreservation of embryos, oocytes, or ovarian tissues is the main option for female fertility preservation. Oocyte cryopreservation has emerged as especially important: the dramatic increase in the number of infants born from vitrified oocytes indicates that it is becoming one of the most important intervention options. However, oocyte cryopreservation with standard controlled ovarian hyperstimulation may not be feasible for some cancer patients as there are serious concerns about the effect of ovarian stimulation with hormones on the risk of cancer recurrence. Also, urgent gonadotoxic cancer treatment may not allow sufficient time for a patient to undergo hormonal ovarian stimulation. Thus, immature oocyte retrieval from ovaries without ovarian stimulation followed by in vitro maturation and vitrification is a promising fertility preservation option for women who cannot undergo ovarian stimulation or cannot delay their gonadotoxic cancer treatment. Immature oocytes can be collected from the ovaries during both the follicular and luteal phases, which maximizes the possibility for fertility preservation. The combination of ovarian tissue cryopreservation with immature oocyte collection from the tissue followed by oocyte vitrification via in vitro maturation represents another promising approach of fertility preservation in young women with cancer.


Gao J.,University of Nebraska - Lincoln | Qin R.,University of Nebraska - Lincoln | Qin R.,Nanjing Medical University | Li M.,University of Nebraska - Lincoln
Journal of Psychopharmacology | Year: 2015

The present study investigated how repeated administration of aripiprazole (a novel antipsychotic drug) alters its behavioral effects in two behavioral tests of antipsychotic activity and whether this alteration is correlated with an increase in dopamine D2 receptor function. Male adult Sprague-Dawley rats were first repeatedly tested with aripiprazole (3, 10 and 30 mg/kg, subcutaneously (sc)) or vehicle in a conditioned avoidance response (CAR) test or a phencyclidine (PCP) (3.20 mg/kg, sc)-induced hyperlocomotion test daily for five consecutive days. After 2-3 days of drug-free retraining or resting, all rats were then challenged with aripiprazole (1.5 or 3.0 mg/kg, sc). Repeated administration of aripiprazole progressively increased its inhibition of avoidance responding and PCP-induced hyperlocomotion. More importantly, rats previously treated with aripiprazole showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle in the challenge tests. An increased sensitivity to quinpirole (a selective D2/3 agonist) in prior aripiprazole-treated rats was also found in the quinpirole-induced hyperlocomotion test, suggesting an enhanced D2/3-mediated function. These findings suggest that aripiprazole, despite its distinct receptor mechanisms of action, induces a sensitization effect similar to those induced by other antipsychotic drugs and this effect may be partially mediated by brain plasticity involving D2/3 receptor systems. © The Author(s) 2014.


Shu Q.,Nanjing Medical University | Shu Q.,University of Nebraska - Lincoln | Hu G.,Nanjing Medical University | Li M.,University of Nebraska - Lincoln
Journal of Psychopharmacology | Year: 2014

This study examined how repeated olanzapine (OLZ) or clozapine (CLZ) treatment in adolescence alters sensitivity to the same drug in adulthood in the phencyclidine (PCP) hyperlocomotion model. Male adolescent Sprague-Dawley rats (postnatal day (P) 44-48) were first treated with OLZ (1.0 or 2.0 mg/kg, subcutaneously (sc)) or CLZ (10.0 or 20.0 mg/kg, sc) and tested in the PCP (3.2 mg/kg, sc)-induced hyperlocomotion model for five consecutive days. Then a challenge test with OLZ (0.5 mg/kg) or CLZ (5.0 mg/kg) was administered either during adolescence (∼P 51) or after the rats matured into adults (∼P 76 and 91). During adolescence, repeated OLZ or CLZ treatment produced a persistent inhibition of PCP-induced hyperlocomotion across the five test days. In the challenge test during adolescence, rats previously treated with OLZ did not show a significantly stronger inhibition of PCP-induced hyperlocomotion than those previously treated with vehicle (VEH). In contrast, those previously treated with CLZ showed a weaker inhibition than the VEH controls. When assessed in adulthood, the enhanced sensitivity to OLZ and the decreased sensitivity to CLZ were detected on ∼P 76, even on ∼P 91 in the case of OLZ. These findings suggest that adolescent OLZ or CLZ exposure can induce long-term alterations in antipsychotic response that persist into adulthood. © 2013 The Author(s).


Wang R.-X.,Mayo Medical School | Wang R.-X.,Nanjing Medical University | Chai Q.,Mayo Medical School | Chai Q.,Shandong Academy of Sciences | And 2 more authors.
Cardiovascular Research | Year: 2011

Aimsn-3 Polyunsaturated fatty acids (PUFAs) are known to protect the cardiovascular system and improve blood pressure control. These important dietary constituents are converted into bioactive metabolites, but their role in regulation of the cardiovascular system is unclear. In particular, the functions of the cytochrome P450 (CYP) metabolites of n-3 PUFAs remain virtually unexplored. In this study, we examined the effects of docosahexaenoic acid (DHA) on the regulation of large-conductance calcium-activated potassium (BK) channel activities in coronary arterial smooth muscle cells.Methods and resultsUsing whole-cell patch-clamp techniques, we found that DHA is a potent activator of BK currents in rat coronary arterial smooth muscle cells with an EC50 of 0.23 ± 0.03 M. This effect was abolished by pre-incubation with the CYP epoxygenase inhibitor, SKF525A (10 M). The effects of DHA on the BK channels were reproduced by 16,17-epoxydocosapentaenoic acid (16,17-EpDPE) with an EC50 of 19.7 ± 2.8 nM. The physiological role of the CYP metabolites of DHA was confirmed by measuring DHA-mediated vasodilatation in isolated rat coronary arteries. DHA dilated pressurized isolated coronary arteries in a dose-dependent manner, and the DHA effects were abolished after pre-treatment with SKF525A (10 M) or with iberiotoxin (100 nM). In addition, 16,17-EpDPE directly produced coronary vasodilatation that was iberiotoxin sensitive.ConclusionThese results suggest that DHA-mediated vasodilatation is mediated through CYP epoxygenase metabolites by activation of vascular BK channels. © 2010 The Author.


Niu Y.-M.,Hubei University of Medicine | Yuan H.,Nanjing Medical University | Zhou Y.,Anhui Medical University
Mediators of Inflammation | Year: 2014

Epidemiological studies have suggested that interleukin-17 (IL-17) polymorphisms are associated with cancer risk. However, the results of these studies are inconsistent. Therefore, we performed a meta-analysis to obtain a precise conclusion. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association of the IL-17A rs2275913G > A and IL-17F rs763780T > C polymorphisms with cancer risk. Publication bias and sensitivity analyses were performed to ensure the statistical power. Overall, 10 relevant case-control studies involving 4,516 cases and 5,645 controls were included. The pooled ORs with 95% CIs indicated that the IL-17A rs2275913G > A polymorphism was significantly associated with increased cancer risk (for A versus G: OR = 1.28, 95% CI: 1.16-1.41, P < 0.001, I 2 = 61.1 %; for GA versus GG: OR = 1.12, 95% CI: 1.02-1.23, P = 0.015, I 2 = 27.8 %; for AA versus GG: OR = 1.71, 95% CI: 1.38-2.41, P < 0.001, I 2 = 69.6 %; for GA + AA versus GG: OR = 1.23, 95% CI: 1.13-1.34, P < 0.001, I 2 = 6.4 %; for AA versus GG + GA: OR = 1.62, 95% CI: 1.27-2.07, P < 0.001, I 2 = 81.4 %). Succeeding analysis of HWE and stratified analysis of gastric cancer and the Asian (and Chinese) population revealed similar results. The IL-17F rs763780T>C polymorphism was also significantly associated with gastric cancer development. Overall, the present meta-analysis suggests that IL-17 polymorphisms increase the risk of developing cancer, particularly gastric cancer, in the Asian (and Chinese) population. © 2014 Yu-Ming Niu et al.


Chian R.-C.,McGill University | Chian R.-C.,Nanjing Medical University | Wang Y.,McGill University | Li Y.-R.,McGill University
Journal of Assisted Reproduction and Genetics | Year: 2014

Background: Recent advances in vitrification technology have markedly improved the efficacy of oocyte cryopreservation in terms of oocyte survival and pregnancy, as well as live birth rates. However, there still remains room for improvement in terms of vitrification techniques. Objective: The remaining challenges include the development of a less cytotoxic vitrification solution and of a safe vitrification device in order to have vitrification techniques considered as a standard clinical laboratory procedure. Methods: A systematic electronic literature search strategy has been conducted using PubMed (Medline) databases with the use of the following key words: oocyte, vitrification, cryoprotectant, preservation, pregnancy, and live birth. A list of published papers focused on the improvement of vitrification techniques to have the vitrification protocol standardized have been evaluated in full text for this review. Only key references were cited. Conclusions: Vitrification technology has made significant advancements and holds great promise, but many issues remains to be addressed before it becomes a standardized procedure in clinical laboratories such as the fact that oocyte vitrification may not require a high concentration of cryoprotectant in the vitrification solution when it has a suitable cooling and warming rate. There is also no consistent evidence that indicates the absence of risk to the vitrified oocytes when they are stored for a prolonged period of time in direct-contact with liquid nitrogen. The long-term development of infants born as a result of this technology equally remains to be evaluated. © 2014 Springer Science+Business Media New York.


Lv L.,Nanjing Medical University | Lv L.,Peoples Hospital of Jiangsu Province | Wang P.,Peoples Hospital of Jiangsu Province | Zhou X.,Peoples Hospital of Jiangsu Province | Sun B.,Nanjing Medical University
Tumor Biology | Year: 2013

Previous studies regarding the association of p53 codon 72 Arg/Pro polymorphism with hepatocellular carcinoma (HCC) risk have provided conflicting and inconclusive findings. Thus, a meta-analysis of all currently available publications was performed to address this issue. Eleven individual case-control studies involving a total of 2,718 cases and 3,752 controls were identified after a systematic search of the PubMed, Embase, Web of Science, and Wanfang databases. The strength of the association of p53 codon 72 Arg/Pro polymorphism with HCC risk was estimated by the pooled odds ratio (OR) with its corresponding 95 % confidence interval (95 % CI). Subgroup analyses stratified by ethnicity, source of controls, gender, hepatitis virus infection status, and family history of HCC were also conducted to assess the association. Overall, significantly increased risk of HCC was identified among carriers of the homozygous genotype ProPro (ORProPro vs. ArgArg = 1.38 (95 % CI, 1.03-1.85), P OR = 0.033; ORProPro vs. ArgArg + ArgPro = 1.28 (95 % CI, 1.03-1.59), P OR = 0.026). In subgroup analysis by ethnicity, the pooled results suggested that the p53 codon 72 Arg/Pro polymorphism was associated with an increased risk of HCC in Asians and Caucasians (for Asians, ORProPro vs. ArgArg + ArgPro = 1.17 (95 % CI, 1.02-1.34), P OR = 0.025; for Caucasians, ORProPro vs. ArgArg = 1.65 (95 % CI, 1.07-2.56), P OR = 0.025; OR ProPro vs. ArgArg + ArgPro = 1.74 (95 % CI, 1.14-2.66), P OR = 0.010). Subgroup analyses by source of controls and hepatitis virus infection status further demonstrated the significant association, whereas stratification factors involving gender and family history of HCC did not modify the association between p53 codon 72 Arg/Pro polymorphism and HCC risk. This meta-analysis suggests that the p53 codon 72 Arg/Pro polymorphism may play a critical role in the development of HCC, and gender and family history of HCC may not modulate the effect of p53 codon 72 Arg/Pro in HCC risk. © 2013 International Society of Oncology and BioMarkers (ISOBM).


Guo R.-B.,Nanjing Medical University | Wang G.-F.,The General Hospital of Jinan Military Area Command of PLA | Zhao A.-P.,Nanjing Medical University | Gu J.,Nanjing Medical University | And 2 more authors.
PLoS ONE | Year: 2012

Paeoniflorin (PF), the principal component of Paeoniae Radix prescribed in traditional Chinese medicine, has been reported to exhibit many pharmacological effects including protection against ischemic injury. However, the mechanisms underlying the protective effects of PF on cerebral ischemia are still under investigation. The present study showed that PF treatment for 14 days could significantly inhibit transient middle cerebral artery occlusion (MCAO)-induced over-activation of astrocytes and microglia, and prevented up-regulations of pro-inflamamtory mediators (TNFα, IL-1β, iNOS, COX2 and 5-LOX) in plasma and brain. Further study demonstrated that chronic treatment with PF suppressed the activations of JNK and p38 MAPK, but enhanced ERK activation. And PF could reverse ischemia-induced activation of NF-κB signaling pathway. Moreover, our in vitro study revealed that PF treatment protected against TNFα-induced cell apoptosis and neuronal loss. Taken together, the present study demonstrates that PF produces a delayed protection in the ischemia-injured rats via inhibiting MAPKs/NF-κB mediated peripheral and cerebral inflammatory response. Our study reveals that PF might be a potential neuroprotective agent for stroke. © 2012 Guo et al.


Cui F.,Nanjing Medical University | Wang J.,Nanjing Medical University | Chen D.,Norwegian University of Science and Technology | Chen Y.-J.,Nanjing Medical University
Oncology Reports | Year: 2011

Lung cancer is the most common cause of cancer-related death worldwide. Current investigations in the field of cancer research have intensively focused on the 'cancer stem cell' or 'tumor-initiating cell'. While CD133 was initially considered as a stem cell marker only in the hematopoietic system and the nervous system, the membrane antigen also identifies tumorigenic cells in certain solid tumors. In this study, we investigated the human lung cancer cell lines A549, H157, H226, Calu-1, H292 and H446. The results of real-time PCR analysis after chemotherapy drug selection and the fluorescence-activated cell sorting analysis showed that CD133 only functioned as a marker in the small cell lung cancer line H446. The sorted CD133+ subset presented stem cell-like features, including self-renewal, differentiation, proliferation and tumorigenic capacity in subsequent assays. Furthermore, a proportion of the CD133+ cells had a tendency to remain stable, which may explain the controversies arising from previous studies. Therefore, the CD133+ subset should provide an enriched source of tumor-initiating cells among H446 cells. Moreover, the antigen could be used as an investigative marker of the tumorigenic process and an effective treatment for small cell lung cancer.


Yao Z.,Tongji University | Shen C.,Nanjing Medical University | Zhong Y.,Fudan University
Clinical Therapeutics | Year: 2015

Background: Pregabalin has been used as an adjuvant in some trials to control postoperative pain after gynecologic surgery. However, the potential clinical advantage remains debatable. Objective: We performed a meta-analysis of clinical trials of pregabalin to evaluate its ability to control acute postoperative pain after gynecologic surgery. Methods: We searched PubMed, ScienceDiret, and the Cochrane Library of Randomized Controlled Trials up to January 2014. We performed a systematic review and meta-analysis of prospective controlled studies reporting pregabalin for gynecologic surgery. The primary outcome was pain outcomes and postoperative cumulative opioid consumption. Data were reported as weighted mean differences (WMDs) and 95% CIs. The secondary outcome was adverse effects after surgery. Results: Six valid randomized trials met the eligibility criteria and were included in the meta-analysis. Pooled data were collected from 452 patients between 2007 and 2012 (These trials were separately conducted in Greece 2012, India 2011-2012, Turkey 2011, Denmark 2009 and Australia 2007). The pregabalin-treated patients consumed fewer opioids during the first 24 hours postoperatively (WMD, -8.50 mg; 95% CI, -11.29 to -5.71 mg; P < 0.00001). Pain intensity at rest and on movement or coughing revealed a statistically significant pain relief effect of pregabalin during 24 hours postoperatively (at rest: WMD, -6.20 mm; 95% CI, -11.83 to -0.58 mm; P = 0.03; on movement or coughing: WMD, -5.32 mm; 95% CI, -9.73 to -0.91 mm; P = 0.02). No differences were found between the pregabalin and control groups for the adverse effects. Conclusions: Pregabalin has an analgesic and opioid-sparing effect and does not increase the frequency of adverse effects in acute postoperative pain management after gynecologic surgery. © 2015 Elsevier HS Journals, Inc. All rights reserved.


Zhang W.-B.,Nanjing Medical University | Zhong W.-J.,Shanghai Stomatological Disease Center | Wang L.,Nanjing Medical University
Bone | Year: 2014

Human adipose-derived stem cells (hASCs) have become a highly attractive source of seed cells in bone regenerative. It has become a key issue how to effectively improve osteogenic differentiation of hASCs in the bone tissue engineering.Numerous regulatory pathways dominate osteogenic differentiation of hASCs involve transcriptional factors and signaling molecules. However, how these factors combine with each other to regulate hASCs osteogenic differentiation still remain to be illustrated. The identification of microRNAs will illuminate this and might permit finely tuning the osteogenic differentiation process. Here, we present evidence that miR-218 acts as a positive regulator of hASCs osteogenesis. Real-time PCR shows that miR-218 was up-regulated during osteogenic differentiation. Overexpression of exogenous miR-218 enhanced osteogenic differentiation in vitro, whereas inhibition of miR-218 would suppress osteogenic differentiation. Furthermore, miR-218 directly targeted SFRP2 and DKK2, which is a WNT signaling pathway antagonist, and enhanced Wnt/β-catenin signaling activity. Finally, we found that mimicking Wnt/β-catenin signal strengthened the expression level of miR-218, while blocking the signal attenuated the expression level of miR-218. This feed-forward regulatory circuit provides additional insight into how miRNAs acting as a signal amplifier interact with signal molecules during hASCs osteogenic differentiation. Taken together, we have established a regulatory network with a central role for the miR-218 in hASCs osteogenic differentiation. © 2013 Elsevier Inc.


Xu Y.,Nantong University | An Y.,First Peoples Hospital of Changzhou | Wang X.,Nanjing Medical University | Zha W.,Nantong University | Li X.,Nanjing Medical University
Oncology Reports | Year: 2014

The HH signaling pathway is a 'core' signal transduction pathway in pancreatic cancer that promotes the tumorigenesis of pancreatic cancers via enhancing cell proliferation, increasing invasion and metastasis and protecting against apoptosis. In the present study, we found that HH signaling regulates autophagy in pancreatic cancer cells. Activation of HH signaling inhibits autophagy, while inhibition of the HH pathway induces autophagy. Although the role of autophagy in cell survival and apoptosis may depend on tumor type and the microenvironment, our data clearly demonstrated that GANT61-induced autophagy contributed to reduced viability and increased apoptosis in pancreatic cancer cells both in vivo and in vitro, and these effects were reversed by the autophagy inhibitor, 3-MA. We propose that HH signaling by regulating autophagy plays an important role in determining the cellular response to HH-targeted therapy in pancreatic cancer and further investigation of the interaction between autophagy and HH signaling is particularly important.


Sha S.,Nanjing Medical University | Qu W.-J.,Nanjing Medical University | Li L.,Nanjing Medical University | Lu Z.-H.,Nanjing Medical University | And 2 more authors.
CNS Neuroscience and Therapeutics | Year: 2013

Summary: Aims: This study investigated the influence of sigma-1 receptor (σ1R) deficiency on adult neurogenesis. Methods: We employed 8-week-old male σ1R knockout (σ1R-/-) mice to examine the proliferation and differentiation of progenitor cells, and the survival and neurite growth of newborn neurons in hippocampal dentate gyrus (DG). Results: In comparison with wild-type (WT) littermates, the numbers of 24-h-old BrdU+ cells and Ki67+ cells in σ1R-/- mice increased, while the number of 28-day-old BrdU+ cells decreased without changes in proportion of BrdU+/NeuN+ cells and BrdU+/GFAP+ cells. The neurite density of newborn neurons was slightly reduced in σ1R-/- mice. In DG granular cells, N-methyl-d-aspartate (NMDA)-activated current (INMDA) and phosphorylation of NMDA receptor (NMDAr) NR2B were reduced in σ1R-/- mice without the alteration of NR2B expression and membrane properties compared to WT mice. The NR2B antagonist abolished the difference in INMDA between σ1R-/- mice and WT mice. The application of NMDAr agonist in σ1R-/- mice prevented the over-proliferation of cells and reduction in newborn neurons, but it had no effects on the hypoplastic neurite. The administration of NMDAr antagonist in WT mice enhanced the cell proliferation and depressed the survival of newborn neurons. Conclusion: The σ1R deficiency impairs neurogenesis in DG through down-regulation of NMDArs. © 2013 John Wiley & Sons Ltd.


Zhang S.,Fudan University | Zhang S.,Soochow University of China | Chen H.,Fudan University | Zhao X.,Fudan University | And 7 more authors.
Oncogene | Year: 2013

REV3Lp, the catalytic subunit of DNA polymerase zeta, is the major participant in translesion DNA synthesis. Recent evidence suggests that REV3L has an important role in the maintenance of genome stability despite its mutagenic characteristics. Such a function makes it a cancer susceptibility candidate gene. To investigate association between REV3L polymorphisms and lung cancer risk in a Chinese population, we first genotyped 15 common polymorphisms of the REV3L gene and found that three single nucleotide polymorphisms (rs465646, rs459809 and rs1002481) were significantly associated with lung cancer risk. One of the strongest associations observed was for the 3′-terminal untranslated region (3′UTR) 460 T>C polymorphism (rs465646) (adjusted odds ratio (OR)=0.69 for TC/CC; P=0.007, compared with TT). Similar results were obtained in a subsequent replication study (adjusted OR=0.72; P=0.016). Combined data from the two studies of 1072 lung cancer patients and 1064 cancer-free controls generated an even stronger association (adjusted OR=0.71; P=3.04 × 10-4). This 3′UTR 460 T>C variant was predicted to modulate the binding of several micro RNAs. Surface plasmon resonance analysis and luciferase assays showed that the T allele demonstrated a stronger binding affinity for miR-25 and miR-32, resulting in significantly weaker reporter expression levels. Additional experiments revealed that miR-25/32 could downregulate endogenous REV3L. Furthermore, the tumor-suppressing role of REV3L was confirmed by the foci formation assay. These results support our hypothesis that the REV3L rs465646 variant modifies lung cancer susceptibility in Chinese Han population by affecting miRNA-mediated gene regulation. © 2013 Macmillan Publishers Limited All rights reserved.


Wang F.,Tongji University | Xiao W.,Fudan University | Sun J.,Nanjing Medical University | Han D.,Fudan University | Zhu Y.,Tongji University
Tumor Biology | Year: 2014

As the most aggressive malignant primary human brain tumor, glioblastoma is noted with extremely poor patient survival. Previous studies have demonstrated that expression of matrix metalloproteinase-9 (MMP9) in glioblastoma cells is critical for cancer metastasis. However, the molecular signaling pathways that control MMP9 activation remain undefined. Here, we reported a strong negative correlation of microRNA (miRNA)-181c levels with either MMP9 levels or activation of epidermal growth factor receptor (EGFR) signaling in glioblastoma patients. EGF-induced activation of EGFR in a human glioblastoma line, A-172 cells, increased MMP9 expression through activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway, without affecting expression of miRNA-181c. On the other hand, overexpression of miRNA-181c in A-172 cells inhibited MMP9 expression by inhibiting Akt phosphorylation, but not phosphorylation of EGFR receptor. Taken together, these findings suggest that EGFR signaling activates downstream PI3K/Akt to increase MMP9 expression in glioblastoma, while phosphorylation of Akt is a control point by miRNA-181c. Our work thus provides new insights into the molecular basis underlying the metastasis of glioblastoma. © 2014, International Society of Oncology and BioMarkers (ISOBM).


Zhao F.,Nanjing Medical University | Chen X.,Nanjing Medical University | Meng T.,Jiangyan Peoples Hosptial | Hao B.,Nanjing Medical University | And 2 more authors.
BMC Cancer | Year: 2012

Background: In vitro and in vivo studies have suggested that osteopontin (OPN) is associated with many types of cancers. However, no studies have reported the incidence of OPN polymorphisms and the risk of gastric cancer. The aim of this study was to investigate the association between OPN polymorphisms and gastric cancer in a Chinese patient population.Methods: Three genetic variants in the OPN promoter were genotyped using direct sequencing in 200 gastric cancer patients and 200 gender- and age-matched cancer-free controls. The 4-year survival curve was calculated using the Kaplan-Meier method and compared using the log-rank test for each single nucleotide polymorphism (SNP) site. We measured the promoter activity of the -443 T → C polymorphism using a dual luciferase reporter assay.Result: For the variant at nt -443 (CC), there was a significant difference between the number of patients with stage IV and those with stage I gastric cancer (IA + IB; P = 0.014) and between those with stage IV and all other stages of gastric cancer (IA + IB + II + III; P = 0.02). For the variant at nt -443 (CT), there was a significant difference between the number of gastric cancer patients with stage IV and those with stage II (P = 0.013). The survival rates for patients with the C/C genotype were significantly lower than for patients with the other two genotypes (C/T, T/T). Moreover, significantly higher luciferase activities were observed in the pGL3-C construct compared to the pGL3-T construct.Conclusions: This study provides the first evidence that variation at nt -443 in the OPN promoter increases the potential for gastric cancer metastasis and subsequent death in the Chinese population. © 2012 Zhao et al.; licensee BioMed Central Ltd.


Xin H.,Fudan University | Xin H.,Nanjing Medical University | Sha X.,Fudan University | Jiang X.,Fudan University | And 3 more authors.
Biomaterials | Year: 2012

Therapeutic effect of glioma is often limited due to low permeability of delivery systems across the Blood-Brain Barrier (BBB) and poor penetration into the tumor tissue. In order to overcome the two barriers, we proposed Angiopep-conjugated PEG-PCL nanoparticles (ANG-PEG-NP) as a dual targeting drug delivery system for glioma treatment basing on low density lipoprotein receptor related protein (LRP) receptor not only over-expressed on BBB but also on glioma cells. This system could transport across BBB through LRP-mediated transcytosis and then targeted glioma via LRP-mediated endocytosis. In this study, we evaluated the preliminary availability and safety of ANG-PEG-NP for glioma treatment. The penetration, distribution, and accumulation into 3D glioma spheroid and in vivo glioma region of ANG-PEG-NP were obviously higher than that of plain PEG-PCL nanoparticles (PEG-NP). The anti-glioblastoma efficacy of paclitaxel (PTX) loading ANG-PEG-NP was significantly enhanced as compared to that of Taxol and PEG-NP. Preliminary safety results showed that no acute toxicity to hematological system, liver, kidney and brain tissue was observed after intravenous administration with a dose of 100 mg/kg blank ANG-PEG-NP per day for a week. Results indicate that Angiopep-conjugated dual targeting PEG-PCL nanoparticle is a potential brain targeting drug delivery system for glioma treatment. © 2012 Elsevier Ltd.


Wang W.,Texas Tech University Health Sciences Center | Qin J.-J.,Texas Tech University Health Sciences Center | Voruganti S.,Texas Tech University Health Sciences Center | Wang M.-H.,Texas Tech University Health Sciences Center | And 7 more authors.
Gastroenterology | Year: 2014

Background & Aims The oncogene MDM2, which encodes an E3 ubiquitin ligase, is overexpressed in pancreatic cancers and is therefore a therapeutic target. Current inhibitors of MDM2 target the interaction between MDM2 and P53; these would have no effect on cancer cells that do not express full-length P53, including many pancreatic cancer cells. We searched for a compound that specifically inhibits MDM2 itself. Methods We performed a virtual screen and structure-based design to identify specific inhibitors of MDM2. We tested the activities of compounds identified on viability, proliferation, and protein levels of HPAC, Panc-1, AsPC-1, and Mia-Paca-2 pancreatic cancer cell lines. We tested whether intraperitoneal injections of one of the compounds identified affected growth of xenograft tumors from Panc-1 cells, or orthotopic tumors from Panc-1 and AsPC-1 cells (injected into pancreata), in nude mice. Results We identified a compound, called SP141, which bound directly to MDM2, promoting its auto-ubiquitination and degradation by the proteasome. The compound reduced levels of MDM2 in pancreatic cancer cell lines, as well as their proliferation, with 50% inhibitory concentrations <0.5 μM (0.38-0.50 μM). Increasing concentrations of SP141 induced increasing levels of apoptosis and G2-M-phase arrest of pancreatic cancer cell lines, whether or not they expressed functional P53. Injection of nude mice with SP141 (40 mg/kg/d) inhibited growth of xenograft tumors (by 75% compared with control mice), and led to regression of orthotopic tumors. Conclusions In a screen for specific inhibitors of MDM2, we identified a compound called SP141 that reduces levels of MDM2 in pancreatic cancer cell lines, as well as their proliferation and ability to form tumors in nude mice. SP141 is a new class of MDM2 inhibitor that promotes MDM2 auto-ubiquitination and degradation. It might be further developed as a therapeutic agent for pancreatic cancer. © 2014 AGA Institute.


Ji C.,Nanjing Medical University | Yang B.,Fudan University | Yang Y.-L.,Nanjing Medical University | He S.-H.,Nanjing Medical University | And 3 more authors.
Oncogene | Year: 2010

New chemotherapy-enhancing strategies are needed for better cancer therapy. Previous studies suggest that exogenous cell-permeable C6 ceramide may be a useful adjunct to the anti-tumor effects of chemotherapeutic agents (such as Taxol) against multiple cancers. Here we demonstrate that exogenous cell-permeable C6 ceramide largely sensitizes multiple progressive cancer cell lines to Doxorubicin-induced cell death and apoptosis. We found for the first time that Doxorubicin induces AMP-activated protein kinase (AMPK) activation in a reactive oxygen species-dependent manner. Activation of AMPK contributes to Doxorubicin-induced cancer cell death and apoptosis. Inhibition of AMPK by small interfering RNA knockdown or a pharmacological inhibitor reduces Doxorubicin-induced cancer cell apoptosis, whereas AMPK activator AICAR enhances it. Importantly, we found that C6 ceramide largely enhances Doxorubicin-induced activation of AMPK, which leads to mTOR complex 1 inhibition and chemo-sensitization. Our data suggest that the combination of C6 ceramide with traditional chemotherapy drugs such as Doxorubicin may have the potential to be used as a new therapeutic intervention against multiple cancers. © 2010 Macmillan Publishers Limited All rights reserved.


Liu W.,Nanjing Medical University | Zhang S.,Nanjing Medical University | Gu S.,Seirei Christopher College | Sang L.,Liaoning Medical University | Dai C.,Nanjing Medical University
Cellular Physiology and Biochemistry | Year: 2015

Background/Aims: Transplantation of mesenchymal stem cells (MSCs) has been shown to alleviate dextran sulfate sodium (DSS)-induced colitis through modulation of transforming growth factor β (TGFβ) receptor signaling. However, the exact molecular mechanisms are not known. Methods: Here, we transplanted primary mouse MSCs or injected TGFβ1 into mice with DSS-induced colitis. Cells were purified by flow cytometry. Gene expression was analyzed by RT-qPCR. Results: We found that MSCs significantly alleviated the DSS-induced colitis, and the major sources for TGFβ1 were macrophages that were recruited by MSCs. Specific ablation of macrophages completely abolished the anti-inflammatory effects of MSCs. On the other hand, TGFβ1 administration, without the presence of MSCs, was sufficient to reduce the severity of DSS-induced colitis. Conclusions: Taken together, our data suggest that MSCs transplantation may recruit macrophages to produce TGFβ1, which mitigates the pathology of colitis. Thus, MSCs transplantation appears to be a promising therapy for severe enteritis. © 2015 S. Karger AG, Basel.


Liu K.,Nanjing Medical University | Liu K.,Fudan University | Xie P.,Nanjing Medical University | Peng W.,Fudan University | Zhou Z.,Fudan University
Journal of Magnetic Resonance Imaging | Year: 2014

Purpose To retrospectively analyze MRI and computed tomographic (CT) findings from renal carcinomas associated with Xp11.2 translocations/TFE3 gene fusions (Xp11-RCC). Materials and Methods Institutional review board permission was obtained to review patient medical records, and the requirement for informed consent was waved. The clinical and MRI/CT features of five cases with Xp11-RCC that were confirmed by pathology were analyzed retrospectively. The image characteristics included the lesion location and size, contribution of cystic and solid components, intratumoral necrosis or hemorrhage, invasion of perinephric tissue and renal sinus, lymphadenopathy, major venous or arterial vascular invasion, pattern of the tumor growth, intratumor calcification and lipids, homogeneity of SI on T2-weighted images, attenuation and SI of the mass with respect to the normal renal cortex on precontrast and contrasted CT/MRI images, tumor SIs, tumor attenuations and tumor-to-cortex indices, homogeneity of enhancement on the contrasted images. Results The mean age was 32 years (range, 15-47 years). Most patients (4/5) were women. All tumors showed a cortical location. The average tumor size was 9 cm (range, 4-18 cm). Four tumors comprised a predominantly solid lesion with focal necrosis, and one tumor comprised a solid lesion with significant necrosis. All tumors showed intertumor hemorrhage, infiltrative growth and invasion of the perirenal adipose/renal sinus. Four cases showed retroperitoneal lymphadenopathy, of which one case showed simultaneous mediastinal and supraclavicular lymphadenopathy. All tumors from four cases showed mild hyperintensity on T1-weighted MRI images, and three tumors showed hypointensity on T2-weighted MRI images relative to the renal cortex except for 1 tumor that showed significant hemorrhage and a relative hyperintensity. For 3 cases who were imaged with CT, two tumors imaged using nonenhanced CT images showed mild hyperdensity relative to the renal cortex. Calcification was noted in all three tumors. All tumors showed mild, persistent enhancement. Conclusion Typical Xp11-RCC manifests as an advanced, solid renal mass with mild persistent enhancement, a prevalence of intertumor hemorrhage/calcification, and a cortical epicenter location. The predilection for children and young adults is a useful clinical feature when confirming a diagnosis of Xp11-RCC. © 2013 Wiley Periodicals, Inc.


Wu Z.,Nanjing Medical University | Huang X.,Wuxi Traditional Medicine Hospital | Huang X.,Nanjing Medical University | Zou Q.,Fudan University | Guo Y.,Nanjing Medical University
Journal of Experimental and Clinical Cancer Research | Year: 2013

Mir-29 microRNA families are involved in regulation of various types of cancers. Although Mir-29 was shown to play an inhibitory role in tumorigenesis, the role of Mir-29 in breast cancer still remains obscure. In this study, we showed that Mir-29a is the dominant isoform in its family in mammary cells and expression of Mir-29a was down-regulated in different types of breast cancers. Furthermore, over-expression of Mir-29a resulted in significant slower growth of breast cancer cells and caused higher percentage of cells at G0/G1 phase. Consistent with this over-expression data, knockdown of Mir-29a in normal mammary cells lead to higher cell growth rate, and higher percentage of cells entering S phase. We further found that Mir-29a negatively regulated expression of B-Myb, which is a transcription factor associated with tumorigenesis. The protein levels of Cyclin A2 and D1 are consistent with the protein level of B-Myb. Taken together, our data suggests Mir-29a plays an important role in inhibiting growth of breast cancer cells and arresting cells at G0/G1 phase. Our data also suggests that Mir-29a may suppress tumor growth through down-regulating B-Myb. © 2013 Wu et al.; licensee BioMed Central Ltd.


Cheng Z.,Vanderbilt University | Cheng Z.,Nanjing Medical University | Gong Y.,Vanderbilt University | Ma Y.,Vanderbilt University | And 7 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Glioblastoma is refractory to conventional therapies. The bromodomain and extraterminal domain (BET) proteins are epigenetic readers that selectively bind to acetylated lysine residues on histone tails. These proteins recently emerged as important therapeutic targets in NUT midline carcinoma and several types of hematopoietic cancers. In this study, the therapeutic potential of a novel BET bromodomain inhibitor, JQ1, was assessed in a panel of genetically heterogeneous glioblastoma samples. Experimental Design: The antineoplastic effects of JQ1 were shown using ex vivo cultures derived from primary glioblastoma xenograft lines and surgical specimens of different genetic background. The in vivo efficacy was assessed in orthotopic glioblastoma tumors. Results: We showed that JQ1 induced marked G1 cell-cycle arrest and apoptosis, which was phenocopied by knockdown of individual BET family members. JQ1 treatment resulted in significant changes in expression of genes that play important roles in glioblastoma such as c-Myc, p21 CIP1/WAF1, hTERT, Bcl-2, and Bcl-xL. Unlike the observations in some hematopoietic cancer cell lines, exogenous c-Myc did not significantly protect glioblastoma cells against JQ1. In contrast, ectopically expressed Bcl-xL partially rescued cells from JQ1-induced apoptosis, and knockdown of p21 CIP1/WAF1 attenuated JQ1-induced cell-cycle arrest. Cells genetically engineered for Akt hyperactivation or p53/Rb inactivation did not compromise JQ1 efficacy, suggesting that these frequently mutated signaling pathways may not confer resistance to JQ1. Furthermore, JQ1 significantly repressed growth of orthotopic glioblastoma tumors. Conclusion: Our results suggest potentially broad therapeutic use of BET bromodomain inhibitors for treating genetically diverse glioblastoma tumors. ©2013 AACR.


Liu X.Z.,Nanjing Medical University | Fang H.,Nanjing University
Scientometrics | Year: 2012

In our previous work (Scientometrics 87:293-301, 2011), a numerical model of over-competitive research funding in "peer-group-assessed-grant-based-funding-system" was proposed and the process was firstly investigated quantitatively. The simulation results show that the mainstream of a very complicated research topic could obtain monopoly supremacy with only the aid of the mechanism the model described. Here, the numbers of publications of cosmology back to 1950 are utilized to empirically test this positive feedback mechanism. The development of three main theories of cosmology, Big Bang, Steady State and Plasma Universe, are revisited. The later two, which are non-mainstream opinions, both state in their peer reviewed papers, that their theories fit the phenomena that support the standard theory. The ratios of publications of the orthodox theory, Big Bang, approximately satisfy the numeric calculating results of our model. The reason for the discrepancy between the model and actual situation is discussed. A further question about the controversy is presented. © 2011 Akadémiai Kiadó, Budapest, Hungary.


Tan C.-C.,Qingdao University | Yu J.-T.,Qingdao University | Yu J.-T.,Ocean University of China | Yu J.-T.,Nanjing Medical University | And 6 more authors.
Neurobiology of Aging | Year: 2014

Neurodegenerative diseases, such as Alzheimer's disease Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, share a common cellular and molecular pathogenetic mechanism involving aberrant misfolded protein or peptide aggregation and deposition. Autophagy represents a major route for degradation of aggregated cellular proteins and dysfunctional organelles. Emerging studies have demonstrated that up-regulation of autophagy can lead to decreased levels of these toxic aggregate-prone proteins, and is beneficial in the context of aging and various models of neurodegenerative diseases. Understanding the signaling pathways involved in the regulation of autophagy is crucial to the development of strategies for therapy. This review will discuss the cellular and molecular mechanisms of autophagy and its important role in the pathogenesis of aging and neurodegenerative diseases, and the ongoing drug discovery strategies for therapeutic modulation. © 2014 Elsevier Inc.


He S.,Nanjing Medical University | Zhang H.,Hainan Medical College | Zeng X.,Nanjing Medical University | Yang P.,McMaster University
Current Molecular Medicine | Year: 2012

Allergic diseases are major diseases involving approximately 22% of world population. In recent years, accumulated evidence suggests that apart from IgE, allergens may provoke immediate allergic reactions via other pathways such as IgG, toll like receptor (TLR) dependent ones. In addition, large numbers of low molecular weight molecules (LMWM) such as sphingosine-1-phosphate and iodinated contrast agents have been observed to cause allergy. Therefore, the current definition of allergy, a group of IgE mediated diseases appears difficult to cover all allergic reactions. Since even IgE dependent allergic reactions are carried out through activation of mast cells and basophils, and all allergens mentioned above can activate these cells, we hypothesize that allergic reactions are mast cell and basophil mediated inflammatory process as it is the activated mast cells and basophils that initiate the pathological process of the immediate allergic reactions, whereas IgE only serves as one of the activators of these cells. © 2012 Bentham Science Publishers.


Xu N.,Nanjing University | Wang F.,Nanjing Medical University | Lv M.,Nanjing Medical University | Cheng L.,Nanjing Medical University
Biomedicine and Pharmacotherapy | Year: 2015

Breast cancer (BC) is the most commonly diagnosed cancer and the second leading cause of cancer death among women. Long non-coding RNAs (lncRNAs) are key regulators of gene expression. Numerous lncRNAs have performed critical roles in cancer biology including breast cancer (BC). The expression levels of certain lncRNAs are associated with tumor development, recurrence, metastasis, and prognosis. However, the potential roles that lncRNAs regulate breast cancer tumorigenesis and tumor progression are still poorly understood. To investigate the potential roles of lncRNAs in the breast cancer, we constructed BC related lncRNA libraries by using microarray. Microarray expression profiling suggests 790 up-regulated and 637 down-regulated (log fold-change. > 2.3) lncRNAs were differently expressed between BC tissues and its paired adjacent tissues. Furthermore, we found differently expressed lncRNAs associated with immune regulation. RP4-583P15.10, an up-regulated lncRNA, was found to be located downstream of the natural antisense of the ZBTB46 gene, which may regulated breast cancer through influence immune system. In conclusion, our results for the first time indicate that distinct lncRNAs expression profiles of BC, which related to the immune network, may provide information for further research on immune regulation during the BC process. © 2014 Elsevier Masson SAS.


Li P.,Nanjing University | Guo W.,Nanjing University | Du L.,Nanjing University | Zhao J.,Nanjing University | And 5 more authors.
Clinical Science | Year: 2013

PE (pre-eclampsia), a pregnancy-specific disorder, is characterized by increased trophoblast cell death and deficient trophoblast invasion and reduced trophoblast-mediated remodelling of spiral arteries. The present study was performed to determine the function of miR-29b (microRNA-29b) in trophoblast cells and its underlying role in the pathogenesisof PE. The prediction of miR-29b target genes was performed using computer-based programs, including Targetscan, Pictar andmiRBase. The function of these target genes was analysed further by gene ontology (GO). The effects of miR-29b on apoptosis, and invasion and angiogenesis of trophoblast cell lines (HTR-8/SVneo, BeWo and JAR) were examined by flow cytometryand Matrigel assay respectively. We found that miR-29b induced apoptosis and inhibited invasion and angiogenesis of trophoblast cells. Further studies confirmed that miR-29b regulated the expression of MCL1 (myeloid cell leukaemia sequence 1), MMP2 (encoding matrix metallproteinase 2), VEGFA (vascular endothelial growth factor A) and ITGB1 (integrin β1) genes by directly binding to their 3'-UTRs (untranslated regions). Moreover, we identified that there was an inverse correlation between miR-29b and its target genes in subjects with PE. Taken together, these findings support a novel role for miR-29b in invasion, apoptosis and angiogenesis of trophoblast cells, and miR-29b may become a new potential therapeutictarget for PE. © The Authors Journal compilation © 2013 Biochemical Society.


Zhou X.,Nanjing Medical University | Zhou X.,Soochow University of China | An G.,Soochow University of China | Lu X.,Nanjing Medical University
Clinical Science | Year: 2015

There is growing evidence that H2S has beneficial effects in treatment of various cardiovascular diseases. However, it remains unclear whether H2S can attenuate the development of diabetic cardiomyopathy (DCM). The present study was designed to investigate the protective effects of H2S against DCM. Diabetic rats were induced by intraperitoneal injection of streptozotocin and administered with the H2S donor sodium hydrosulfide (NaHS) for 16 weeks. Neonatal rat cardiomyocytes (NRCMs) transfected with nuclear factor erythroid 2-related factor 2 (Nrf2)-specific siRNA or pre-treated with SP600125, SB203580 or LY294002 prior to high glucose exposure were used to confirm the involvement of Nrf2/antioxidant response element (ARE), mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K)/Akt signalling pathways in the protective effects of H2S. The echocardiographical and histopathological data indicated that H2S improved left ventricular function and prevented cardiac hypertrophy and myocardial fibrosis in diabetic rats. H2S was also found to attenuate hyperglycaemiainduced inflammation, oxidative stress and apoptosis in the cardiac tissue. In addition, H2S could activate the Nrf2/ARE signalling pathway and up-regulate the expression of antioxidant proteins haem oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) in the diabetic myocardium. Moreover, H2S was found to reduce high glucose-induced apoptosis both in vitro and in vivo by inhibiting c-Jun N-terminal kinase (JNK) and p38 MAPK pathways and activating PI3K/Akt signalling. In conclusion, our study demonstrates that H2S alleviates the development of DCM via attenuation of inflammation, oxidative stress and apoptosis. © 2015 Biochemical Society.


Sun Q.,Nanjing University | Sun Q.,Nanjing Medical University | Zou X.,Nanjing University | Zhang T.,Nanjing Medical University | And 3 more authors.
Gynecologic Oncology | Year: 2014

Objective Vasculogenic mimicry (VM) indicates that aggressive cancer cells can form de novo vascular networks and provide a perfusion pathway for rapidly growing tumors. MiR-200a has been reported significantly deregulated in ovarian cancer. However, miR-200a regulation of VM and its clinical significance in ovarian cancer remain not elucidated. Methods In this study, we identified the VM structure by CD34-PAS staining in ovarian cancer tissue. MiR-200a and protein expression was tested by quantitative RT-PCR and western blot. Bioinformatics prediction, luciferase assay and intervention experiments were employed to identify the target of miR-200a. Results We certified the VM structure in ovarian cancer, and found that the VM positive rate was significantly associated with tumor grade, stage and metastasis. Further study showed that miR-200a expression levels were significantly lower in VM positive ovarian cancer. In addition, our results suggested that miR-200a inhibited VM by negatively regulated EphA2 expression. Consistently, the inverse correlation of miR-200a and EphA2 has also been found in ovarian cancer patients. Moreover, the expression of miR-200a/EphA2 was significantly associated with patient's clinicopathological parameter, such as tumor stage and metastases. Kaplan-Meier curves confirmed that the patients with low miR-200a expression and/or VM positive had a significantly shorter overall survival. Conclusions Our research demonstrates that VM, miR-200a and EphA2 play key roles in the progression and prognosis of ovarian cancer, and for the first time suggests that miR-200a inhibits VM by directly regulating EphA2. Therefore, we might have identified a genetic mechanism underlying the involvement of miR-200a in ovarian cancer VM. © 2014 Elsevier Inc.


Tian W.,Nanjing Medical University | Xu H.,Nanjing Medical University | Fang F.,Nanjing Medical University | Chen Q.,Nanjing Medical University | And 2 more authors.
Hepatology | Year: 2013

Chronic inflammation, inflicted by the spillover of proinflammatory mediators, links metabolic dysfunction to nonalcoholic steatohepatitis (NASH). The epigenetic maneuverings that underscore accelerated synthesis of proinflammatory mediators in response to nutritional inputs are not clearly defined. Here we report that the ATP-dependent chromatin remodeling proteins Brahma-related gene 1 (Brg1) and Brahma (Brm) were up-regulated in vitro in cultured hepatocytes treated with free fatty acid or glucose and in vivo in animal models of NASH. Occupancy of Brg1 and Brm on the promoter regions of proinflammatory genes was increased in vitro in cells and ex vivo in liver tissues. Estradiol suppressed the induction and recruitment of Brg1/Brm by palmitate. Recruitment of Brg1 and Brm relied on nuclear factor kappa B/p65; reciprocally, Brg1 and Brm contributed to the stabilization of p65 binding. Importantly, overexpression of Brg1/Brm enhanced, whereas knockdown of Brg1/Brm attenuated, the induction of proinflammatory mediators in hepatocytes challenged with excessive nutrient. Mechanistically, Brg1 and Brm were involved in the maintenance of a chromatin microenvironment marked by active histone modifications and friendly to the access of the general transcriptional machinery. Finally, depletion of Brg1/Brm by short hairpin RNA attenuated the release of proinflammatory mediators in the liver and significantly ameliorated hepatic pathology in NASH mice. Conclusion: Our data illustrate a Brg1-dependent pathway that connects the epigenetic regulation of proinflammatory genes to the pathogenesis of NASH and point to a potential druggable target in the therapeutic intervention of NASH. © 2013 American Association for the Study of Liver Diseases.


Li C.,Nanjing Medical University | Fang Z.,Nanjing University | Jiang T.,Nanjing University | Zhang Q.,Nanjing Medical University | And 3 more authors.
BMC Medical Genomics | Year: 2013

Background: In order to identify miRNAs expression profiling from genome-wide screen for diagnosis of acute myocardial infarction (AMI) and angina pectoris (AP), we investigated the altered profile of serum microRNAs in AMI and AP patients at a relative early stage. Methods. Serum samples were taken from 117 AMI patients, 182 AP patients and 100 age-and gender-matched controls. An initial screening of miRNAs expression was performed by Solexa sequencing. Differential expression was validated using RT-qPCR in individuals samples, the samples were arranged in a two-phase selection and validation. Results: The Solexa sequencing results demonstrated marked upregulation of serum miRNAs in AMI patients compared with controls. RT-qPCR analysis identified a profile of six serum miRNAs (miR-1, miR-134, miR-186, miR-208, miR-223 and miR-499) as AMI biomarkers. MiR-208 and miR-499 were elevated higher in AP cases than in AMI cases. The ROC curves indicated a panel of six miRNAs has a great potential to offer sensitive and specific diagnostic tests for AMI. More especially, the panel of six miRNAs presents significantly differences between the AMI and AP cases. Conclusions: The six-miRNAs signature identified from genome-wide serum miRNA expression profiling may serves as a fingerprint for AMI and AP diagnosis. © 2013 Li et al.; licensee BioMed Central Ltd.


Cheng W.,Nanjing University | Su Y.,Nanjing Medical University | Xu F.,Nanjing University
Molecular Cancer | Year: 2013

Comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer and ~ 140 driver genes have been identified, but not all of them have been extensively investigated. CHD1L (chromodomain helicase/ATPase DNA binding protein 1-like gene) or ALC1 (amplified in liver cancer 1) is a newly identified oncogene located at Chr1q21 and it is amplified in many solid tumors. Functional studies of CHD1L in hepatocellular carcinoma and other tumors strongly suggested that its oncogenic role in tumorigenesis is through unleashed cell proliferation, G1/S transition and inhibition of apoptosis. The underlying mechanisms of CHD1L activation may disrupt the cell death program via binding the apoptotic protein Nur77 or through activation of the AKT pathway by up-regulation of CHD1L-mediated target genes (e.g., ARHGEF9, SPOCK1 or TCTP). CHD1L is now considered to be a novel independent biomarker for progression, prognosis and survival in several solid tumors. The accumulated knowledge about its functions will provide a focus to search for targeted treatment in specific subtypes of tumors. © 2013 Cheng et al.; licensee BioMed Central Ltd.


Zhao A.-P.,Nanjing Medical University | Dong Y.-F.,Nanjing University | Liu W.,Nanjing Medical University | Gu J.,Nanjing Medical University | Sun X.-L.,Nanjing Medical University
CNS Neuroscience and Therapeutics | Year: 2014

Background and purpose: Our previous studies have demonstrated adenosine triphosphate-sensitive potassium channel (KATP channel) openers could protect against inflammatory response in brain disease, but little is known about the mechanisms involved in KATP channel openers inhibiting neuroinflammation. Methods and results: In the present study, we found that oxygen-glucose deprivation (OGD) resulted in BV-2 cells activation, significantly increased tumor necrosis factor-alpha and interleukin-1beta (IL-1β) levels, accompanied by downregulating Kir6.1 subunit. Pretreatment with nicorandil, a KATP channel opener, could attenuate OGD-induced BV-2 cells activation and inhibit pro-inflammatory factors release. Further study demonstrated that OGD activated Toll-like receptor-4 (TLR4) signaling pathway and NOD-like receptor pyrin domain containing three inflammasome, thereby increased IL-1β production. Pretreatment with nicorandil could reverse the two pathways involved in IL-1β production. Conclusions: Our findings reveal that KATP channel openers could protect against OGD-induced neuroinflammation via inhibiting inflammasome activation and TLR4 signal transduction. © 2013 John Wiley & Sons Ltd.


Zhao H.,Nantong University | Kong Z.,Nanjing Medical University
Oncotarget | Year: 2016

Although the leucine-rich repeat kinase 2 (LRRK2) R1628P polymorphism has been associated with the risk of Parkinson's disease (PD) in Taiwan, China, and Singapore, there are conflicting findings regarding this relationship. Thus, the aim of the present meta-analysis was to evaluate the associations between the LRRK2 R1628P polymorphism (rs33949390) and PD in Asian populations. A search for eligible studies was performed in PubMed, Embase, SinoMed, and the China Knowledge Resource Integrated Database, and pooled odds ratios and 95% confidence intervals were used to evaluate the strength of the association between the R1628P polymorphism and PD. This meta-analysis assessed 19 studies from 14 papers that involved a total of 9,927 PD patients and 8,602 controls and found that the R1628P polymorphism was significantly associated with the risk of PD in Asian populations. Moreover, stratification analyses indicated that the R1628P polymorphism was significantly associated with an increased risk of PD among Chinese as well as non-Chinese Asian populations and an increased risk of PD in Chinese patients from China, Taiwan, and Singapore. In a stratified analysis conducted according to age, significant associations were found for both late-onset PD and early-onset PD. The present data indicate that the R1628P polymorphism of the LRRK2 gene contributes to PD susceptibility in Asian, especially Chinese, populations.


Wang Y.,Soochow University of China | Wang Y.,Nanjing Medical University | Li J.,Nanjing Medical University | Song W.,Soochow University of China | Yu J.,Nanjing Medical University
Cell Proliferation | Year: 2014

Objectives: The aim of this study was to investigate effects of mineral trioxide aggregate (MTA) on odonto/osteogenic differentiation of bone marrow stromal cells (BMSCs) from craniofacial bones. Materials and methods: Craniofacial BMSCs were isolated from rat mandible and effects of MTA on their proliferation, differentiation and MAPK pathway involvement were subsequently investigated, in vitro. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2,5-tetrazoliumbromide) assay was performed to evaluate proliferation of the MTA-treated cells. Alkaline phosphatase (ALP) activity, alizarin red staining, real-time reverse transcription polymerase chain reaction and western blot assays were used to assess differentiation capacity as well as MAPK pathway involvement. Results: 0.02 mg/ml MTA-treated BMSCs had significantly higher ALP activity and formed more mineralized nodules than the untreated group. Odonto/osteoblastic marker genes/proteins (Alp, Runx2/RUNX2, Osx/OSX, Ocn/OCN and Dspp/DSP respectively) in MTA-treated cells were remarkably upregulated compared to untreated ones. Mechanistically, phosphorylated Jun N-terminal kinase (P-JNK) and phosphorylated extracellular regulated protein kinases (P-ERK) in MTA-treated BMSCs increased significantly in a time-dependent manner, while inhibition of JNK and ERK MAPK pathways dramatically blocked MTA-induced odonto/osteoblastic differentiation, as indicated by reduced ALP levels, weakened mineralization capacity and downregulated levels of odonto/osteoblastic marker genes (Alp, Runx2, Osx, Ocn and Dspp). Conclusion: Mineral trioxide aggregate promoted odonto/osteogenic capacity of craniofacial BMSCs via JNK and ERK MAPK signalling pathways. © 2014 John Wiley & Sons Ltd.


Wang H.,Nanjing Medical University | Zhu L.-J.,Nanjing Medical University | Yang Y.-C.,Nanjing Medical University | Wang Z.-X.,Nanjing Medical University | Wang R.,Nanjing University
British Journal of Cancer | Year: 2014

Background:Increasing evidence has shown that microRNAs (miRNAs) can serve as oncogenes and tumour suppressors to participate in tumour development. However, the roles of miRNAs in chemoresistance of human lung adenocarcinoma (LA) remain largely undefined.Methods:On the basis of miRNA microarray data, miR-224 was identified as the most upregulated miRNA in cisplatin (DDP; cis-diamminedichloroplatinum II)-resistant A549 cells compared with parental A549 cells. The aim of our study was to investigate the roles of miR-224 in the formation of DDP-resistant phenotype of LA cells and its possible molecular mechanisms.Results:Here we showed that miR-224 could promote the in vitro and in vivo DDP resistance of LA cells via regulating G1/S cell cycle transition and apoptosis. p21WAF1/CIP1, a potent cyclin-dependent kinase inhibitor, was identified as the direct and functional target gene of miR-224. Overexpression of p21WAF1/CIP1 could phenocopy the effect of miR-224 downregulation and silencing of p21WAF1/CIP1 could partially reverse the effect of miR-224 downregulation on DDP resistance of DDP-resistant LA cells. In addition, miR-224 could affect the G 1/S transition of cell cycle and apoptosis in LA cells through the p21WAF1/CIP1-pRb pathway and the intrinsic mitochondrial death pathway. Furthermore, miR-224 was found to be downregulated in DDP-responding LA tissues, and its expression was inversely correlated with p21WAF1/CIP1. Multivariate analyses indicated that the status of miR-224 might be an independent prognostic factor for predicting the survival of LA patients.Conclusions:Our findings shed novel light on the roles of miR-224/p21WAF1/CIP1 signalling in the DDP resistance of LA cells, and targeting it will be a potential strategic approach for reversing the DDP resistance in human LAs. © 2014 Cancer Research UK.


Hong Y.,Nanjing Medical University | Hong Y.,Nanjing University | Li S.-Q.,Nanjing Medical University | Hu Y.-L.,Nanjing Medical University | Wang Z.-Q.,Nanjing Medical University
BMC Infectious Diseases | Year: 2013

Background: The prevalence, genotypes, and vertical transmission characteristics of human papillomavirus (HPV) among pregnant women from Nanjing, China was investigated.Methods: Cervical cells were collected from healthy pregnant women (n = 3139; stage of gestation, 24.6 ± 2.1 weeks) for cytological evaluation and determination of HPV infection status. Exfoliated oral and genital cells were collected from neonates (<1-day-old, n = 233) whose mothers were positive for HPV DNA. We used HPV Gene Chip technology with 23 HPV genotype probes to conduct our analysis.Results: Overall prevalence of HPV DNA among pregnant women was 13.4% (422/3139). The most frequently detected HPV genotypes were HPV-16 (29.6%, 125/422), -18 (14.7%, 62/422), and -58 (14.2%, 60/422). The rate of concordance for HPV DNA in maternal-neonatal pairs was 23.6% (55/233), with HPV type-specific concordance occurring in 26 cases. A higher prevalence of HPV DNA was apparent in female neonates compared with males (17.7 vs. 11.6%).Conclusions: The prevalence of cervical HPV DNA in pregnant women from Nanjing was low, with vertical transmission rates slightly higher. From our findings, we concluded that there was efficient vertical transmission of three HPV genotypes, with HPV-16 the most prevalent type in pregnant women and newborn babies. © 2013 Hong et al; licensee BioMed Central Ltd.


Xu W.,Qingdao University | Tan L.,Qingdao University | Tan L.,Ocean University of China | Tan L.,Nanjing Medical University | And 3 more authors.
Neurobiology of Aging | Year: 2015

The groundbreaking discovery of mutations in the SNCA gene in a rare familial form of Parkinson's disease (PD) has revolutionized our basic understanding of the etiology of PD and other related disorders. Genome-wide Association Studies has demonstrated a wide array of single-nucleotide polymorphisms associated with the increasing risk of developing the more common type, sporadic PD, further corroborating the genetic etiology of PD. Among them, SNCA is a gene responsible for encoding α-synuclein, a protein found to be the major component of Lewy body and Lewy neurite, both of these components are the pathognomonic hallmarks of PD. Thus, it has been postulated that this gene plays specific roles in pathogenesis of PD. Here, we summarize the basic biological characteristics of the wild type of the protein (wt-α-synuclein) as well as genetic and epigenetic features of its encoding gene (SNCA) in PD. Based on these characteristics, SNCA may be involved in PD pathogenesis in at least 2 ways: wt-α-synuclein overexpression and its mutation types via different mechanisms. Associations between SNCA mutations and other Lewy body disorders, such as dementia with Lewy bodies and multiple system atrophy, are also mentioned. Finally, it is necessary to explore the influences which SNCA exerts on clinical and neuropathological phenotypes by promoting the transfer of scientific research into practice, such as clinical evaluation, diagnosis, and treatment of the disease. We believe it is promising to target SNCA for developing novel therapeutic strategies for parkinsonism. © 2015 Elsevier Inc.


Zhang W.-H.,Nanjing University | Yang J.,Nanjing University | Yang J.,Nanjing Medical University | Yu J.-S.,Nanjing University
Journal of Materials Chemistry | Year: 2012

HgTe/CdS core/shell nanocrystals (NCs) with highly-stable near-infrared (NIR) emissions were synthesized by employing dihydrolipoic acid (DHLA) as a stabilizer. This synthetic route was performed using Te powder as the tellurium source to prepare HgTe NCs, and H 2S generated by the reaction of Na 2S-H 2SO 4 as the sulfur source for synthesizing HgTe/CdS core/shell NCs at room temperature. The fluorescence emission peaks of DHLA-capped HgTe/CdS NCs could be facilely tuned from 910 nm to 1200 nm by varying the reflux time at 100 °C, with a maximum photoluminescence quantum yield of 52%. The obtained HgTe/CdS NCs exhibited an NIR stable emission when heated at 75 °C. Correspondingly, these HgTe/CdS core/shell NCs displayed excellent colloidal dispersion stability and long exciton lifetimes that reached up to 47.6 ns in an aqueous medium. The resultant HgTe/CdSe NCs have been successfully used to fabricate NIR emitting thin films on the surface of polymers and to perform fluorescence imaging in a live animal. This journal is © The Royal Society of Chemistry 2012.


Zhou X.,Soochow University of China | Chen J.,Soochow University of China | Zhang Q.,Nanjing Medical University | Shao J.,Nanjing Medical University | And 3 more authors.
Journal of the American College of Cardiology | Year: 2016

Background Recent studies in animal models and humans have shown that corin is critically involved in the regulation of salt-water balance, blood pressure, and cardiac function. Objectives The goal of this study was to investigate the prognostic value of plasma soluble corin in patients with acute myocardial infarction (AMI). Methods We enrolled 1,382 consecutive AMI patients in a prospective cohort study and explored the association of plasma corin with AMI outcomes using multivariable Cox proportional hazards analysis. Results Patients with low corin levels were more likely to be female and to have histories of hypertension and heart failure (HF). Kaplan-Meier survival curves indicated that patients with corin levels above the median had a lower incidence of major adverse cardiac events (MACE) and all-cause mortality compared with those whose corin levels were below the median. Multivariate Cox regression analysis suggested that log corin was an independent predictor of MACE (hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.42 to 0.96; p = 0.029), together with age, previous histories of AMI, HF, and diabetes, Killip class, percutaneous coronary intervention, coronary artery bypass graft, beta-blocker use, and log N-terminal pro-B-type natriuretic peptide. The C-statistic and integrated discrimination improvement for MACE were improved significantly by the addition of corin to the reference model. Moreover, log corin was also found to be a significant predictor of death (HR: 0.65; 95% CI: 0.41 to 0.97; p = 0.036) and HF hospitalization (HR: 0.48; 95% CI: 0.23 to 0.90; p = 0.009) after adjustment for clinical variables and established biomarkers of adverse prognosis. Conclusions Our study demonstrates that corin is a valuable prognostic marker of MACE in patients with AMI, independent of established conventional risk factors. © 2016 American College of Cardiology Foundation.


Chen Q.,Nanjing University of Science and Technology | Fan W.,Nanjing Medical University | Niu S.,Nanjing University of Science and Technology | Shi J.,Nanjing University of Science and Technology | And 2 more authors.
Optics Express | Year: 2015

The choroid is an important structure of the eye and plays a vital role in the pathology of retinal diseases. This paper presents an automated choroid segmentation method for high-definition optical coherence tomography (HD-OCT) images, including Bruch's membrane (BM) segmentation and choroidal-scleral interface (CSI) segmentation. An improved retinal nerve fiber layer (RNFL) complex removal algorithm is presented to segment BM by considering the structure characteristics of retinal layers. By analyzing the characteristics of CSI boundaries, we present a novel algorithm to generate a gradual intensity distance image. Then an improved 2-D graph search method with curve smooth constraints is used to obtain the CSI segmentation. Experimental results with 212 HDOCT images from 110 eyes in 66 patients demonstrate that the proposed method can achieve high segmentation accuracy. The mean choroid thickness difference and overlap ratio between our proposed method and outlines drawn by experts was 6.72μm and 85.04%, respectively. © 2015 Optical Society of America.


Fan H.,Nanjing University | Fan H.,Nanjing Medical University
Journal of immunology research | Year: 2014

The aim of the present study was to investigate mechanism of the gender differences of B cells. The results showed that 358 differential gene expressions (DEGs) were displayed between healthy females and males. Compared with male, 226 and 132 genes were found to be up- and downregulated in the female. 116 genes displayed possible correlation with estrogen. Moreover, the upregulated DEGs (Cav1, CD200R1, TNFRSF17, and CXCR3) and downregulated DEGs (EIF1AY and DDX3Y) in healthy female may be involved in gender predominance of some immune diseases. Furthermore, signaling pathway analysis for estrogen-relevant DEGs showed that only 26 genes were downregulated in SLE female versus SLE male, of which expressions of 8 genes had significant difference between SLE females and SLE males but are having nonsignificant difference between healthy females and healthy males. Except for the 5 Y-chromosome-related genes or varients, only 3 DEGs (LTF, CAMP, and DEFA4) were selected and qRT-PCR confirmed that the expressions of LTF and CAMP decreased significantly in B cells from female SLE patients. These data indicated that the gender differences were existent in global gene expression of B cells and the difference may be related to estrogen.


Wang M.,Nanjing Medical University | Yuan L.,Nanjing Medical University | Wu D.,Nanjing Medical University | Zhang Z.,Nanjing Medical University | And 3 more authors.
Oncogene | Year: 2010

Xeroderma pigmentosum group F (XPF) has an essential role in the nucleotide excision repair pathway that removes a wide variety of DNA lesions. We hypothesized that genetic variants in XPF are associated with bladder cancer risk and recurrence. We selected three tagging single nucleotide polymorphisms (tagSNPs) from the HapMap database for the Chinese and genotyped them in a two-stage case-control study to evaluate the association and further examined the functionality of a novel polymorphism in the promoter. The two-stage analysis found that the rs744154 tagSNP in the XPF intron 1, which was linkage disequilibrium with the-357AC polymorphism in the promoter region, was associated with a protective effect on bladder cancer risk. Electrophoretic mobility shift assay (EMSA) further revealed that the-357C allele decreased the binding ability of transcriptional factors to the XPF promoter. The vector construct containing the-357C allele had a lower luciferase expression than did the-357A allele. The-357C allele in the transcription factor-binding site was also associated with decreased expression levels of both XPF mRNA and protein in bladder cancer tissues. Furthermore, patients with the-357C allele had a shorter overall recurrence-free survival than did patients with the-357A allele. Our results suggest that the XPF promoter-357AC polymorphism may regulate the expression of XPF and thereby contribute to susceptibility to and prognosis of bladder cancer. Further larger studies with different populations are warranted to confirm these findings. © 2010 Macmillan Publishers Limited All rights reserved.


Liu X.Z.,Nanjing Medical University | Fang H.,Nanjing University
Scientometrics | Year: 2012

Except the alphabetic ordering authorship papers, the citations of multi-authored papers are allocated to the authors based on their contributions to the paper. For papers without clarification of contribution proportion, a function of author number and rank is presented to rightly determine the credit allocated proportion and allocated citations of each author. Our citation allocation scheme is between the equally fractional counting and the one using the inverse of author rank. It has a parameter to adjust the credit distribution among the different authors. The allocated citations can either be used alone to indicate one's performance in a paper, or can be applied in the modification of h-index and g-index to represent the achievement of a scientist on the whole. The modified h-index and g-index of an author makes use of more papers in which he or she played important roles. Our method is suitable for the papers with wide range of author numbers. © 2011 Akadémiai Kiadó, Budapest, Hungary.


Zhang H.,Hainan Medical College | Yang H.,Nanjing Medical University | He S.,Nanjing Medical University
Cellular Physiology and Biochemistry | Year: 2010

Tumor necrosis factor (TNF) is a proinflammatory cytokine which has been shown to be actively involved in the pathogenesis of allergic inflammation. However, little is known of the effects of TNF on cytokine secretion and protease activated receptor (PAR) expression in mast cells. In the present study, we examined potential influence of TNF on IL-4 and IL-12 release from P815 cells and PAR expression in P815 cells by using flow cytometry analysis, quantitative real time PCR, ELISA and cellular activation of signaling ELISA (CASE) techniques. The results showed that TNF induced up to 2.7-fold increase in IL-4, but not IL-12 release from P815 cells, and PAR-2 antagonist peptide FSLLRY-NH 2 and PAR-4 antagonist peptide trans-cinnamoyl (tc)-YPGKF-NH 2 did not affect TNF induced IL-4 release. Approximately up to 2.4 and 2.3 fold increases in expression of PAR-2 and PAR-4 were observed when cells were incubated with TNF. Pretreatment of cells with TNF for 60 min enhanced trypsin and tryptase induced PAR-2 expression by 2.4 and 2.3 fold; PAR-3 expression by 1.6 and 1.7 fold and PAR-4 expression by 1.6 and 1.7 fold, respectively. LY294002, an inhibitor PI3K abolished TNF induced IL-4 release and phosphorylation of Akt in P815 cells, indicating Akt cell signalling pathway is involved in the event. In conclusion, TNF can stimulate IL-4 release from mast cells through an Akt cell signalling pathway dependent, but PAR independent mechanism. TNF may serve as a regulator for IL-4 production and PAR expression, and through which participates in the mast cell related inflammation. © 2010 S. Karger AG, Basel.


Lin F.-Q.,Tongji University | Qiu M.-T.,Nanjing Medical University | Ding X.-X.,Nanjing Medical University | Fu S.-K.,Tongji University | Li Q.,Tongji University
CNS Neuroscience and Therapeutics | Year: 2012

Aims: A systematic literature review comparing the efficacy of ephedrine and phenylephrine for the management of spinal anesthesia-induced hypotension during Cesarean sections (C-sections) was published in 2002. A number of well-designed trials with controversial results have been published afterward. Therefore, an updated meta-analysis was necessary. Methods: The MEDLINE, EMBASE, and the Cochrane Library databases were searched (last search performed on September 26, 2011). Pooled risk ratio (RR) or standard mean difference (SMD) and their 95% confidence intervals (95% CI) were calculated for the incidence of intra-operative hypotension or umbilical blood pH values. Results: A total number of 15 trials and 742 parturients under elective C-sections were analyzed. When used to prevent hypotension, patients receiving ephedrine and phenylephrine did not differ significantly in the incidence of hypotension (RR = 1.22; 95% CI, 0.83-1.80), umbilical arterial pH values (SMD = -0.38; 95% CI, -1.67 to 0.92) or venous pH values (SMD = -0.18; 95% CI, -0.44 to 0.07). And administration routes did not affect the incidence of hypotension and umbilical blood pH values. When used to treat hypotension, patients given ephedrine and phenylephrine had comparable incidence of intra-operative hypotension (RR = 0.79; 95% CI, 0.40-1.56), while parturients receiving phenylephrine had neonates with higher umbilical arterial pH values (SMD = -1.32; 95% CI, -2.35 to -0.30) and venous pH values (SMD = -0.79; 95% CI, -1.09 to -0.49) than those given ephedrine. Conclusion: Prophylactic use of ephedrine and phenylephrine were both effective in preventing maternal hypotension during C-section under spinal anesthesia; phenylephrine was superior to ephedrine in treating hypotension, evidenced by higher umbilical blood pH values. © 2012 Blackwell Publishing Ltd.


Zheng X.,Nanjing Medical University | Sun T.,Nanjing University | Wang X.,Nanjing Medical University
Biochemical and Biophysical Research Communications | Year: 2013

Abnormal fatty acid oxidation has been associated with obesity and type 2 diabetes. At the transcriptional level, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) has been reported to strongly increase the ability of hormone nuclear receptors PPARα and ERRα to drive transcription of fatty acid oxidation enzymes. In this study, we report that a specific agonist of the type 2 cannabinoid receptor (CB2R) can lead to fatty acid oxidation through the PGC-1α pathway. We have found that CB2R is expressed in differentiated C2C12 myotubes, and that use of the specific agonist trans-caryophyllene (TC) stimulates sirtuin 1 (SIRT1) deacetylase activity by increasing the phosphorylation of cAMP response element-binding protein (CREB), thus leading to increased levels of PGC-1α deacetylation. This use of TC treatment increases the expression of genes linked to the fatty acid oxidation pathway in a SIRT1/PGC-1α-dependent mechanism and also drastically accelerates the rate of complete fatty acid oxidation in C2C12 myotubes, neither of which occur when CB2R mRNA is knocked down using siRNA. These results reveal that activation of CB2R by a selective agonist promotes lipid oxidation through a signaling/transcriptional pathway. Our findings imply that pharmacological manipulation of CB2R may provide therapeutic possibilities to treat metabolic diseases associated with lipid dysregulation. © 2013 Elsevier Inc.


Shen X.-J.,Nanjing Medical University | Zhou J.-D.,Nanjing Medical University | Dong J.-Y.,Soochow University of China | Ding W.-Q.,The University of Oklahoma Health Sciences Center | Wu J.-C.,Nanjing Medical University
British Journal of Nutrition | Year: 2012

Preclinical studies have suggested an anti-colorectal cancer effect of n-3 fatty acids, yet epidemiological studies have reported mixed results. The goal of the present meta-analysis was to examine the association between the dietary intake of n-3 fatty acids and colorectal cancer risk by conducting a meta-analysis of prospective cohort studies. We searched the PubMed database up to February 2012 to identify eligible studies. Either a fixed- or random-effects model was used to obtain a pooled relative risk (RR) comparing the highest intake of n-3 fatty acids with the lowest. We conducted subgroup analyses according to sex, geographic region, length of follow-up, cancer site and type of n-3 fatty acids. We included seven prospective studies in the meta-analysis, comprising 489465 participants and 4656 incident cases. The pooled RR of colorectal cancer in relation to n-3 fatty acids was 0.98 (95% CI 0.88, 1.09). The results from subgroup analysis indicated a significant reduced risk of colorectal cancer in relation to n-3 fatty acids among men (RR 0.87, 95% CI 0.75, 1.00; n 4). No significant association was observed in other subgroups. There was no evidence of publication bias as suggested by Begg's test (P=0.76) and Egger's test (P=0.66). The present meta-analysis showed insufficient evidence of a protective effect of n-3 fatty acids on colorectal cancer risk. However, a reduced risk observed in men warrants further investigation. © 2012 The Authors.


Wang P.,Nanjing Medical University | Guo Z.S.,Pennsylvania State University | Guo Z.S.,Tongji University
International Journal of Clinical and Experimental Pathology | Year: 2013

The regulatory T (Treg) cells play an important role in the maintenance of homeostasis and the prevention of autoimmune diseases. Although most studies are focusing on the role of Treg cells in T cells and T cells-mediated diseases, these cells also directly affect B cells and other non-T cells. This manuscript updates the role of Treg cells on the B cells and B cell-mediated diseases. In addition, the mechanisms whereby Treg cells suppress B cell responses have been discussed.


Pan X.,Cancer Hospital of Jiangsu Province | Wang R.,Nanjing University | Wang Z.-X.,Nanjing Medical University
Molecular Cancer Therapeutics | Year: 2013

MicroRNAs (miRNA) are small noncoding RNAs that converge to maintain an intrinsic balance of various processes, including cell proliferation, differentiation, and apoptosis. Recent research efforts have been devoted to translating these basic discoveries into applications that could improve the early diagnosis and therapeutic outcome of patients with cancer. Early studies have shown that miRNA-451 (miR-451) is widely dysregulated in human cancers and plays a critical role in tumorigenesis and tumor progression. In this review, we summarize the potential use of miR-451 for cancer diagnosis, prognosis, and treatment. In addition, we discuss the possible mechanisms of miR-451 dysregulation and future challenges in development of miR-451 as a noninvasive biomarker and a potential therapeutic target in human cancers. ©2013 AACR.


Jiang T.,Nanjing Medical University | Yu J.-T.,Nanjing Medical University | Yu J.-T.,Qingdao University | Yu J.-T.,Ocean University of China
Journal of Alzheimer's Disease | Year: 2012

Alzheimer's disease (AD) is the most common progressive dementia in the elderly and places an enormous burden on the individual and society. Presently, the treatments for AD are only symptomatic and do not halt the progression of the disease. With the recent advances in the understanding of the pathogenesis of AD in past years, numerous therapies which could modify the disease process are under active investigation. These therapies could attenuate or even reverse the neurodegenerative process by interfering with the underlying pathogenesis including amyloid-β production, tau hyperphosphorylation, oxidative stress, inflammation, and excitotoxicity. In this review, new disease-modifying therapies which reduce amyloid-β production, prevent tau hyperphosphorylation, and provide neuroprotective effects are described, including the results of in vitro and in vivo studies and clinical trials. Some typical therapies with disease-modifying effects have also been discussed. © 2012-IOS Press and the authors. All rights reserved.


Luzzo K.M.,University of Washington | Wang Q.,Nanjing Medical University | Purcell S.H.,University of Washington | Chi M.,University of Washington | And 4 more authors.
PLoS ONE | Year: 2012

Background: Maternal obesity is associated with poor outcomes across the reproductive spectrum including infertility, increased time to pregnancy, early pregnancy loss, fetal loss, congenital abnormalities and neonatal conditions. Furthermore, the proportion of reproductive-aged woman that are obese in the population is increasing sharply. From current studies it is not clear if the origin of the reproductive complications is attributable to problems that arise in the oocyte or the uterine environment. Methodology/Principal Findings: We examined the developmental basis of the reproductive phenotypes in obese animals by employing a high fat diet mouse model of obesity. We analyzed very early embryonic and fetal phenotypes, which can be parsed into three abnormal developmental processes that occur in obese mothers. The first is oocyte meiotic aneuploidy that then leads to early embryonic loss. The second is an abnormal process distinct from meiotic aneuploidy that also leads to early embryonic loss. The third is fetal growth retardation and brain developmental abnormalities, which based on embryo transfer experiments are not due to the obese uterine environment but instead must be from a defect that arises prior to the blastocyst stage. Conclusions/Significance: Our results suggest that reproductive complications in obese females are, at least in part, from oocyte maternal effects. This conclusion is consistent with IVF studies where the increased pregnancy failure rate in obese women returns to the normal rate if donor oocytes are used instead of autologous oocytes. We postulate that preconceptional weight gain adversely affects pregnancy outcomes and fetal development. In light of our findings, preconceptional counseling may be indicated as the preferable, earlier target for intervention in obese women desiring pregnancy and healthy outcomes. © 2012 Luzzo et al.


Yin Y.,Nanjing Medical University | Han X.,Nanjing Medical University | Shi Q.,Soochow University of China | Zhao Y.,Jiangsu Institute of Hematology | He Y.,Jiangsu Institute of Hematology
European Journal of Obstetrics Gynecology and Reproductive Biology | Year: 2012

Objectives: The purpose of this study was to examine whether adoptive transfer with in vitro expanded CD4 +CD25 + regulatory T cells (Tregs) could prevent immune response-mediated spontaneous abortion in mice. Study design: Female CBA/J mice were mated with male Balb/c as the control with normal pregnancy or with DBA/2J mice as a model of spontaneous abortion. The CBA/J mice mated with DBA/2J were treated intravenously with freshly isolated or in vitro expanded Tregs on day 1 or 4 of pregnancy, respectively. The numbers of surviving and reabsorbed fetuses in the different groups of mice were counted on day 14 of pregnancy, and the concentrations of cytokines in individual sera and the supernatants of cultured Tregs were measured by ELISA. Results: Adoptive transfer with freshly isolated Tregs only slightly reduced the fetal resorption rate, which was not significantly different from that of the mice without Treg treatment, regardless of treatment at early stage and implementation of pregnancy. In contrast, adoptive transfer with in vitro expanded Tregs significantly reduced the fetal resorption rates, particularly for treatment at early stage of pregnancy (P < 0.05). Furthermore, adoptive transfer with in vitro expanded Tregs at early stage of pregnancy significantly increased the levels of serum IL-10, TGF-β1, and the ratios of IL-10 to IFN-γ. Conclusions: Our data clearly indicated that adoptive transfer with in vitro expanded Tregs at early stage of pregnancy protected fetuses from spontaneous abortion by re-establishing immune tolerance in mice. © 2012 Elsevier Ireland Ltd. All rights reserved.


Jiang H.,Nanjing University | Zhang G.,Nanjing University | Zhang G.,Nanjing Medical University | Wu J.-H.,Nanjing University | Jiang C.-P.,Nanjing University
Oncology Reports | Year: 2014

microRNAs (miRNAs) are non-coding RNAs which have the capacity to regulate gene expression at the post-transcriptional level, and have emerging as key factors involved in cancer at all stages ranging from initiation to metastasis. In the present review, we summmarize the diverse roles of the microRNA-29 (miR-29) family in cancer. First, we present a concise introduction to the miR-29 family and the expression profile of miR-29 in various cancer types. We next highlight the upstream regulatory pathway of miR-29 and describe the relationship between miR-29 and cancer in detail. As a tumor suppressor, miR-29 restrains cancer progression by promoting tumor cell apoptosis, by suppressing DNA methylation of tumor-suppressor genes, by reducing proliferation of tumors and by increasing chemosensitivity. However, as a tumor promoter, miR-29 mediates epithelial-mesenchymal transition (EMT) and promotes metastasis in breast cancer and colon cancer. Finally, we suggest that miR-29 represents a novel diagnostic and prognostic biomarker or a therapeutic target for cancer. Our review highlights the diverse relationship between miR-29 and cancer (particularly digestive system neoplasms). Further research of miR-29 in cancer is warranted.


Wang L.,Nantong University | Yao M.,Nantong University | Dong Z.,Nantong University | Zhang Y.,Nanjing Medical University | Yao D.,Nantong University
Tumor Biology | Year: 2014

Hepatocellular carcinoma (HCC) is one of the most common and rapidly fatal malignancies worldwide with a multi-factorial, multi-step, complex process and poor prognosis. Its early diagnosis and metastasis monitoring are of the utmost importance. Hepatoma tissues synthesize various tumor-related proteins, genes, enzymes, microRNA, etc. and then secrete into the blood. Detections of circulating biomarkers are useful to find tumor at an early stage or monitor metastasis after postoperative treatment. This paper summarizes recent studies of specific biomarkers at early diagnosis or in monitoring metastasis or postoperative recurrence of HCC.


Zong C.,Nanjing University | Wu J.,Nanjing University | Liu M.,Nanjing University | Yan F.,Nanjing Medical University | Ju H.,Nanjing University
Chemical Science | Year: 2015

This work integrates target-induced DNA assembly and cleavage on a DNA chip to design a versatile imaging strategy as an assay for multiple proteins. The DNA assembly is achieved via immunological recognition to trigger the proximity hybridization for releasing a DNA sequence, which then hybridizes with FITC-DNA1 immobilized on the chip to induce the enzymatic cleavage of DNA1 and thus decrease the signals. The signal readout is performed with both fluorescent imaging of the left FITC and chemiluminescent (CL) imaging, by adding peroxidase labelled anti-FITC in assembly solution and CL substrates to produce CL emission. This one-step incubation can be completed in 30 min. The imaging method shows wide detection ranges and detection limits down to pg mL-1 for the simultaneous detection of 4 protein biomarkers. This high-throughput strategy with good practicability can be easily extended to other protein analytes, providing a powerful protocol for protein analysis and clinical diagnosis. © 2015 The Royal Society of Chemistry.


Zhou Y.,Nanjing Medical University | Xiong M.,Nanjing Medical University | Niu J.,Nanjing Medical University | Sun Q.,Nanjing Medical University | And 4 more authors.
Journal of Cell Science | Year: 2014

Tubular epithelial cell apoptosis contributes to tubulointerstitial fibrosis but its regulation remains unclear. Here, in fibrotic kidney induced by unilateral ureteral obstruction (UUO), we demonstrate that miR-34a is markedly upregulated in tubulointerstitial spaces and microvesicles isolated from obstructed kidney. However, miR-34a is not de novo synthesized by proximal tubular epithelial cells but by fibroblasts after incubation with TGF-β1. miR-34a is markedly upregulated in microvesicles isolated from the cell culture medium of TGF-β1-treated fibroblasts. These microvesicles act as a vector for delivery of upregulated miR-34a from fibroblasts to tubular cells. The fibroblast-derived miR-34a-containing microvesicles induce the apoptosis of tubular cells. The exogenous miR-34a regulates tubular apoptosis by modulating the expression of the antiapoptotic protein Bcl-2. Moreover, injection of exogenous miR-34acontaining microvesicles enhances tubular cell apoptosis in mice. This study suggests that secreted fibroblast miR-34a transported by microvesicles induces tubular cell apoptosis in obstructed kidney. This study reveals a new mechanism whereby microvesiclemediated communication of miRNA between fibroblasts and tubular cells is involved in regulating tubular cell apoptosis, which might provide new therapeutic targets for renal tubulointerstitial fibrosis. © 2014. Published by The Company of Biologists Ltd.


Ren K.,Nanjing University | Wu J.,Nanjing University | Ju H.,Nanjing University | Yan F.,Nanjing Medical University
Analytical Chemistry | Year: 2015

A simple electrochemical immunosensing method is presented for highly sensitive and selective detection of protein biomarker. This method uses a newly designed assembly of Mg2+-dependent MNAzyme via target-driven triple-binder proximity hybridization to catalyze the cleavage of methylene blue (MB)-labeled hairpin, which leads to the departure of MB from the electrode surface and thus an amplified decrease of electrochemical signal for immunoassay of the target protein. The MNAzyme assembly is achieved by the simultaneous recognition of target protein with three DNA-labeled antibodies in the presence of Mg2+, which greatly improves the detection sensitivity and selectivity. As a proof of concept, this strategy can detect carcinoembryonic antigen (CEA) ranging from 0.002 to 500 ng mL-1 with a detection limit of 1.5 pg mL-1. The whole assay including the target-driven MNAzyme formation and subsequent cleavage of hairpin can be completed with one step in 40 min. The immunosensor, prepared with a hairpin DNA, possesses good extensibility for large protein biomarkers as CEA by using corresponding antibodies, though the protein target size dependence was not investigated in this work. The proposed immunoassay method shows the advantages of easy operation, high sensitivity, wide concentration range, good selectivity, and excellent versatility, displaying potential application for protein analysis. © 2015 American Chemical Society.


Liu L.,Nanjing University | Wang Y.,Nanjing University | Fan H.,Nanjing University | Zhao X.,Nanjing University | And 5 more authors.
Stem Cells | Year: 2012

Mesenchymal stem cells (MSCs) exhibit extensive self-renewal potential and can modulate immunocyte activation. Our previous study reported that miR-181a expression was significantly increased in placenta from women with severe preeclampsia (PE), but the mechanisms by which miR-181a regulates MSCs are unknown. In this study, we asked if and how miR-181a regulates MSCs' proliferation and immunosuppressive properties. We found that the expression of miR-181a in the MSCs derived from the umbilical cord and decidua of PE patients increased relative to MSCs derived from normal patients. Transfection with miR-181a oligos prevented MSCs proliferation but did not affect MSCs apoptosis. Overexpression of miR-181a blocked activation of the TGF-β signaling pathway and caused downregulation of target gene (TGFBR1 and TGFBRAP1) mRNA and protein expression. Reporter genes with putative miR-181a binding sites from the TGFBR1 and TGFBRAP1 3′-untranslated regions (3′-UTRs) were downregulated in the presence of miR-181a, suggesting that miR-181a binds to TGFBR1 and TGFBRAP1 3′-UTRs. In contrast, transfection of MSCs with miR-181a oligo enhanced expression of IL-6 and indoleamine 2,3-dioxygenase by activating p38 and JNK signaling pathways, respectively. MSCs transfected with miR-181a also enhanced the proliferation of T cells in a short-term culture. Additionally, treatment with control MSCs, but not miR-181a transfected MSCs, improved dextran sulfate sodium-induced experimental colitis, suggesting that miR-181a attenuates the immunosuppressive properties of MSCs in vivo. Together, our data demonstrate that miR-181a is an important endogenous regulator in the proliferation and immunosuppressive properties of MSCs. © AlphaMed Press.


Feng L.-N.,Nanjing University | Bian Z.-P.,Nanjing Medical University | Peng J.,Nanjing University | Jiang F.,Nanjing University | And 5 more authors.
Analytical Chemistry | Year: 2012

A novel multianalyte electrochemical immunoassay was developed for ultrasensitive detection of human cardiopathy biomarkers cardiac troponin I (cTnI) and human heart-type fatty-acid-binding protein (FABP) using metal ion functionalized titanium phosphate nanospheres (TiP-metal ion) as labels. The metal ions could be detected directly through square wave voltammetry (SWV) without metal preconcentration, and the distinct voltammetric peaks had a close relationship with each sandwich-type immunoreaction. The position and size of the peaks reflected the identity and level of the corresponding antigen. The large amount of metal ions loading on the TiP nanospheres greatly amplified the detection signals, and the good biocompatibility of graphene nanoribbons (GONRs) retained good stability for the sandwich-type immunoassay. The proposed immunoassay exhibited high sensitivity and selectivity for the detection of cTnI and FABP. The linear relationships between electrochemical signals and the concentrations of cTnI and FABP were obtained in the range of 0.05 pg/mL-50 ng/mL and 0.05 pg/mL-50 ng/mL, respectively. The detection limits of cTnI and HIgG were 1 and 3 fg/mL (S/N = 3), respectively. Moreover, the immunoassay accurately detected the concentrations of cTnI and FABP in human serum samples, which were demonstrated to have excellent correlations with the standard enzyme linked immunosorbent assay (ELISA) method. The results suggested that the electrochemical immunoassay would be promising in the point-of-care diagnostics application of clinical screening of acute myocardial infarction (AMI) biomarkers. © 2012 American Chemical Society.


Zhu X.,Nanjing Medical University | Lv M.,Nanjing Medical University | Wang H.,Nanjing University | Guan W.,Nanjing University
Digestive Diseases and Sciences | Year: 2014

Background: Recent studies show that microRNAs (miRNAs) in serum or plasma can be stably detected and used as potential biomarkers in cancer diagnosis. Objectives: To systematically evaluate circulating miRNAs from numerous gastric cancer (GC) expression profiling studies and to determine miRNA biomarkers for GC detection. Methods: A systematic review and meta-analysis of published studies comparing the circulating miRNA expressions between GC patients and healthy controls were carried out. An miRNA ranking system that considered the number of comparisons in agreement, total number of samples, and average fold change was used. Then the receiver-operating characteristic curve (ROC) results of the top miRNAs were combined to further evaluate their diagnostic value by using Meta-disc 1.4. Results: A total of 35 miRNAs were reported in the 22 included studies, with 7 miRNAs reported in at least 2 studies. MiR-21 is the most consistently reported miRNA with upregulation. In further analysis, the sensitivity, specificity, and area under the curve of summary ROC for miR-21 in GC diagnosis are 0.78 (95 % CI 0.71-0.85), 0.89 (95 % CI 0.82-0.94), and 0.91, respectively. Conclusion: Circulating miR-21 can serve as a potential biomarker for detection of GC. © 2013 Springer Science+Business Media.


Tian W.,Nanjing Medical University | Hao C.,Nanjing Medical University | Fan Z.,Nanjing Medical University | Weng X.,Nanjing Medical University | And 6 more authors.
Journal of Hepatology | Year: 2015

Background & Aims Activation of hepatic stellate cells (HSCs) represents a key process in liver injury and, in the absence of intervention, leads to irreversible cirrhosis contributing significantly to the mortality of patients with liver disease. A missing link in the current understanding of HSC activation is the involvement of the epigenetic machinery. We investigated the role of the myocardin related transcription factor A (MRTF-A) in HSC activation.Methods Liver fibrosis was induced in wild type (WT) and MRTF-A deficient (KO) mice by CCl4 injection. Expression of mRNA and protein was measured by real-time PCR, Western blotting, and immunohistochemistry. Protein binding to DNA was assayed by chromatin immunoprecipitation (ChIP). Knockdown of endogenous proteins was mediated by either small interfering RNA (siRNA) or short hairpin RNA (shRNA), carried by lentiviral particles.Results KO mice exhibited resistance to CCl4-induced liver fibrosis compared to WT littermates. The expression of activated HSC signature genes was suppressed in the absence of MRTF-A. ChIP assays revealed that MRTF-A deficiency led to the erasure of key histone modifications, associated with transcriptional activation, such as H3K4 di- and tri-methylation, on the promoter regions of fibrogenic genes. Mechanistically, MRTF-A recruited a histone methyltransferase complex (COMPASS) to the promoters of fibrogenic genes to activate transcription. Silencing of individual COMPASS components dampened transactivation of fibrogenic genes in vitro and blocked liver fibrosis in mice. Oestradiol suppressed HSC activation by dampening the expression and binding activity of COMPASS.Conclusions Our data illustrate a novel mechanism that connects MRTF-A dependent histone H3K4 methylation to HSC activation. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Pan X.,Nanjing Medical University | Wang Z.-X.,Nanjing Medical University | Wang R.,Nanjing University
Cancer Biology and Therapy | Year: 2010

Resistance to anticancer agents is a major clinical obstacle to the successful treatment of cancer, yet the mechanisms underlying drug resistance have not been fully characterized. MicroRNAs (miRNAs) are endogenous, small (19-25 nucleotides in length) noncoding RNAs, which function by base pairing with messenger RNAs, thereby regulating protein expression. Emerging evidence shows that alteration of miRNAs is involved in cancer initiation and progression. MiR-21 is a miRNA that is overexpressed in most tumor types, and acts as an oncogene by targeting many tumor suppressor genes related to proliferation, apoptosis and invasion. In vivo and in vitro studies suggest that miR-21 may serve as a diagnostic and prognostic marker for human malignancies. More recently, studies have identified an important role for miR-21 in anticancer drug resistance. Here, we review the mechanisms underlying miR-21-mediated chemoresistance and the potential use of miR-21 as a novel molecular target for cancer chemotherapy. © 2010 Landes Bioscience.


Li J.,Soochow University of China | Hu W.,Nanjing Medical University | Lan Q.,Soochow University of China
Journal of Neuro-Oncology | Year: 2012

We previously reported that sEH inhibitor t-AUCB suppresses the growth of human glioblastoma U251 and U87 cell lines and induces cell-cycle G0/G1 phase arrest. In present study, we found even 96 h-treatment of 200 μM t-AUCB can not induce apoptosis in U251 and U87 cells. We also revealed that 200 μM t-AUCB significantly elevates the activation of p38 MAPK, MAPKAPK2 and Hsp27. The p38 MAPK inhibitor SB203580 and the inhibitor of Hsp27 phosphorylation, KRIBB3, were used to investigate the mechanism of the apoptosis-resistance. The results showed that, after blocking the activation of Hsp27 by SB203580 or KRIBB3, 200 μM t-AUCB significantly induces apoptosis and increases caspase-3 activities in U251 and U87 cells. Our data demonstrated that t-AUCB induces cell apoptosis after blocking itself-induced activation of Hsp27, and that the activation of Hsp27 may confer chemoresistance in GBM cells. The combination of t-AUCB and the inhibitor of Hsp27 phosphorylation may be a potential strategy for treatment of glioblastoma. © 2012 Springer Science+Business Media, LLC.


Wen Y.T.,Nanjing University | Dai J.H.,Nanjing Medical University | Gao Q.,Nanjing University
Nutrition, Metabolism and Cardiovascular Diseases | Year: 2014

Aim: There is considerable discrepancy regarding the protective effects of Omega-3 polyunsaturated fatty acids (Omega-3 PUFAs) in patients with coronary heart disease (CHD) from the early-phase clinical randomized controlled trials (RCTs). We conducted a meta-analysis of RCTs to address this issue. Data synthesis: Pubmed, the Cochrane Central Register of Controlled Trials, and EMBASE databases (~May 2013) were systematically searched. Odds ratios (OR) and associated 95% CI were retrieved by using random-effect model according to heterogeneity. A total of 14 RCTs involving 16,338 individuals in the Omega-3 PUFAs group and 16,318 in the control group were identified. Patients assigned to Omega-3 PUFAs did not demonstrate satisfactory improvements on major cardiovascular events (OR, 0.93; 95% CI, 0.86 to 1.01; P=0.08; I2=46%). By contrast, the reduced risks of death from cardiac causes, sudden cardiac death and death from all causes (OR, 0.88; 95% CI, 0.80 to 0.96; P=0.003; I2=0%; OR, 0.86; 95% CI, 0.76 to 0.98; P=0.03; I2=29%; and OR, 0.92; 95% CI, 0.85 to 0.99; P=0.02; I2=6%; respectively) were shown. Conclusions: Supplement of Omega-3 PUFAs in patients with CHD is not associated with a protective effect on major cardiovascular events, while it does exert beneficial effects in reducing death from cardiac causes, sudden cardiac death and death from all causes. However, with currently available cardio-protective therapies, whether dietary supplementation with Omega-3 PUFAs should be still considered in patients with CHD is currently debated. © 2013 Elsevier B.V.


Liu X.Z.,Nanjing Medical University | Fang H.,Nanjing University
Scientometrics | Year: 2014

Leaders are important for scientific groups. Authors of a research paper whose names are listed in the byline first, last, or as the corresponding author are often considered particularly important to that paper. The authorship preferences of scientific group leaders are examined for seven research fields and 11 geographic locations. There are some similarities and differences among research fields and geographic locations in listing group leaders. In the fields of "Mathematics" and "Physics, Particles & Fields", although the custom is for papers to list authors alphabetically, scientific group leaders from Egypt and Shanghai typically list their names first or last in the byline, the same as group leaders in other research fields. Opposite to the group leaders from other locations, leaders from Egypt often appear as the first authors. Scientific group leaders who are listed first in the byline typically also serve as the corresponding authors. For group leaders who are listed last in the byline, the proportion also serving as corresponding authors changes significantly. Accordingly, the proportion of papers in which group leaders are corresponding authors varies considerably among different research fields and geographic locations. The meaning of authorship for research group leaders is discussed in the end from the perspective of their roles in paper production. © 2013 Akadémiai Kiadó, Budapest, Hungary.


Wang R.,Nanjing University | Wang Z.-X.,Nanjing Medical University | Yang J.-S.,Nanjing Medical University | Pan X.,Nanjing Medical University | And 2 more authors.
Oncogene | Year: 2011

Accumulating evidence suggests that microRNAs (miRNAs) are important gene regulators, which can have critical roles in diverse biological processes including tumorigenesis. In this study, we analyzed the miRNA expression profiles in non-small cell lung carcinoma (NSCLC) by use of a miRNA microarray platform and identified 40 differentially expressed miRNAs. We showed that miRNA (miR)-451 was the most downregulated in NSCLC tissues. The expression level of miR-451 was found to be significantly correlated with tumor differentiation, pathological stage and lymph-node metastasis. Moreover, low miR-451 expression level was also correlated with shorter overall survival of NSCLC patients (P=0.001). Ectopic miR-451 expression significantly suppressed the in vitro proliferation and colony formation of NSCLC cells and the development of tumors in nude mice by enhancing apoptosis, which might be associated with inactivation of Akt signaling pathway. Interestingly, ectopic miR-451 expression could significantly inhibit RAB14 protein expression and decrease a luciferase-reporter activity containing the RAB14 3′-untranslated region (UTR). In addition, RNA interference silencing of RAB14 gene could recapitulate the tumor suppressor function of miR-451, whereas restoration of RAB14 expression could partially attenuate the tumor suppressor function of miR-451 in NSCLC cells. Furthermore, we also showed that strong positive immunoreactivity of RAB14 protein was significantly associated with downregulation of miR-451 (P=0.01). These findings suggest that miR-451 regulates survival of NSCLC cells partially through the downregulation of RAB14. Therefore, targeting with the miR-451/RAB14 interaction might serve as a novel therapeutic application to treat NSCLC patients. © 2011 Macmillan Publishers Limited All rights reserved.


Huang R.,Nanjing University | Hao Y.,Nanjing Medical University | Zhang J.,Nanjing University | Wu C.,Nanjing Medical University
Hepatology Research | Year: 2013

Aim: The therapeutic effect of interferon (IFN)-α plus adefovir (ADV) combination therapy versus IFN-α monotherapy in chronic hepatitis B (CHB) treatment remains under debate. The objective of the present study was to compare the efficacy between these two regimens in CHB treatment. Methods: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature Database, National Knowledge Infrastructure, WANFANG and VIP databases were searched until 15 April 2012. All randomized controlled trials (RCT) comparing IFN-α plus ADV combination therapy versus IFN-α monotherapy for treating CHB patients were included. Review Manager ver.5.1.0 was used for meta-analysis. Results: Our results showed that the rate of undetectable serum hepatitis B virus (HBV) DNA was significantly higher in the IFN-α plus ADV combination group than in the IFN-α monotherapy group, both at 24 weeks (relative risk [RR]=1.74, 95% confidence interval [CI]=1.47-2.05, P<0.00001) and 48 weeks (RR=1.56, 95% CI=1.35-1.80, P<0.00001) of treatment and after treatment (RR=1.35, 95% CI=1.10-1.66, P=0.004). The serum hepatitis B e-antigen (HBeAg) negativation and HBeAg seroconversion rates were also higher in the combination group. However, a greater hepatitis B surface antigen loss rate was not found in the combination group. Forty-eight weeks of combination therapy improved the alanine aminotransferase normalization rate, but did not improve the rate of undetectable HBV DNA or that of HBeAg seroconversion as compared with 24 weeks of combination therapy. Conclusion: Based on the current studies, the efficacy of IFN-α plus ADV combination therapy is superior to IFN-α monotherapy. © 2013 The Japan Society of Hepatology.


Qiu Y.-D.,Nanjing University | Bai J.-L.,Nanjing Medical University | Xu F.-G.,Nanjing University | Ding Y.-T.,Nanjing University
World Journal of Gastroenterology | Year: 2011

AIM: To evaluate the effect of preoperative biliary drainage (PBD) on obstructive jaundice resulting from malignant tumors. METHODS: According to the requirements of Cochrane systematic review, studies in the English language were retrieved from MEDLINE and Embase databases from 1995 to 2009 with the key word "preoperative biliary drainage". Two reviewers independently screened the eligible studies, evaluated their academic level and extracted the data from the eligible studies confirmed by cross-checking. Data about patients with and without PBD after resection of malignant tumors were processed for meta-analysis using the Stata 9.2 software, including postoperative mortality, incidence of postoperative pancreatic and bile leakage, abdominal abscess, delayed gastric emptying and incision infection. RESULTS: Fourteen retrospective cohort studies involving 1826 patients with malignant obstructive jaundice accorded with our inclusion criteria, and were included in meta-analysis. Their baseline characteristics were comparable in all the studies. No significant difference was found in combined risk ratio (RR) of postoperative mortality and incidence of pancreatic and bile leakage, abdominal abscess, delayed gastric emptying between patients with and without PBD. However, the combined RR for the incidence of postoperative incision infection was improved better in patients with PBD than in those without PBD (P < 0.05). CONCLUSION: PBD cannot significantly reduce the postoperative mortality and complications of malignant obstructive jaundice, and therefore should not be used as a preoperative routine procedure for malignant obstructive jaundice. © 2011 Baishideng. All rights reserved.


Chen D.-Q.,Nanjing University | Pan B.-Z.,Nanjing University | Huang J.-Y.,Nanjing University | Zhang K.,Nanjing University | And 4 more authors.
Oncotarget | Year: 2014

Chemoresistance is one of the most significant obstacles in lung adenocarcinoma (LAD) treatment, and this process involves genetic and epigenetic dysregulation of chemoresistance-related genes. Previously, we have shown that restoration of microRNA (miR)-200b significantly reverses chemoresistance of human LAD cells by targeting E2F3. However, the molecular mechanisms involved in the silencing of miR-200b are still unclear. Here we showed that histone deacetylase (HDAC) inhibitors could restore the expression of miR-200b and reverse chemoresistant phenotypes of docetaxel-resistant LAD cells. HDAC1/4 repression significantly increased miR-200b expression by upregulating histone-H3 acetylation level at the two miR-200b promoters partially via a Sp1-dependent pathway. Furthermore, silencing of HDAC1/4 suppressed cell proliferation, promoted cell apoptosis, induced G2/M cell cycle arrest and ultimately reversed in vitro and in vivo chemoresistance of docetaxel-resistant LAD cells, at least partially in a miR-200b-dependent manner. HDAC1/4 suppression-induced rescue of miR-200b contributed to downregulation of E2F3, survivin and Aurora-A, and upregulation of cleaved-caspase-3. HDAC1/4 levels in docetaxel-insensitive human LAD tissues, inversely correlated with miR-200b, were upregulated compared with docetaxel-sensitive tissues. Taken together, our findings suggest that the HDAC1/4/Sp1/miR-200b/E2F3 pathway is responsible for chemoresistance of docetaxel-resistant LAD cells. © 2008-2014 Impact Journals, LLC.


Rui W.,Nanjing University | Bing F.,Nanjing University | Hai-Zhu S.,Nanjing University | Wei D.,Nanjing Medical University | Long-Bang C.,Nanjing University
Journal of Cellular and Molecular Medicine | Year: 2010

Docetaxel has been used as first-line chemotherapy in advanced non-small cell lung carcinoma (NSCLC), but further extensive and effective application is prevented by drug resistance. MicroRNAs (miRNAs) have recently been identified as important posttranscriptional regulators, which are involved in various biological processes. The aim of this study was to identify microRNA expression profiles involved in the development of docetaxel resistance in NSCLC. Here, microarray chip technology was employed to identify miRNA expression profiles in docetaxel-resistant human NSCLC cell line (SPC-A1/docetaxel). Then, the changes of miRNAs expression (>2-fold compared with control SPC-A1 cell line) were testified by quantitative real-time RT-PCR (qRT-PCR) assay. Furthermore, the potential target genes regulated by selected miRNAs were analysed by various target prediction tools. The expression of a total of 52 miRNAs showed significant difference between SPC-A1/docetaxel cells and control SPC-A1 cells (P < 0.01). Six miRNAs (miR-192, 200b, 194, 424, 98 and 212) exhibited more than 2-fold changes in their expression levels, which were validated by qRT-PCR. The expression of three miRNAs (miR-200b, 194 and 212) was significantly down-regulated in SPC-A1/docetaxel cells, while the expression of other three miRNAs (miR-192, 424 and 98) was significantly up-regulated in SPC-A1/docetaxel cells (P < 0.01). Potential target genes controlled by six selected miRNAs were divided into four groups according to various functions: apoptosis and proliferation (71 genes), cell cycle (68 genes), DNA damage (26 genes) and DNA repair (59 genes). The expression of a few target genes in SPC-A1/docetaxel and SPC-A1 cells were further confirmed by qRT-PCR and Western blot. Taken together, the identification of microRNA expression profiles in docetaxel-resistant NSCLC cells could provide a better understanding of mechanisms involved in drug sensitivity or resistance, which would be helpful to develop novel strategies for targeted therapies in chemorefractive NSCLC patients. © 2009 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.


Tucker J.D.,Chinese Academy of Sciences | Tucker J.D.,Massachusetts General Hospital | Bu J.,Chinese Academy of Sciences | Bu J.,Nanjing Medical University | And 4 more authors.
The Lancet Infectious Diseases | Year: 2010

Syphilis is a persistent public health issue in many low-income countries that have limited capacity for testing, which traditionally relies on a sensitive non-treponemal test and then a specific treponemal test. However, the development of a new rapid treponemal test provides an opportunity to scale up syphilis screening in many settings where traditional tests are unavailable. This systematic review of immunochromatographic strip (ICS) syphilis tests describes the sensitivity and specificity in two important clinical settings: sexually transmitted infection (STI) clinics and antenatal clinics. Clinical data from more than 22 000 whole blood, plasma, or fingerstick ICS tests obtained at STI or antenatal clinics were retrieved from 15 studies. ICS syphilis tests have a high sensitivity (median 0·86, interquartile range 0·75-0·94) and a higher specificity (0·99, 0·98-0·99), both comparable with non-treponemal screening test characteristics. Further research evaluating ICS syphilis tests among primary syphilis cases and among patients infected with HIV will be essential for the effective roll-out of syphilis screening programmes. © 2010 Elsevier Ltd. All rights reserved.


Hua J.,Tongji University | Hua J.,Nanjing Medical University | Gong J.,Tongji University | Yao L.,Tongji University | And 2 more authors.
American Journal of Surgery | Year: 2014

Background The feasibility and safety of low-pressure pneumoperitoneum in laparoscopic cholecystectomy remain unclear. Methods A meta-analysis of randomized controlled trials comparing low-pressure with standard-pressure pneumoperitoneum was performed. Results A total of 1,263 patients were included. Low-pressure pneumoperitoneum was associated with significantly decreased postoperative pain. The requirement for increased pressure was significantly greater in the low-pressure group (risk ratio = 6.16; P <.001). Operative time was similar, with only a slight statistical significance (weighted mean difference = 2.07; P <.001). Length of hospital stay was shorter in the low-pressure group (weighted mean difference = -.27; P =.01). No significant differences were found in surgical complications or conversion to open surgery. Conclusions Low-pressure pneumoperitoneum is feasible and safe and results in reduced postoperative pain and near-equal operative time compared with standard-pressure pneumoperitoneum. More studies are required to investigate the potential benefits of the reduced length of hospital stay. © 2014 Elsevier Inc. All rights reserved.


Ren K.,Nanjing University | Wu J.,Nanjing University | Yan F.,Nanjing Medical University | Zhang Y.,Nanjing University | Ju H.,Nanjing University
Biosensors and Bioelectronics | Year: 2015

A sensitive ratiometric electrochemical readout was designed with an immunoreaction-triggered DNA assembly for one-step, fast and flexible assay of protein biomarker. The sensing interface was prepared by immobilizing a ferrocene (Fc)-labeled hairpin DNA on a gold electrode. In the presence of DNA2-antibody2 (Ab2) and methylene blue (MB)-labeled DNA1-Ab1 probes, the addition of target protein could induce the sandwich immunoreaction among two probes and the protein to trigger the hybridization of DNA1 and DNA2, which subsequently unfolded the hairpin DNA to form a three-arm DNA structure on the sensing interface. The DNA assembly caused the departure of Fc from the electrode and the approach of MB to the electrode, which led to the signal decrease and increase of Fc and MB respectively for ratiometric readout. Using prostate specific antigen (PSA) as a model target, the ratiometric electrochemical assay showed a linear detection range from 0.01 to 200. ng/mL with a detection limit of 4.3. pg/mL (the mean signal of blank measures+3. σ). By changing the affinity probe pairs this method could be easily expanded for other protein analytes, showing promising potential for point-of-care testing and extensive applications in bioanalysis. © 2014 Elsevier B.V.


Xie J.,Nanjing Medical University | Liu M.,Nanjing Medical University | Li Y.,Nanjing Medical University | Nie Y.,Nanjing University | And 2 more authors.
Cellular and Molecular Immunology | Year: 2014

MicroRNAs (miRNAs) are a class of small non-coding regulatory RNAs, and changes in miRNAs are involved in tumor origin and progression. Studies have shown that miR-20a is overexpressed in human ovarian cancer tissues and that this miRNA enhances long-term cellular proliferation and invasion capabilities. In this study, a positive correlation between serum miR-20a expression and ovarian cancer stage was observed. We found that miR-20a binds directly to the 3′-untranslated region of MICA/B mRNA, resulting in its degradation and reducing its protein levels on the plasma membrane. Reduction of membrane-bound MICA/B proteins, which are ligands of the natural killer group 2 member D (NKG2D) receptor found on natural killer (NK) cells, γδ+ T cells and CD8+ T cells, allows tumor cells to evade immune-mediated killing. Notably, antagonizing miR-20a action enhanced the NKG2D-mediated killing of tumor cells in both in vitro and in vivo models of tumors. Taken together, our data indicate that increased levels of miR-20a in tumor cells may indirectly suppress NK cell cytotoxicity by downregulating MICA/B expression. These data provide a potential link between metastasis capability and immune escape of tumor cells from NK cells. © 2014 CSI and USTC. All rights reserved.