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.

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Liu X.Z.,Nanjing Medical University | Fang H.,Nanjing University
Scientometrics | Year: 2017

To explore whether there are other factors than count and sentiment that should be incorporated in evaluating research papers with social media mentions, this paper analyses the content of tweets linking to the top 100 papers of 2015 taken from www.altmetric.com, focusing on the goals, functions and features of research. We discuss three basic issues inherent in using tweets for research evaluation: whose tweets can be used to assess a paper, what objects can be evaluated, and how to score the paper according to each tweet. We suggest that tweets written by those involved in publication of the paper in question should not be included in the paper’s evaluation. Tweets unrelated to the content of the paper should also be excluded. Because controversies in research are inevitable and difficult to resolve, we suggest omitting somewhat supportive and negative tweets in research evaluation. Logically, neutral tweets (such as those linking to, and excerpts from, papers) express a degree of compliment, agreement, interest, or surprise, albeit less so than the tweets explicitly expressing these sentiments. Recommendation tweets also reflect one or more of these sentiments. Expansion tweets, which are inspired by the papers, reflect the function of research. Therefore, we suggest giving a higher weight to praise, agreement, interest, surprise, recommendation and expansion tweets linking to an academic paper than neutral tweets when scoring a paper. Issues related to electronic publishing and social media as learned from tweets are also discussed. © 2017 Akadémiai Kiadó, Budapest, Hungary

Li S.,Nanjing University of Aeronautics and Astronautics | Yu Y.,Nanjing University of Aeronautics and Astronautics | Chen H.,Nanjing Medical University
Pacific Asia Conference on Information Systems, PACIS 2016 - Proceedings | Year: 2016

The aim of this article was to use the Support Vector Machine (SVM) to predict the benign and malignant solitary pulmonary nodules (SPNs) in early-stage lung cancer in order to lessen the patient's pain and save the money. Fifty and one patient records were collected.Each record consisted of four clinical characteristics and nine morphological characteristics. The SVM classifier was built by radial basis kernel function. The penalty factor C and kernel parameter s were optimized by comparing particle swarm optimization (PSO), grid search algorithm (GSA) and genetic algorithm (GA) and then employed to diagnose the SPNs. By comparison with a Logistic regression (LR) model, the overall results of our calculation demonstrated that the area under the receiver operator characteristic (ROC) curve for the model (0.913 ± 0.051, p<0.05) was higher than the LR model. The accuracy, sensitivity and specificity in the model were 90.7%, 89.3% and 93.3% respectively. It is represented that the PSO-SVM model can be used in predicting the early-stage lung nodules.

Chen C.,Nanjing Medical University | Chen C.,First Peoples Hospital of Changzhou | Qian Y.,Nanjing Medical University
Folia Neuropathologica | Year: 2016

Unmethylated CpG DNA, as a stimulatory molecule, has potent pro-inflammatory effects in the central nervous system (CNS). Dexmedetomidine (DEX) has been confirmed to exert anti-inflammatory effects in CNS. Our study was aimed to explore the effects of DEX on tumor necrosis factor-α (TNF-α) expression in unmethylated CpG DNA-challenged microglia. In vivo, after 3 d intracisternal injection of ODN1668, we evaluated the severity of meningitis with or without DEX via pathobiology method and detected the expression of TNF-α from molecular and protein levels. In vitro, we explored whether the ODN1668 could activate microglia to express TNF-α and the inhibition mechanism of DEX. Our results demonstrated that DEX could alleviate the severity of ODN1668-induced meningitis. And while BV2 microglia was stimulated by ODN1668 for different time, TNF-α was increased in mRNA and protein levels but the effect was attenuated by DEX via decreasing phosphorylated AKT and ERK.

Zhong J.,Nanjing Medical University | Wang L.-P.,Nanjing Medical University
Chinese Journal of New Drugs | Year: 2016

Clinical trials of innovative drugs are explorations involving complex technology, thus having high and diverse risks. At present, the rapid development of innovative drugs makes China's researchers of clinical trials face many challenges, especially how to avoid the risk of trials and protect the safety and benefits of subjects. This paper mainly discusses how to strengthen the protection of subjects from the aspects of environment and personnel, project design, ethical review, safety supervision, damage compensation and so on. © 2016, Chinese Journal of New Drugs Co. Ltd. All right reserved.

STUDY DESIGN.: A genetic association study. OBJECTIVE.: To investigate whether NUCKS1 is a susceptible gene of adolescent idiopathic scoliosis (AIS) in Chinese population and to further narrate its association with the clinical phenotypes. SUMMARY OF BACKGROUND DATA.: AIS is characterized by late onset of menarche and disturbed growth rhythm. Previous studies showed that NUCKS1 is associated with age at menarche and pubertal height growth. METHODS.: SNP rs951366 of NUCKS1 was genotyped in 972 patients and 1454 healthy controls. The differences of genotype and allele distributions between AIS patients and healthy controls were evaluated using the Chi-square test. One-way ANOVA test was used to compare the relationship between different genotypes and clinical features including tissue expression of NUCKS1, age at menarche and curve magnitude. RESULTS.: Patients were found to have a significantly lower frequency of CC than the controls (5.9% vs. 10.6%, p?

An X.,Nanjing Medical University | Zhang J.,Nanjing Medical University
Chinese Journal of Emergency Medicine | Year: 2016

Cardiovascular drugs are commonly used in clinical medicine, which can cause refractory shock and cardiac arrest when poisoning. Lipid emulsion was mainly used for detoxification of lipophilic anesthetics poisoning in the past. Recently more and more studies and clinical cases suggest that lipid emulsion can be adopted as one of therapies for cardiovascular drugs poisoning. Now we review and focus on the research status of the lipid emulsion in the treatment of cardiovascular drugs poisoning, the related mechanisms of detoxification, therapeutic regimen and adverse effect.

Li W.-H.,Nanjing Medical University | Wang P.,Nanjing Medical University
Chinese Journal of Schistosomiasis Control | Year: 2016

The stem cell is a class of primitive cells with self-renewal, and multiple pluripotent potential capacities, which can differentiate into multiple specialized cells and generate human organs and tissues. Stem cell therapy is an interventional treatment that introduces new stem cells to damaged tissues, which facilitates the regeneration of trauma, disease and ageing-in- duced damaged human tissues to repair or replace the damaged tissues, thereby achieving the goal of disease treatment. It has been proved that the stem cell therapy is effective in the treatment of multiple human diseases, including cancer, diabetes, neurological disorders, autoimmune diseases, cardiovascular disorders and blood diseases. This review summarizes the advances in the research of stem cell therapy for human parasitic infections.

Xu P.,Nanjing Medical University | Liu X.,Nanjing Medical University | Ouyang J.,Nanjing Medical University | Chen B.,Nanjing Medical University
PLoS ONE | Year: 2017

Non-Hodgkin lymphoma (NHL) is a group of malignant hematologic disorders with high heterogeneity. The diagnosis, clinical manifestations, classification, and prognosis of this condition differ among numerous NHL subgroups. The prognostic significance of the mutation of TP53, a tumor suppressor gene involved in cell cycle regulation, should be confirmed in NHL. In this study, our searching strategy and inclusion criteria were implemented, and the pooled hazard ratios (HRs) of the included studies were calculated directly or indirectly. A total of 1,851 patients were enrolled in 22 studies. A meta-analysis was then performed using STATA version 12.0 to confirm the correlation between the status of TP53 mutation and the survival time of patients with NHL. Statistical heterogeneity was assessed with a chi-square-based Q statistical test and Inconsistency index (I2) statistic. Sensitivity analysis and publication bias were also evaluated. A total of 22 studies were included in our metaanalysis. The pooled HR of the overall survival from 20 studies was 2.30 (95% CI: 1.92-2.76, p = 0.001) with heterogeneity (I2 30.2% p = 0.099). The pooled HR of the progression free survival provided in 5 articles was 2.28 (95% CI: 1.78-2.93, p = 0.001) with heterogeneity (I2 39.8% p = 0.156). No publication bias was found among the included studies, and sensitivity analysis suggested that the combined HRs were stable after any of the studies was excluded from our meta-analysis. This study identified the prognostic significance of TP53 mutation that varied in different NHL subgroups. The group with a mutated TP53 was significantly associated with poor prognosis in patients with NHL. This parameter is a valuable basis for accurate individual therapeutic regimens. © 2017 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Wang R.,Nanjing Medical University | Fang D.,Nanjing Medical University
RSC Advances | Year: 2017

Phosphatidylserine (PS) in the plasma membrane of single apoptotic cells was detected using luminol electrochemiluminescence for the first time. Membrane PS was converted by aqueous phospholipase D and l-amino acid oxidase to generate hydrogen peroxide, inducing electrochemically generated luminescence. The successful observation of PS in the cellular membrane provided a special strategy for the observation of cellular apoptosis of single cells. © The Royal Society of Chemistry.

Huang X.,Nanjing Medical University | Lu S.,Nanjing Medical University
Molecular and Cellular Biochemistry | Year: 2017

The functional impact of recently discovered miRNAs in human cancer remains to be clarified. One miRNA in colorectal cancer which has attracted attention is miR-545. In this study, we examined the function of miR-545 in proliferation of colorectal cancer cells. Expressions of HOTAIR, miRNA-545, and epidermal growth factor receptor (EGFR) mRNA were measured in 100 paired cancerous and non-cancerous tissues as well as in SW480 and LOVO colorectal cancer cell (CRC) lines by quantitative RT-PCR. The relative protein level of EGFR was measured using western blotting. Effects of miRNA-545 and HOTAIR on gastric cancer cells were studied by overexpression and RNA interference approaches. Insight of mechanism of promotion cancer by miR-545 was gained from luciferase reporter assay and gene expression analysis. CRC proliferation was evaluated using clone formation and MTT assay. Differential expressions of HOTAIR, miR-545, and EGFR were observed in cancerous tissues in comparison to non-cancerous tissues. By expressional management of miR-545, we observed that miR-545 negatively regulated cell proliferation. Also luciferase reporter assay revealed that miR-545 inhibited regulated EGFR expression by affecting its 3′-UTR activity. In addition, miR-545 expression was suppressed by HOTAIR overexpression whereas enhanced by HOTAIR silence. Suppression of EGFR expression by miR-545 mimic was abrogated by HOTAIR overexpression. Monitoring of tumor growth in mice showed that miR-545 overexpression suppressed LOVO tumor growth. Our data suggested that HOTAIR long non-coding RNA mediates microR-545 regulating colorectal cancer cells proliferation. © 2017 Springer Science+Business Media New York

Li S.,Wenzhou Central Hospital | Jin Z.,Wenzhou Central Hospital | Lu X.,Nanjing Medical University
Molecular and Cellular Biochemistry | Year: 2017

Fibroblast-like synoviocytes (FLSs) play an important role in the pathogenesis of rheumatoid arthritis (RA). This study was conducted to explore the role of microRNA (miR)-192 in the regulation of the biology of RA-FLSs. The expression of miR-192 in RA and healthy synovial tissues was measured. The effects of overexpression of miR-192 on RA-FLS proliferation and apoptosis were investigated. Luciferase reporter assay and Western blot analysis were performed to identify direct target genes of miR-192. RA synovial tissues had significantly lower levels of miR-192 than healthy controls (P = 0.004). Moreover, miR-192 levels were 2.9-fold lower in RA-FLSs relative to normal human FLSs (P < 0.05). Ectopic expression of miR-192 significantly inhibited the proliferation and caused a cell cycle arrest at the G0/G1 phase in RA-FLSs. Moreover, miR-192 overexpression triggered apoptosis, which was accompanied by an increase in caspase-3 activity and Bax/Bcl-2 ratio. Caveolin 1 (CAV1) was identified to be a direct target of miR-192. Overexpression of miR-192 led to a reduction of endogenous CAV1 in RA-FLSs. Silencing of CAV1 significantly decreased cell proliferation and promoted apoptosis in RA-FLSs. Rescue experiments with a miR-192-resistant variant of CAV1 showed that enforced expression of CAV1 restored cell proliferation and attenuated apoptosis in miR-192-overexpressing RA-FLSs. In conclusion, miR-192 is downregulated in RA synovial tissues and restoration of its expression elicits growth-suppressive effects on RA-FLSs by targeting CAV1. The miR-192/CAV1 pathway may represent a novel target for prevention and treatment of RA. © 2017 Springer Science+Business Media New York

MTA1 is a metastasis-associated protein, which is essential to epithelial-to-mesenchymal transition (EMT). However, information concerning its up- and downstream regulation is rare. We investigated its upstream regulation and downstream effector in human hepatocellular carcinoma (HCC). In total, 94 paired HCC and adjacent tissue samples were involved in the study, and the results indicated that decreased miR-30e levels were associated with increased MTA1 levels in human HCC. miR-30e exerted its regulation of MTA1 transcription by binding to its 3′-untranslated region, and was negatively associated with EMT. Furthermore, significantly higher expression of MTA1 was associated with overexpression of v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ErbB2) in human HCC, and MTA1 can promote transcription of ErbB2 by binding with histone deacetylase 2 (HDAC2) and acting as a promoter. The EMT promotion effect caused by MTA1 largely depended on ErbB2, and reducing the activity of ErbB2 can significantly attenuate EMT promotion by causing overexpression of MTA1 both in vitro and in vivo. In general, downregulation of miR-30e can increase levels of MTA1 in human HCC, and furthermore promote cell invasion and metastasis by promoting ErbB2.Oncogene advance online publication, 13 March 2017; doi:10.1038/onc.2016.491. © 2017 Macmillan Publishers Limited, part of Springer Nature.

Yan J.-J.,Nanjing Medical University | Lu Y.,Nanjing Medical University | Kuai Z.-P.,Nanjing Medical University | Yong Y.-H.,Nanjing Medical University
Journal of Cellular and Molecular Medicine | Year: 2017

Epidemiologic studies are inconsistent regarding the association between plasma copeptin level and heart failure (HF). The aim of this study was to perform a meta-analysis to determine whether high level of copeptin is correlated with incidence of HF and mortality in patients with HF. We searched PUBMED and EMBASE databases for studies conducted from 1966 through May 2016 to identify studies reporting hazard ratio (HR) estimates with 95% confidence intervals (CIs) for the association between plasma copeptin level and HF. A random-effects model was used to combine study-specific risk estimates. A total of 13 studies were included in the meta-analysis, with five studies on the incidence of HF and eight studies on the mortality of patients with HF. For incidence of HF, the summary HR indicated a borderline positive association of high plasma copeptin level with HF risk (HR, 1.60; 95% CI, 0.90-2.85). Furthermore, an increase of 1 standard deviation in log copeptin level was associated with a 17% increase in the risk of incident HF (HR, 1.17; 95% CI, 1.02-1.33). For all-cause mortality of patients with HF, we also found a significant association between elevated plasma copeptin level and increased mortality of HF (HR, 1.76; 95% CI, 1.33-2.33). Our dose-response analysis indicated that an increment in copeptin level of 1 pmol/l was associated with a 3% increase in all-cause mortality (HR, 1.03; 95% CI, 1.01-1.05). In conclusion, our results suggest that elevated plasma copeptin level is associated with an increased risk of HF and all-cause mortality in patients with HF. © 2017 Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Rong C.,Nanjing Medical University | Feng Y.,Nanjing Medical University | Ye Z.,Nanjing Medical University
Oncology Letters | Year: 2017

Cervical cancer, which is the second most common female malignancy, is characterized by the consistent presence of human papillomavirus. Inappropriate activation of Notch signaling has been associated with various types of cancer; however, the role of Notch in cervical cancer remains unclear. The present study aimed to investigate the role of Notch in cervical cancer. The methods used included the generation of plasmids, viability assays, polymerase chain reaction and western blotting The present findings demonstrated that cervical cancer samples also consistently exhibit abnormal activation of the Notch pathway. The data also indicated that different Numb isoforms may have opposite effects on the proliferation of cervical cancer cells. As a result, the activated Notch signaling pathway regulates the alternative splicing of the Numb gene, which affects the proliferation of the cervical cancer cells. These findings suggest that activated Notch signaling may lead to the development of cervical cancer by regulating Numb splicing. Thus, Numb splice variants may be a potential clinical marker for indicating cervical cancer genesis and development. © 2017, Spandidos Publications. All rights reserved.

Liu S.,Nanjing Medical University | Zhu B.,Nanjing Medical University
Chinese Journal of Medical Imaging Technology | Year: 2016

Development of MRI technology will enable uterus better visualization and shed light on the relationship of its movement and function. Cine-MRI was a suitable method for the detection of pelvic organ motion and the functional examination. The research progresses on Cine-MRI of endometrial peristalsis in physiological and pathological state were reviewed in this article. Copyright © 2016 by the Press of Chinese Journal of Medical Imaging and Technology.

Wu Y.-Z.,Nanjing Medical University | Sun J.,Nanjing Medical University | Wang Y.-B.,Nanjing Medical University
Carbohydrate Polymers | Year: 2017

A polysaccharide named SpaTA, as novel selective estrogen receptor modulator, was isolated from water extraction of traditional Chinese herbal medicine Sparganii Rhizoma. SpaTA had a backbone consisting of 2-O-grailsine-β-xylose (4 → 6)-α-glucose (1 → 4) −β-mannose osamine. There is an aluminium element combined with nitrogen on both grailsine and mannose osamine in repeating unit of SpaTA. The anticancer effect of SpaTA was assessed using ZR-75-1 human breast cancer cells. The results showed that SpaTA induced sequential increases in proliferation and apoptosis through a time- and concentration-dependent manner. Further studies revealed that SpaTA regulated the expression and nuclear translocation of ERα, then modulated the downstream estrogen signaling pathway. Moreover, knock-down ERα in ZR-75-1 cells and overexpress ERα in MDA-MB-231 cells also provided evidences that SpaTA activated the apoptosis-related caspase −3, −8, −9 and PARP in an ERα-dependent manner. Taken together, these results indicated that SpaTA can induce the apoptosis of breast cancer cells through regulating ERα. Therefore, SpaTA may be considered as an effective agent against human breast cancer. © 2017 Elsevier Ltd

Ai J.-W.,Henan University | Liu B.,The Second Peoples Hospital of Liaocheng | Liu W.-D.,Nanjing Medical University
Materials Science and Engineering C | Year: 2017

In this study, folic acid surface modified-Titanium dioxide nanoparticles (FA-TiNP) were prepared as a suitable alternative to conventional chemotherapeutic agents to treat human osteosarcoma. The particle size of TiNP increased marked after polymer assembly on the nanoparticles (NP) surface with a spherical morphology. FA-TiNP exhibited a superior anticancer effect in osteosarcoma cancer cells compared to that of bare TiNP. The reason might due to the specific interaction of FA with the folate receptor which is overexpressed in the cancer cells. Especially, FA-TiNP treated cells exhibited chromatin condensation, cell shrinkage and membrane blebbing. FA-TiNP showed significantly higher cancer cell apoptosis with nearly 38% of cells in apoptosis chamber (early and late) compared to only ~ 16% for TiNP. The higher proportion of Annexin V positive cells for FA-TiNP treated group was mainly attributed to the higher intracellular uptake of the TiO2. Importantly, FA-TiNP increased the sub-G0 population to ~ 25% indicating its superior anticancer effect. The results clearly indicated that FA-TiNP induced greater reactive oxygen species (ROS) generation that resulted in higher sub-G0 cell population with higher cell apoptosis. FA-TiNP showed a remarkably higher expression of cytochrome C (Cyt C) with a marked increase in the expression of cleaved caspase-3 and PARP. Overall, results suggest that surface modification of TiNP with a specific targeting moiety could enhance the chances of having successful therapies for cancer diseases. © 2017 Elsevier B.V.

OBJECTIVE: To Verify the value of the ratio of sensory nerves conductive velocity along palm-median finger /wrist-palm minus 1 for diagnosis of the mild-moderate carpal tunnel syndrome(CTS).METHODS: The different value between 1 and the ratio of sensory nerves conductive velocity along palm-median finger/wrist-palm was defined as index-CTS which was used to assess the severity of CTS.The index-CTS of 100 palms from healthy controls and 58 palms from mild-moderate CTS patients were calculated and compared.Multiple regression was used to identify the relative factors of index-CTS.The ROC curve was used to evaluate the sensitivity and specificity of index-CTS at different values.RESULTS: The value of index-CTS from healthy controls and patients both fitted Gaussian distribution.The mean value were -0.053±0.042 vs 0.055±0.074 in the controls and the patients respectively.The difference was statistically significant between the two groups by T-test(P<0.001). Multiple regression analysis showed that Tinel sign, Phalen sign, laterality, clinical grade, electrical grade were identifiable factors related to index-CTS.When index-CTS was over 0.001 and Ⅳ-DL over 0.395 ms , specificity of diagnosis by both can get 92%, but index-CTS showed more higher sensitivity(98.3% vs 89.7%).CONCLUSIONS: Rising index-CTS could be the most significant electrophysiological feature in CTS.It can be used as a sensitive marker to assess the extent of conduction block of median nerve in carpal tunnel.

Qian S.-H.,Nanjing Medical University
Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics | Year: 2016

OBJECTIVE: To study the association between wheezing and Mycoplasma pneumoniae (MP) infection in infants and young children.METHODS: A total of 228 hospitalized infants and young children who were diagnosed with lower respiratory tract infection were enrolled and classified into initial wheezing group (n=65), recurrent wheezing group (n=83), and non-wheezing group (n=80). Fasting serum was collected on the day or the second day of admission. ELISA was used to measure MP-IgM, chemiluminescence was used to measure serum total immunoglobulin E (TIgE), and EUROLine was used to measure the common serum allergen specific immunoglobulin E (sIgE). The data on the manifestations of atopic constitution and the family history of allergic diseases were collected.RESULTS: The initial wheezing group and the recurrent wheezing group showed significantly higher positive MP infection rate and serum TIgE level than the non-wheezing group (P<0.05). The recurrent wheezing group showed a significantly higher positive rate of sIgE than the initial wheezing group and the non-wheezing group (P<0.05), and in these patients, the manifestations of atopic constitution and the family history of allergic diseases were closed associated with the pathogenesis of wheezing.CONCLUSIONS: MP infection is closely associated with wheezing in infants and young children. MP is one of the most common pathogens for wheezing in infants and young children, and the allergen sIgE, atopic constitution, and a family history of allergic diseases are important risk factors for recurrent wheezing.

OBJECTIVE: To evaluate the efficacy of a growth-guidance growing rod in an established porcine scoliosis model via the Cobb angle correction and the continued spinal growth.METHODS: Immature pigs (age: 6 weeks old, weight: 6-8 kg) were instrumented and tethered using a three separate incisions fashion.After considerable scoliosis was induced, the pigs were randomly assigned to an experiment group (EG) and a sham group (SG). In EG, the growing rod was implanted and the pigs were euthanized 8 weeks postoperatively; while in SG, the whole instrumentations were only removed and the pigs were followed up over a 8-week period.Dorsoventral (DV) X-ray radiographs were taken prior to and immediately after the growing rod implanting surgery, and at 4-week intervals to assess the Cobb angle orrection and instrumentation positioning.The continued spinal growth and the rod sliding were also assessed from the radiographs.RESULTS: Of the 16 pigs, one pig encountered infection during the inducement of the experimental scoliosis and thus was excluded from analysis.Of the remaining 15 pigs, all animals developed progressive, structural scoliosis.The 15 pigs were randomized into EG(n=10) and SG(n=5). Two pigs in EG encountered infection and were also excluded from analysis.Of the remaining 8 pigs in EG, no neurologic complications, implant failure or infection were observed.In EG, the Cobb angle of the scoliosis before the growing rod implanted was (52.1 ±14.1)° and it decreased to (25.4±15.2)° postoperatively.After 8 weeks, the Cobb angle was (20.2±11.4)°.In SG, the Cobb angle of the scoliosis after 8-week tethering period was (55.2±15.7)° and it decreased to (53.6±15.8)° after removal of the tethering.The curvature remained stable (51.2°) during the subsequent 8 weeks.During the 8-16th week, the spinal height increased 14.2 cm and radiographic analysis of the growing rod sliding revealed an average distraction of 39.8 mm in EG; while in SG, the increased spinal height was 14.9 cm.The difference of the increased spinal height between EG and SG was not significant (P=0.821).CONCLUSION: The novel growing rod system can provide substantial correction of deformity, and additionally, allow for continually spinal growth without significant growing disturbance.

Cao Y.J.,Nanjing Medical University
Zhonghua wai ke za zhi [Chinese journal of surgery] | Year: 2016

Objective: To explore the prognostic factors of portal hypertension treated with devascularization. Methods: A total of 397 patients with portal hypertension underwent devascularization in Nanjing Drum Tower Hospital from February 1993 to April 2014, among which there were 242 male and 155 female patients with median age of 48 years. The perioperative data were retrospectively collected. Logistic regression was used to find the risk factors which affect the operative complications. Follow-up evaluation was in progress regularly. Kaplan-Meier survival curve, Log-rank test and Cox regression model were used to find out factors which affect the long-term results. Results: All together 397 patients underwent devascularization, in whom 8 patients died perioperative, 389 patients discharged successfully. Logistic regression showed that age (≥48 years) (χ2=4.559, OR=2.048, P=0.033), red color sign before surgery (χ2=4.959, OR=2.129, P=0.026) and without portosystemic collateral vessels reserved (χ2=13.348, OR=5.122, P=0.000) were risk factors of perioperative complications. The follow-up time was (5.7±4.6) years. Totally 27 patients were lost from follow-up, 103 patients died for the disease during follow-up. The survival rate at 1-, 3-, 5-, 10-, 15- and 20-years was 93.6%, 86.9%, 80.1%, 59.3%, 54.1% and 38.5% respectively.Univariate analysis showed that gender (male), age (≥48 years), hemorrhage before surgery (≥500 ml per time), hepatitis virus and without portosystemic collateral vessels reserved were risk factors of the long-term survival (P<0.05). Cox regression analysis showed that age (≥48 years) (χ2=9.850, RR=1.904, P=0.002), hemorrhage before surgery (≥500 ml per time) (χ2=34.402, RR=3.273, P=0.000), hepatitis virus (χ2=7.573, RR=2.525, P=0.006) and without portosystemic collateral vessels reserved (χ2=5.905, RR=1.889, P=0.015) were independent risk factors that affect the long-term survival. Conclusion: Devascularization with portosystemic collateral vessels reserved has favorable perioperative and long-term outcome, and it definitely is a very safe and effective technique for portal hypertension.

Chen L.W.,Nanjing Medical University
Zhonghua xin xue guan bing za zhi | Year: 2016

OBJECTIVE: To explore the potential role and mechanism of microRNA(miR)-30a in myocardial fibrosis after myocardial infarction (MI).METHODS: Rats were randomly divided into 1 week MI group (n=11), 2 weeks MI group (n=13) and 4 weeks MI group (n=15) by applying random number table after left anterior descending coronary artery ligation. Rats in Sham group were examined at respective time points (n=16). Heart function was monitored by echocardiography. Myocardial collagen volume fraction (CVF) was determined on Masson stained sections. Myocardial expression of collagen Ⅰ and Ⅲ was determined by immunohistochemistry. The myocardial mRNA level of miR-30a, TGF-β1 and CTGF were detected by real time-quantitative PCR analysis. The myocardial protein levels of TGF-β1 and CTGF were measured by Western blot analysis.RESULTS: The LVEDD ((8.37±0.58) mm) and LVESD ((6.12±0.82) mm) in 4 weeks MI group were significantly higher than those in Sham group ((6.08±0.57) mm, (4.17±0.60) mm), all P<0.01. The FS ((27.0±3.9) %) and LVEF ((51.0±6.3) %) in 4 weeks MI group were significantly lower than those in Sham group ((47.0±2.1) %, (82.0±2.3)%), all P<0.01. The level of myocardial CVF in 1 week MI group, 2 weeks MI group and 4 weeks MI group were significantly higher than in Sham group (all P<0.01) in a time-dependent manner. The level of myocardial collagen Ⅰ and Ⅲ was increased gradually from 1 week to 4 weeks post MI compared with Sham group (all P<0.01). The collagen Ⅰ/Ⅲ ratio was similar between 1 week MI group and Sham group (P=0.58), however, which was significantly higher in 2 weeks MI group and 4 weeks MI group compared with Sham group (all P<0.01), and the ratio was significantly higher in 4 weeks MI group than 2 weeks MI group (P<0.01). The level of miR-30a was significantly and gradually reduced in all MI groups compared with Sham group (all P<0.01). The mRNA and protein levels of TGF-β1 and CTGF were significantly and gradually increased after MI compared with Sham group (all P<0.001).CONCLUSIONS: Our results indicate that overexpression of miR-30a after MI might be a potential strategy for suppressing myocardial fibrosis by modulating the mRNA and protein levels of TGF-β1 and CTGF.

Chen C.,Nanjing Medical University | Guo D.,Jiangnan University | Lu G.,Nanjing Medical University
Molecular Medicine Reports | Year: 2017

Inflammation in the retinal pigment epithelium is an important contributor to the pathogenesis of age-related macular degeneration. Wogonin is a flavonoid isolated from the root of Scutellaria baicalensis and has multiple pharmacological effects, including anti-inflammatory effects. The present study sought to determine if the pharmacological effects of wogonin were relevant to the treatment of AMD. ARPE-19 cells were pre-conditioned with different concentrations of wogonin (0-50 M) prior to induction of inflammation with LPS (2 g/ml). Transepithelial electrical resistance analysis demonstrated that 24 h treatment with 10 and 50 M wogonin ameliorated LPS-induced changes. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunofl uorescence analyses revealed that wogonin restrained LPS-induced tight junction proteins, claudin-1 and ZO-1. LPS-induced upregulation of inflammatory mediators in ARPE-19 cells, including IL-1β, IL-6, IL-8, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and TNF-α was reduced after pre-treatment with wogonin. In addition, RT-qPCR and western blotting demonstrated that wogonin inhibited the expression of TLR4 in LPS-stimulated ARPE-19 cells. This is a novel mechanism indicating that pre-treatment with wogonin could attenuate the TLR4/NF-κB-mediated inflammatory response in LPS-stimulated ARPE-19 cells, and thus could be a potential therapy for the treatment of AMD.

Mei J.,Nanjing Medical University | Chang K.-K.,Fudan University | Sun H.-X.,Nanjing Medical University
Molecular Medicine Reports | Year: 2017

It was previously demonstrated that anomalous expression of indoleamine 2,3-dioxygenase-1 (IDO1) in endometrial stromal cells (ESCs) stimulated an inflammatory response that subsequently initiated the activation of immunosuppressive macrophages in endometriosis. The aim of the present study was to clarify the effect of IDO1-induced macrophages on the growth of ESCs in endometriosis. Normal ESCs, ectopic ESCs and normal ESCs treated with plasmid pEGFP-N1-IDO1 or SD11-IDO1 short hairpin RNA were co-cultured with peripheral blood-derived monocyte (PBMC)-driven macrophages directly for 48 h. Compared with normal ESCs, the PBMC-driven macrophages that were co-cultured with ectopic ESCs displayed a lower phagocytic ability. pEGFP-N1-IDO1 transfection of normal ESCs also decreased the phagocytic ability of co-cultured macrophages. Additionally, pEGFP-N1-IDO1-transfected ESC-induced macrophages significantly increased the viability and proliferation of ESCs, while ESC apoptosis was decreased, compared with control ESCs. In conclusion, IDO1 educated-macrophages may facilitate the survival of retrograde endometrial tissues, and be involved in the pathogenesis of endometriosis.

Huang G.-Q.,Hubei University of Medicine | Ke Z.-P.,Fudan University | Hu H.-B.,The Affiliated Huaian Hospital of Xuzhou Medical University and The Second Peoples Hospital of Huaian | Gu B.,Nanjing Medical University
Cancer Biology and Therapy | Year: 2017

Lung squamous cell carcinoma(LSCC) is the most common and aggressive lung tumor with poor clinical outcome. Previously studies showed that deregulation of long noncoding RNAs (lncRNAs) were involved in LSCC. We intended to figure out the role of lncRNAs in the regulation process of cancer-related genes and pathways they are involved. Data of 552 samples, including 501 cancer samples and 51 normal ones, were extracted from The Cancer Genome Atlas (TCGA). Differentially expressed lncRNAs (DEIs) were screened out (FDR<0.05, |logFC|>1) and then followed by GO ontology and KEGG annotation analysis. Oncogenes from COSMIC data set and Tumor suppressor genes (TSGs) from TSGene data set were collected and analyzed by gene Set Enrichment Analysis (GSEA). The differentially expressed oncogenes and tumor supressor gene (TSGs) were obtained and co-expression analysis was conducted to generate co-expression lncRNA-gene pairs, which can be helpful in figuring out the role of lncRNA in the regulation of oncogenes and tumor suppressor genes. A total of 31 lncRNAs with low expression levels and 37 lncRNAs with high expression levels were screened out and most of them were enriched in pathways such as meiosis, male gamete generation, defensins. Of note, SFTA1P and CASC2 were found to be related with most of the oncogenes and TSGs by co-expression analysis. We suggested SFTA1P and CASC2 played important role in the regulation of both oncogene and TSGs during the carcinogenesis of LSCC and have the potential to be applied in future diagnosis, prognostic process and target therapy of LSCC. © 2017 Taylor & Francis Group, LLC.

Yu T.,Nanjing Medical University | Li Y.,Nanjing Medical University
Journal of Practical Oncology | Year: 2017

Objective: To analyze the clinical features and prognosis of triple-negative breast cancer (TNBC). Methods: A total of 700 breast cancer patients from the Cancer Genome Atlas (TCGA) were analyzed retrospectively. Based on molecular markers and the status of hormone receptors, breast cancer were categorized. The clinical data of TNBC and non-TNBC patients were analyzed by Kaplan-Meier survival analysis and χ2 test. The prognosis factors were examined by univariate and multi-variates models. Results: Eighty-five TNBC patients were enrolled in this study. Survival analysis demonstrated that the overall survival rates of TNBC patients in 10 years were significantly different with that of non-TNBC patients (P=0.005), and was lower than that of luminal A breast cancer patients (P=0.001), but was not significantly different with other types of breast cancer (P>0.05). Significant differences were also shown in menopause status, histological type, AJCC tumor pathologic status, AJCC nodes pathologic status and age between TNBC and non-TNBC patients (P<0.05). Moreover, combining the results of both univariate and multivariate analyses, the number of metastatic lymph nodes was an important independent prognostic factor of TNBC (P=0.021). The survival time of patients with tumor was significantly shorter than that of patients without tumor (P=0.009). Conclusions: The clinico-pathological features of TNBC were significantly different with other types of breast cancer. Complete removal of tumor by surgery is of great importance to TNBC patients. © 2017, The Second Affiliated Hospital, College of Medicine, Zhejiang University. All right reserved.

Wu C.,Nanjing Medical University | Wei K.,Nanjing Medical University | Jiang Z.,Nanjing Medical University
Reproductive Biology and Endocrinology | Year: 2017

Background: 5aα-reductase activity might be important during the development of polycystic ovary syndrome (PCOS). However, the changes of 5aα-reductase activity in PCOS subjects and the relationship between 5aα-reductase activity and body mass index (BMI), insulin resistance (IR) remain largely unknown. Methods: We performed a meta-analysis to examine 5aα-reductase activity in women with PCOS; exploratory subgroup analyses were also performed. Results: Five articles (with 356 cases and 236 controls) reporting 5aα-reductase activity in patients with PCOS were selected for the meta-analysis. We observed significantly higher ratios of 5aαTHF/THF (5aα-reduced tetrahydrocortisol to 5β-reduced tetrahydrocortisol) and An/Et (androsteroneto/etiocholanolone) levels, which were used to assess 5aα-reductase activity, among the patients with PCOS, [standardized mean differences (SMD) =0.43, 95%confidence intervals (95%CI) =0.25-0.61, P < 0.00001; SMD = 0.86, 95% CI = 0.29-1.44, P = 0.003]. We observed significant heterogeneity between studies for An/Et (I2 = 89% and P < 0.00001). According to the group analysis, women with PCOS exhibited increased 5aα-reductase activity which was significantly associated with homeostasis model assessment of insulin resistance (HOMA-IR) regardless of obesity. Conclusions: 5aα-reductase activity was enhanced in women with PCOS. Increased 5aα-reductase activity in patients with PCOS was related to IR. © 2017 The Author(s).

Ling L.,Soochow University of China | Gu S.,Third Peoples Hospital of Kunshan | Cheng Y.,Nanjing Medical University
Molecular Medicine Reports | Year: 2017

Stem cell antigen-1-positive (Sca-1+) cardiac stem cells (CSCs) therapy for myocardial regeneration following acute myocardial infarction (AMI) is limited by insufficient cell viability and a high rate of apoptosis, due to the poor regional microenvironment. Resveratrol, which is a compound extracted from red wine, has been reported to protect myocardial tissue post-AMI by increasing the expression of angiogenic and chemotactic factors. The present study aimed to investigate the effects of resveratrol on Sca-1+ CSCs, and to optimize Sca-1+ CSCs therapy for myocardial regeneration post-AMI. C57/BL6 mice (age, 6 weeks) were divided into two groups, which received intragastric administration of PBS or 2.5 mg/kg.d resveratrol. The endogenous expression of Sca-1+ CSCs in the heart was assessed on day 7. Furthermore, C57/BL6 mice underwent left anterior descending coronary artery ligation for the construction of an AMI model, and received an injection of 1x106 CSCs into the peri-ischemic area (n=8/group). Mice received intragastric administration of PBS or resveratrol (2.5 mg/kg.d) for 4 weeks after cell transplantation. Echocardiography was used to evaluate cardiac function 4 weeks after cell transplantation. Capillary density and cardiomyocyte apoptosis in the peri-ischemic myocardium were assessed by cluster of differentiation 31 immunofluorescent staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, respectively. Western blot analysis was conducted to detect the protein expression levels of vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1α in the myocardium. Treatment with resveratrol increased the number of endogenous Sca-1+ CSCs in heart tissue after 7 days (PBS vs. Res, 1.85±0.41/field vs. 3.14±0.26/field, P<0.05). Furthermore, intragastric administration of resveratrol significantly increased left ventricle (LV) function 4 weeks after AMI, as determined by an increase in LV fractional shortening (CSCs vs. Res + CSCs, 28.82±1.58% vs. 31.18±2.02%, P<0.05), reduced LV end-diastolic diameter (CSCs vs. Res + CSCs, 0.37±0.01 mm vs. 0.35±0.02 mm, P<0.05), and reduced LV end-systolic diameter (CSCs vs. Res + CSCs, 0.26±0.01 mm vs. 0.23±0.02 mm, P<0.05). These protective effects were predominantly achieved via an increase in capillary density (CSCs vs. Res + CSCs, 281.02±24.08/field vs. 329.75±36.69/field, P<0.05) and a reduction in cardiomyocyte apoptosis (CSCs vs. Res + CSCs, 1.5±0.54/field vs. 0.83±0.40/field, P<0.05) in peri-ischemic myocardium. Western blot analysis indicated that VEGF and SDF-1α were upregulated in resveratrol-treated myocardium after a 7 day treatment or 4 weeks after AMI (7 days VEGF PBS vs. Res, 0.89±0.07 vs. 1.21±0.02, P<0.05; SDF-1α PBS vs. Res, 0.66±0.04 vs. 1.33±0.04, P<0.05; 4 weeks VEGF CSCs vs. Res + CSCs, 0.54±0.03 vs. 0.93±0.13, P<0.05; SDF-1α CSCs vs. Res + CSCs, 0.53±0.03 vs. 0.93±0.03, P<0.05). Resveratrol activated endogenous CSCs, increased capillary density and decreased cardiomyocyte apoptosis in the peri-ischemic myocardium, and augmented the effects of CSCs transplantation. These effects may be caused by the upregulation of VEGF and SDF-1α.

Tang Q.-F.,Nanjing Medical University | Fang Z.-Y.,Nanjing Medical University | Shi C.-H.,Nanjing Medical University
American Journal of Translational Research | Year: 2017

Acute lung injury (ALI) is a disturbance caused by infectious or non-infectious inflammation and lipopolysaccharide (LPS) could induce an artificial pathological ALI process. Sevoflurane has been demonstrated to be an inhaled anesthetic having anti-inflammatory and protective effects on inflammatory injury. To study the protective effects and mechanisms of sevoflurane on LPS-induced acute lung injury in mice. By assessing W/D ratio, sevoflurane can counteract the edema induced by LPS. The ELISA results showed that sevoflurane reduced IFN-γ production and increased IL-10 level. Elevation of PGE2 induced by sevoflurane and LPS in peritoneal macrophages was inhibited by NS-398, an inhibitor of the PGE2 regulator COX-2, indicating that NS-398 blocked COX-2 mediated PGE2 synthesis. NS-398 itself did not cause lung inflammation and mitigated the protective effect of sevoflurane on LPS-induced ALI in mice.LPS changes immune homeostasis, resulting in acute lung inflammatory injury. Inhaled sevoflurane regulates immune homeostasis, thereby playing a protective role in alleviating LPS-induced ALI. © 2017, E-Century Publishing Corporation. All rights reserved.

Chen C.,Nanjing Medical University | Tang S.,Nanjing Medical University | Hu K.,Nanjing Medical University
Nanoscience and Nanotechnology Letters | Year: 2017

Tumor stem cell (TSC) was one of the research hotspots in tumor diagnostics. However, cells with high expression of TSCs-related markers were rare when they were cultured in 2D models. It is important to build in vitro tumor models to enhance the proliferation of cells with TSCs related markers. In this study, the magnetic hydrogel based on magnetic nanoparticle assemblies was applied as the substrate for glioma tumor cell (U251) culture. Tumor cells on the surface of this composite material preferred to form multicellular spheroids through adhesion, migration and emergence. The enhanced expression of TSCs markers indicated the enrichment of TSCs and the stem cell characters of U251 cells cultured on magnetic hydrogel which were further confirmed by drug resistance assay. This composite might provide a valuable platform for TSCs-relative mechanism research and anti-cancer treatment. Copyright © 2017 American Scientific Publishers.

Epithelial–mesenchymal transition (EMT) has been recognized as a key element of cell migration and invasion in lung cancer; however, the underlying mechanisms are not fully elucidated. Recently, emerging evidence suggest that miRNAs have crucial roles in control of EMT and EMT-associated traits such as migration, invasion and chemoresistance. Here, we found that miR-218 expression levels were significantly downregulated in lung cancer tissues compared with adjacent non-cancerous tissues, and the levels of miR-218 were significantly associated with histological grades and lymph node metastasis. Overexpression of miR-218 inhibited cell migration and invasion as well as the EMT process. Of particular importance, miR-218 was involved in the metastatic process of lung cancer cells in vivo by suppressing local invasion and distant colonization. We identified Slug and ZEB2 as direct functional targets of miR-218. Inverse correlations were observed between miR-218 levels and Slug/ZEB2 levels in cancer tissue samples. In addition, overexpression of miR-218 in H1299 increased chemosensitivity of cells to cisplatin treatment through suppression of Slug and ZEB2. These findings highlight an important role of miR-218 in the regulation of EMT-related traits and metastasis of lung cancer in part by modulation of Slug/ZEB2 signaling, and provide a potential therapeutic strategy by targeting miR-218 in NSCLC.Oncogene advance online publication, 13 February 2017; doi:10.1038/onc.2016.414. © 2017 The Author(s)

Guo L.,Nanjing Medical University | Chen D.,Nanjing Medical University
Cancer Research and Clinic | Year: 2016

Personalized combined modality treatments are recommended for advanced non-small cell lung cancer (NSCLC), which is a highly heterogeneous disease. While the deep understanding of the molecular∗ pathways in NSCI.C has led to the emergence of more effective drugs including molecular targeting agents, monoclonal antibodies, immunomodulators, and angiogenesis inhibitors, furthermore, the therapy monitoring in advanced NSCLC is no longer confined to the traditional response evaluation criteria in solid tumor (K EC I ST) according to the tumor size, but expands to several new exploration directions including molecular imaging, molecular pathology and liquid biopsy at the protein and nucleic acid levels, which provides a new direction for the therapy monitoring in advanced NSCLC.

Yi D.,Nanjing Medical University | Song P.,Nanjing Drum Tower Hospital | Huang T.,Nanjing Medical University | Tang X.,Nanjing Drum Tower Hospital | Sang J.,Nanjing Drum Tower Hospital
Oncotarget | Year: 2017

Whether total thyroidectomy reduces the recurrence rate in patients with papillary thyroid microcarcinoma (PTMC) is currently controversy. Conclusions of sporadic, inconsistent, and mono-institutional studies need a meta-analysis to evaluate. 525 relevant studies were obtained from initial search on PubMed, 511 studies were excluded by inclusion and exclusion criteria. Eligible data were extracted from each included study. The Odds ratios (ORs) and 95% confidence interval (CI) were used to assess the difference in the recurrence rates between PTMC patients treated with total thyroidectomy and non-total thyroidectomy. OR and 95% CI were calculated using a fixed-effects or a random-effects model. The Q statistic was used to evaluate homogeneity and Begg's test was used to assess publication bias. 14 studies meeting the inclusion criteria were included in this meta-analysis. The over all recurrence rates of pooled patients with total thyroidectomy and non-total thyroidectomy were 2.83% and 2.84% respectively. Primary random-effects model analysis showed, no significant difference of recurrence rates existed between two operation modes (OR = 0.732, 95% CI: 0.444 - 1.208), while, high heterogeneity among studies was found, I-squared index (I2) = 40.2%. After remove one study with high heterogeneity, the OR of the pooled recurrence rates of the total thyroidectomy and the non-total thyroidectomy groups was 0.786 (95% CI: 0.363 - 1.701), further suggesting no significant difference of the recurrence rate exists between two operation modes. Our meta-analysis demonstrated postoperative recurrence of PTMC is not reduced by total thyroidectomy, non-total thyroidectomy is also a good choice to treat PTMC patients.

Wan K.,Nanjing Medical University | Wang P.,Nanjing Medical University | Zhang L.,Nanjing Medical University
Revista da Sociedade Brasileira de Medicina Tropical | Year: 2017

Introduction: The activity of garlic oil extract against Schistosoma japonicum cercariae was evaluated. Methods: The in vitro and in vivo cercaricidal activities against S. japonicum larvae were determined. Results: Exposure to ≥ 10-6 (v/v) garlic emulsions for 30 min led to 100% cercariae mortality; pre-exposure treatment with ≥ 10-4 (v/v) garlic emulsions showed 100% preventive efficacy against S. japonicum infection, while pre-treatment with 10-5 and 10-6 (v/v) emulsions achieved 20%-40% preventive efficacy and 35.2%-63.6% worm burden reduction. Conclusions: Garlic oil extract has activity against S. japonicum larvae and a promising preventive efficacy against S. japonicum infection. © 2017, Sociedade Brasileira de Medicina Tropical. All rights reserved.

Wu L.,Pukou Hospital of Nanjing | Li H.,Pukou Hospital of Nanjing | Xu L.,Pukou Hospital of Nanjing | Liu J.,Pukou Hospital of Nanjing | Ding C.,Nanjing Medical University
Cancer Research and Clinic | Year: 2016

Objective To investigate the predictive value of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) calculated from 18F-FDG PET-CT results for postoperative recurrence and prognosis in patients with resectable pancreatic cancer. Methods From may 2009 to December 2015, 30 patients with pancreatic cancer who underwent curative resection after PET-CT examination were enrolled, and the clinic pathological data and l8F-FDG PET-CT data were retrospectively analyzed. The prognostic value of SUVmean, SUVmean,MTV, TLG and other prognosis factors were analyzed. Results In 30 patients with pancreatic cancer, preoperativel8F-FDG PET-CT detected all primary lesion (10 0%). 29 patients were recurrence or metastasis, and 26 patients were died with median of 17.8 months (2.6-39.6 months) follow-up. The median progressionfree survival (PFS) time was 6.5 months and the median overall survival (OS) time was 11.6 months. The multivariate analysis revealed the histological differentiation and MTV were the independent influencing factors for PFS (both P<0.05). The lymph node metastasis, MTV and TLG were the independent influencing factors for OS (all P<0.05). Conclusion The MTV and TLG of PET-CT may be predicting the recurrence and survival of patients with pancreatic cancer after curative resection, suggesting that it can be used to guide the individual treatment.

Liu X.,Nanjing Medical University | Han Z.,Nanjing Medical University | Yang C.,Nanjing Medical University
Clinical Genetics | Year: 2016

Single nucleotide polymorphisms (SNPs) are genetic variations that contribute to human phenotypes associated with various diseases. SNPs are involved in the regulation of a broad range of physiological and pathological processes, such as cellular senescence, apoptosis, inflammation, and immune response, by upregulating the expression of classical inflammation markers. Recent studies have suggested that SNPs located in gene-encoding microRNAs (miRNAs) affect various aspects of diseases by regulating the expression or activity of miRNAs. In the last few years, miRNA polymorphisms that increase and/or reduce the risk of developing many diseases, such as cancers, autoimmune diseases, and cardiovascular diseases, have attracted increasing attention not only because of their involvement in the pathophysiology of diseases but also because they can be used as prognostic biomarkers for a variety of diseases. In this review, we summarize the relationships between miRNA SNPs and the pathophysiology and risk of diseases. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Zhi Q.,Nanjing Medical University | Wang J.,Nanjing Medical University
Chinese Journal of Medical Imaging Technology | Year: 2016

Objective: To assess the manifestations of chest MSCT in diagnosis of high fall injuries and to analyze the effect of age, falling height and gender on various chest injuries. Methods: Clinical and chest MSCT materials of 235 patients with high fall injuries were analyzed retrospectivly. The distribution of different injury types were evaluated and possible affecting factors of injuries were assessed preliminarily. Results: There were 104 patients (104/235, 44.26%) with rib fractures, 102 (102/235, 43.40%) with vertebral fractures, 13 (13/235, 5.53%) with sternal fractures, 27 (27/235, 11.49%) with scapular fractures, 10 (10/235, 4.26%) with clavicular fractures, 91 (91/235, 38.72%) with pulmonary parenchymal injuries and 63 (63/235, 26.81%) with pleural injuries. Fifteen patients (15/235, 6.38%) had mediastinal injuries and 13 (13/235, 5.53%) had thoracic soft tissue injuries. Age was associated with the occurrences of rib fractures (OR=1.023, P=0.046), vertebral fractures (OR=1.023, P=0.039) and clavicular fractures (OR=1.073, P=0.017) significantly. Falling height was associated with the occurrences of rib fractures (OR=1.115, P=0.028), vertebral fractures (OR=1.127, P=0.016), pulmonary parenchymal injuries (OR=1.101, P=0.041), pleural injuries (OR=1.105, P=0.041) and soft tissue of chest wall injuries (OR=1.270, P<0.001) apparently. However, gender had no influence on various kinds of chest injuries. Conclusion: MSCT manifestations reveal that multiple organs and multi-parts are involved in chest injuries caused by high fall. Age and falling height are risk factors on the type of chest injuries caused by high fall. Copyright © 2016 by the Press of Chinese Journal of Medical Imaging and Technology.

Qin J.,Nanjing Medical University | Li W.,Nanjing Medical University | Gao S.-J.,University of Southern California | Lu C.,Nanjing Medical University
Trends in Microbiology | Year: 2017

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS), a vascular tumor frequently found in immunodeficient individuals. KSHV encodes 12 pre-microRNAs (pre-miRNAs), which are processed into 25 mature microRNAs (miRNAs). KSHV miRNAs maintain KSHV latency, enhance angiogenesis and dissemination of the infected cells, and interfere with the host immune system by regulating viral and cellular gene expression, ultimately contributing to KS development. In this review, we briefly introduce the biogenesis of miRNAs and then describe the recent advances in defining the roles and mechanisms of action of KSHV miRNAs in KS development. miRNAs play significant roles in different diseases. By binding to target genes, miRNAs post-transcriptionally regulate gene expression. During viral infections, miRNAs manipulate the activities of viruses and host cells. Some viral miRNAs mimic cellular miRNAs, and interfere with cellular activities.KSHV encodes 25 mature miRNAs and all play essential roles in the viral life cycle and cellular activities. Recent studies have focused on the roles of KSHV miRNAs in KSHV induced-tumorigenesis and KS development. Identification of the targets, and delineation of the functions of KSHV miRNAs, could provide novel strategies for treatment and prevention of KSHV-associated malignancies. © 2017 Elsevier Ltd.

Zhang K.,Jiangsu Institute of Nuclear Medicine | Wang K.,Jiangsu Institute of Nuclear Medicine | Zhu X.,Jiangsu Institute of Nuclear Medicine | Xie M.,Jiangsu Institute of Nuclear Medicine | Zhang X.,Nanjing Medical University
Biosensors and Bioelectronics | Year: 2017

Herein, we report a new method which the “stage change” of DNA1 and the cleavage feature upon recycled recognition by DSN was used to detect target microphthalmia-associated transcription factor (MITF) in cell nuclear extracts. In this method, we employed a well-designed DNA1 as a recognition element which can converting in two states, “ON-state” and “OFF-state”. Also, the DNA1 is modified with 2-OMe-RNA on hybridization part in the “OFF-state” to prevent meaningless digestion. By taking advantage of the high amplification efficiency of DSN-aided recycling, high sensitivity of MITF is realized with a detection limit as low as 1.1 pM, which is superior or comparable to that of the reported literature. This method is a fast and easy-to-use one-pot method that was carried out in a tube, while being quantitative and applicable to other proteins in the sample without involving complicated procedures or sophisticated instrumentations. It is very simple and fast, needing only mixing of DNA1, DNA2, MITF and DSN enzyme and incubating within 60 min, which is in the homogeneous solution, and not requiring separation and troublesome procedures. Considering the superior sensitivity and specificity, as well as the multiplex and simple-to-implement features, this method holds great promise of becoming a routine tool for simultaneously quantitative analysis of multiple proteins and supplies valuable information for transcription factor-based early stage cancer diagnosis. © 2016 Elsevier B.V.

BACKGROUND:: The authors and others have previously shown that the up-regulation of spinal ephrin type-b receptor 1 plays an essential role in the pathologic process of nerve injury–induced nociceptive hypersensitivity, but the regulatory mechanism remains unclear. METHODS:: Radiant heat and von Frey filaments were applied to assess nociceptive behaviors. Real-time quantitative polymerase chain reaction, Western blotting, fluorescence in situ hybridization, immunofluorescence, immunohistochemistry, dual-luciferase reporter gene assays, recombinant lentivirus, and small interfering RNA were used to characterize the likely mechanisms. RESULTS:: Periphery nerve injury induced by chronic constriction injury of the sciatic nerve significantly reduced spinal microRNA-182-5p (miR-182-5p) expression levels, which were inversely correlated with spinal ephrin type-b receptor 1 expression (R = 0.90; P < 0.05; n = 8). The overexpression of miR-182-5p in the spinal cord prevented and reversed the nociceptive behaviors induced by sciatic nerve injury, accompanied by a decreased expression of spinal ephrin type-b receptor 1 (recombinant lentiviruses containing pre-microRNA-182: 1.91 ± 0.34 vs. 1.24 ± 0.31, n = 4; miR-182-5p mimic: 2.90 ± 0.48 vs. 1.51 ± 0.25, n = 4). In contrast, the down-regulation of spinal miR-182-5p facilitated the nociceptive behaviors induced by sciatic nerve injury and increased the expression of spinal ephrin type-b receptor 1 (1.0 ± 0.26 vs. 1.74 ± 0.31, n = 4). Moreover, the down-regulation of miR-182-5p and up-regulation of ephrin type-b receptor 1 caused by sciatic nerve injury were mediated by the N-methyl-D-aspartate receptor. CONCLUSIONS:: Collectively, our findings reveal that the spinal ephrin type-b receptor 1 is regulated by miR-182-5p in nerve injury–induced nociceptive hypersensitivity. Copyright © by 2017, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved.

Xia W.,Nanjing Medical University | Chen Y.-C.,Nanjing Medical University | Ma J.,Nanjing Medical University
Frontiers in Aging Neuroscience | Year: 2017

Resting-state functional magnetic resonance imaging (fMRI) studies have revealed abnormal neural activity in patients with type 2 diabetes mellitus (T2DM). Nonetheless, these findings are heterogeneous and have not been quantitatively reviewed. Thus, we aimed to conduct a meta-analysis that identified consistent results of existing resting-state fMRI studies to determine concordant resting-state neural brain activity alterations in T2DM patients. A systematic search was conducted for resting-state fMRI studies comparing T2DM patients with healthy controls. Coordinates were extracted from clusters with significant differences. The meta-analysis was performed using the activation likelihood estimation method, and nine studies were included. This meta-analysis identified robustly reduced resting-state brain activity in the whole brain of T2DM patients, including the bilateral lingual gyrus, left postcentral gyrus, right inferior temporal gyrus, right cerebellar culmen, right insula and right posterior cingulate cortex (PCC). The present study demonstrates a characteristic pattern of resting-state brain anomalies that will contribute to the understanding of neuropathophysiological mechanisms underlying T2DM. © 2017 Xia, Chen and Ma.

Deng X.,Nanjing Medical University | Xie Y.,Nanjing Medical University | Zhang A.,Nanjing Medical University
Renal failure | Year: 2017

Autophagy, a highly conserved mechanism for cell survival, emerges as an important pathway in many biological processes and diseases conditions. Studies of cultured renal cells, human kidney tissues and experimental animal models implicate that autophagy regulation is the critical aspects in chronic kidney diseases (CKD). Here, we summarize the current studies on the role of autophagy in CKD. Unveiling the precise regulation mechanism of autophagy in CKD is essential for developing potential prevention, diagnostic and therapeutic targets of these sticky clinical challenges.

Zhang J.,Nanjing Medical University
Journal of Hypertension | Year: 2017

OBJECTIVES:: Carotid baroreflex plays a crucial role in regulating arterial pressure. Based on this knowledge, electrical stimulation of carotid sinus was designed for treating resistant hypertension. However, the clinical implication of electrical stimulation of carotid sinus is largely restrained due to obvious invasiveness. This study aimed to evaluate the efficacy of magnetic stimulation of carotid sinus (MSCS), a noninvasive strategy, for lowering blood pressure in rabbits. METHODS:: MSCS with graded intensities and frequencies were systematically attempted in normotensive rabbits. Blood pressure was recorded dynamically. Sinoaortic denervation and plasma hormone level analyses were performed. RESULTS:: When the right carotid sinus was stimulated at 1?Hz frequency, a dose–effect relationship was observed between stimulation intensity (100–250% motor threshold) and mean arterial pressure (MAP) decrement (3.6?±?1.0 to 10.4?±?2.3?mmHg). When stimulation intensity was fixed at 200% motor threshold, the median reduction of MAP in 1-Hz group [10.8 (8.6–14.9)?mmHg] was significantly higher than that in other frequency groups (all P?

Xu Y.,Nanjing University | Gu Q.,Nanjing University | Qu C.,Nanjing Medical University
Experimental Lung Research | Year: 2017

Purpose/aim: Pulmonary arterial hypertension (PAH) is a lethal disease associated with pulmonary vascular remodeling as well as inflammation. As a kind of tachykinin secreted by nerves and inflammatory cells, substance P (SP) has been proved to be involved in the progression of PAH. Capsaicin can deplete substance P and provide benefits in PAH. However, the mechanism is still unclear. In this article, we aim to illustrate the possible mechanism involved in the process of capsaicin alleviating PAH. Materials and Methods: A single injection of monocrotaline (MCT) to male Sprague–Dawley (SD) rats was conducted to induce PAH. Capsaicin pretreatment was administered three days before MCT injection to deplete substance P. P38mitogen-activated protein kinase (p38MAPK) activator or inhibitor was given intraperitoneally after MCT injection. After 28 days, hemodynamic studies were carried out, and right ventricular systolic pressure (RVSP), right ventricular (RV)/left ventricle plus septum (LV+S), RV/body weight (BW), and lung weight (LW)/BW were recorded and calculated. In addition, the pulmonary vascular remodeling (pulmonary arterial medial wall thickness, area, perivascualr fibrosis), pro-inflammatory cytokines, the common signal pathways, such as peroxisome proliferator-activated receptor gamma (PPARγ), extracellular signal-regulated kinases (Erk), protein kinase B (Akt), and p38MAPK were also detected. Results: Capsaicin pretreatment reversed PAH, including decreasing RVSP, RV/(LV+S), RV/BW, and LW/BW, and alleviating inflammation. Phosphorylated-p38 (p-p38) MAPK was up-regulated, which was partially reversed by capsaicin pretreatment. Interestingly, expression of Akt, Erk, and PPARγ was not altered by capsaicin pretreatment. Inhibition of p38MAPK provided the same benefits with capsaicin pretreatment, whereas it failed to provide additional improvement in the presence of capsaicin. Besides, p38MAPK activator abolished the effects of capsaicin pretreatment on PAH, suggesting a key role of p38MPAK pathway in the effects of capsaicin reversing PAH. Conclusions: Capsaicin pretreatment reversed PAH by alleviating inflammation via p38MAPK pathway. © 2017 Taylor & Francis

To date, only a few reports described the potential factors influencing the position of conus medullaris. One previous study revealed no significant change of conus locations in patients with idiopathic scoliosis; however, the effect of ankylosing spondylitis (AS)-related thoracolumbar kyphosis on conus position remains unexplored. Therefore, we aimed to investigate the variation of conus medullaris terminations in patients with thoracolumbar kyphosis secondary to AS when compared with normal subjects, and evaluated the relationship between conus positions and the magnitude of kyphosis. In this study, MR images of 96 AS patients with thoracolumbar kyphosis, including 86 males and 10 females with an average of 34.6 years (range, 17-65 years), and 100 age-matched normal controls were reviewed to determine the conus terminations in relation to spinal levels. Sagittal parameters of the AS group measured on radiograph included: global kyphosis (GK), thoracic kyphosis (TK), lumbar lordosis (LL), and thoracolumbar junction (TLJ). Finally, conus tips located at the mean level of the lower 3rd of L1 in both groups, there was no significant difference of the conus distributions between AS and control group (P = 0.49). In addition, conus medullaris displayed similar positions in AS patients among various apical region groups (P = 0.88), and no significant difference was found when AS population was stratified into GK ranges of 30° (P = 0.173). Also, no remarkable correlation of the conus positions with GK (r = -0.15, P = 0.15), TK (r = -0.10, P = 0.34), LL (r = -0.10, P = 0.32), and TLJ (r = -0.06, P = 0.54) was identified. This study showed the conus terminations displayed a wide range of distributions in AS patients with thoracolumbar kyphosis, which was similar to normal subjects. Moreover, the conus located at a relatively fixed position and would not be affected by the change of kyphosis magnitude, which is an important knowledge that surgeons should acquire in surgical correction of the deformity in these patients.

Hua Q.,Nanjing Medical University | Ni J.,Nanjing Medical University
Clinical nuclear medicine | Year: 2017

Pigmented villonodular synovitis (PVNS) is a proliferative disorder of unknown etiology that originates from the synovial membranes of joints. Some PVNS lesions have been misdiagnosed as malignancy due to their tumorlike imaging findings. There are few reports of PVNS on nuclear 3-phase bone imaging. However, 3-phase Tc-MDP bone scan can offer additional information about the dynamic flow features of the lesion, which may do help in differential benign and malignant. The present report describes 3-phase bone imaging in a surgically proven case of PVNS with tumorlike appearance and atypical location.

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

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.

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.