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1.  Down-regulation of miR-34a alleviates mesangial proliferation in vitro and glomerular hypertrophy in early diabetic nephropathy mice by targeting GAS1 
Diabetic nephropathy (DN) is a major diabetic complication characterized by mesangial proliferation and glomerular hypertrophy. MicroRNAs might play an important role in these pathological processes. The aim of this study is to examine the possible association of miR-34a as one of the microRNAs with DN and underlying mechanisms in vitro and in vivo.
According to previous results of microarray which compared the different microRNAs between diabetic and normal control mice, miR-34a was chosen and its expression was detected by qRT-PCR. Cell viability was then assessed using Cell Counting Kit-8 (CCK8) and 5-ethynyl-20-deoxyuridine (EDU) incorporation. Antagomir was injected in db/db mice to down regulate miR-34a. Average diameter of glomeruli was analyzed by periodic acid-Schiff (PAS) stain of kidney. Luciferase gene report assay was then performed to identify the target gene of miR-34a. Additional immunoblotting and immunohistochemical analyses were implemented to verify the expression level of growth arrest-specific 1 (GAS1).
MiR-34a expression level was increased under high glucose condition in vitro and in vivo. Down-regulation of miR-34a inhibits mice mesangial cells (MMCs) proliferation in vitro and alleviates glomerular hypertrophy in vivo. GAS1 was proved to be the target of miR-34a through luciferase report. Moreover, up-regulation of GAS1 expression was observed in the presence of miR-34a antagomir as compared withmiR-34a antagomir-NC in high-glucose-treated MMCs and db/db mice, respectively.
MiR-34a regulated mesangial proliferation and glomerular hypertrophy by directly inhibiting GAS1 in early DN.
PMCID: PMC4087162  PMID: 24560136
Diabetic nephropathy; Glomerular hypertrophy; miR-34a; GAS1
2.  Cardiometabolic Risk Profiles Associated with Chronic Complications in Overweight and Obese Type 2 Diabetes Patients in South China 
PLoS ONE  2014;9(7):e101289.
Type 2 diabetes is often accompanied by altered cardiometabolic risk profiles, including abdominal obesity, hypertension, and dyslipidaemia. The association of altered cardiometabolic risk profiles with chronic complications of diabetes is not well investigated.
We recruited 2954 type 2 diabetes patients with a body mass index ≥25 kg/m2 who visited the diabetes clinics of 62 hospitals in 21 cities in Guangdong province of China from August 2011 to March 2012. Demographic characteristics, personal and family medical histories, and data on chronic complications of diabetes were collected. Clinical examinations and laboratory assessment were conducted.
Abdominal obesity was found in 91.6% of the study population, elevated blood pressure in 78.3%; elevated serum triacylglycerols in 57.8%, and reduced serum HDL-C in 55.9%. Among the cardiometabolic risk factors, elevated blood pressure was significantly associated with almost all the chronic complications of diabetes. After adjusting for age, gender, duration of diabetes, and HbA1c, elevated blood pressure was significantly associated with diabetic retinopathy (OR 1.63, 95% CI: 1.22–2.19), diabetic nephropathy (OR 3.16, 95% CI: 2.25–4.46), cardiovascular disease (OR 2.71, 95% CI: 1.70–4.32), and stroke (OR 1.90, 95% CI: 1.15–3.12). Abdominal adiposity was significantly associated with diabetic nephropathy (OR 1.39, 95% CI: 1.11–1.74). Elevated triacylglycerols was significantly associated with diabetic retinopathy (OR 1.29, 95% CI: 1.05–1.58) and diabetic nephropathy (OR 1.30, 95% CI: 1.05–1.58). Reduced HDL-C was significantly associated with stroke (OR 1.41, 95% CI: 1.05–1.88).
Altered cardiometabolic risk profiles, and elevated blood pressure in particular, were significantly associated with chronic complications in overweight and obese patients with type 2 diabetes. Future studies on the prevention of chronic complications of diabetes might make lowering blood pressure a primary target.
PMCID: PMC4081665  PMID: 24992024
3.  Divalent cations activate TRPV1 through promoting conformational change of the extracellular region 
The Journal of General Physiology  2014;143(1):91-103.
Divalent cations Mg2+ and Ba2+ selectively and directly potentiate transient receptor potential vanilloid type 1 heat activation by lowering the activation threshold into the room temperature range. We found that Mg2+ potentiates channel activation only from the extracellular side; on the intracellular side, Mg2+ inhibits channel current. By dividing the extracellularly accessible region of the channel protein into small segments and perturbing the structure of each segment with sequence replacement mutations, we observed that the S1–S2 linker, the S3–S4 linker, and the pore turret are all required for Mg2+ potentiation. Sequence replacements at these regions substantially reduced or eliminated Mg2+-induced activation at room temperature while sparing capsaicin activation. Heat activation was affected by many, but not all, of these structural alternations. These observations indicate that extracellular linkers and the turret may interact with each other. Site-directed fluorescence resonance energy transfer measurements further revealed that, like heat, Mg2+ also induces structural changes in the pore turret. Interestingly, turret movement induced by Mg2+ precedes channel activation, suggesting that Mg2+-induced conformational change in the extracellular region most likely serves as the cause of channel activation instead of a coincidental or accommodating structural adjustment.
PMCID: PMC3874565  PMID: 24344245
4.  Divalent cations potentiate TRPV1 channel by lowering the heat activation threshold 
Transient receptor potential vanilloid type 1 (TRPV1) channel responds to a wide spectrum of physical and chemical stimuli. In doing so, it serves as a polymodal cellular sensor for temperature change and pain. Many chemicals are known to strongly potentiate TRPV1 activation, though how this is achieved remains unclear. In this study we investigated the molecular mechanism underlying the gating effects of divalent cations Mg2+ and Ba2+. Using a combination of fluorescence imaging and patch-clamp analysis, we found that these cations potentiate TRPV1 gating by most likely promoting the heat activation process. Mg2+ substantially lowers the activation threshold temperature; as a result, a significant fraction of channels are heat-activated at room temperature. Although Mg2+ also potentiates capsaicin- and voltage-dependent activation, these processes were found either to be not required (in the case of capsaicin) or insufficient (in the case of voltage) to mediate the activating effect. In support of a selective effect on heat activation, Mg2+ and Ba2+ cause a Ca2+-independent desensitization that specifically prevents heat-induced channel activation but does not prevent capsaicin-induced activation. These results can be satisfactorily explained within an allosteric gating framework in which divalent cations strongly promote the heat-dependent conformational change or its coupling to channel activation, which is further coupled to the voltage- and capsaicin-dependent processes.
PMCID: PMC3874569  PMID: 24344247
5.  MERS–Related Betacoronavirus in Vespertilio superans Bats, China 
Emerging Infectious Diseases  2014;20(7):1260-1262.
PMCID: PMC4073873  PMID: 24960574
coronavirus; Middle East respiratory syndrome coronavirus; MERS-CoV; Vespertilio superans; bat; reservoir; sequencing; lineage; betacoronaviruses; viruses; MERS–related betacoronavirus; Middle East respiratory syndrome coronavirus–related betacoronavirus; China; lineage C betacoronavirus
6.  Identification of Susceptibility Variants in ADIPOR1 Gene Associated with Type 2 Diabetes, Coronary Artery Disease and the Comorbidity of Type 2 Diabetes and Coronary Artery Disease 
PLoS ONE  2014;9(6):e100339.
Adiponectin receptor 1 (encoded by ADIPOR1) is one of the major adiponectin receptors, and plays an important role in glucose and lipid metabolism. However, few studies have reported simultaneous associations between ADIPOR1 variants and type 2 diabetes (T2D), coronary artery disease (CAD) and T2D with CAD. Based on the “common soil” hypothesis, we investigated whether ADIPOR1 polymorphisms contributed to the etiology of T2D, CAD, or T2D with CAD in a Northern Han Chinese population.
Our multi-disease comparison study enrolled 657 subjects, including 165 with T2D, 173 with CAD, 174 with both T2D and CAD (T2D+CAD), and 145 local healthy controls. Six ADIPOR1 single nucleotide polymorphisms (SNPs) were genotyped and their association with disease risk was analyzed.
Multi-case-control comparison identified two ADIPOR1 variants: rs3737884-G, which was simultaneously associated with an increased risk of T2D, CAD, and T2D+CAD (P-value range, 9.80×10−5−6.30×10−4; odds ratio (OR) range: 1.96–2.42) and 16850797-C, which was separately associated with T2D and T2D+CAD (P-value range: 0.007–0.014; OR range: 1.71–1.77). The risk genotypes of both rs3737884 and 16850797 were consistently associated with common metabolic phenotypes in all three diseases (P-value range: 4.81×10−42−0.001). We observed an increase in the genetic dose-dependent cumulative risk with increasing risk allele numbers in T2D, CAD and T2D+CAD (P trend from 1.35×10−5−0.002).
Our results suggest that ADIPOR1 risk polymorphisms are a strong candidate for the “common soil” hypothesis and could partially contribute to disease susceptibility to T2D, CAD, and T2D with CAD in the Northern Han Chinese population.
PMCID: PMC4072681  PMID: 24967709
7.  Many Local Pattern Texture Features: Which Is Better for Image-Based Multilabel Human Protein Subcellular Localization Classification? 
The Scientific World Journal  2014;2014:429049.
Human protein subcellular location prediction can provide critical knowledge for understanding a protein's function. Since significant progress has been made on digital microscopy, automated image-based protein subcellular location classification is urgently needed. In this paper, we aim to investigate more representative image features that can be effectively used for dealing with the multilabel subcellular image samples. We prepared a large multilabel immunohistochemistry (IHC) image benchmark from the Human Protein Atlas database and tested the performance of different local texture features, including completed local binary pattern, local tetra pattern, and the standard local binary pattern feature. According to our experimental results from binary relevance multilabel machine learning models, the completed local binary pattern, and local tetra pattern are more discriminative for describing IHC images when compared to the traditional local binary pattern descriptor. The combination of these two novel local pattern features and the conventional global texture features is also studied. The enhanced performance of final binary relevance classification model trained on the combined feature space demonstrates that different features are complementary to each other and thus capable of improving the accuracy of classification.
PMCID: PMC4094881  PMID: 25050396
8.  LIM and SH3 Domain Protein 1 (LASP-1) Overexpression Was Associated with Aggressive Phenotype and Poor Prognosis in Clear Cell Renal Cell Cancer 
PLoS ONE  2014;9(6):e100557.
LIM and SH3 protein 1 (LASP-1) is a specific focal adhesion protein that is known to be involved in numerous biological and pathological processes. LASP-1 overexpression has been described in several types of cancers, but its expression and role in clear cell renal cell cancer (ccRCC) remains unknown.
Using immunohistochemistry, we analyzed LASP-1 protein expression in 216 clinicopathologically characterized ccRCC cases. We also examined LASP-1 expression in 20 paired ccRCC tissues and in 2 cell lines by real-time PCR and Western blot. Using RNA interference, we investigated the effects of LASP-1 depletion on tumor cell behavior in vitro. Statistical analyses were used to determine the associations between LASP-1 levels, tumor features and patient outcomes.
LASP-1 overexpression was observed in ccRCC tissues (P<0.0001) compared to adjuvant nontumorous tissues, and its expression levels were closely correlated with overall survival and recurrence-free survival (P = 0.044 and 0.006, respectively) in patients with ccRCC. RNA interference-mediated silencing of the LASP-1 gene in 786–0 ccRCC cells significantly inhibited cell migration.
The results of the present study indicate that LASP-1 may serve as a prognostic biomarker for ccRCC patients and may be a promising target for the treatment of ccRCC.
PMCID: PMC4067378  PMID: 24955835
9.  Reliable Multi-Label Learning via Conformal Predictor and Random Forest for Syndrome Differentiation of Chronic Fatigue in Traditional Chinese Medicine 
PLoS ONE  2014;9(6):e99565.
Chronic Fatigue (CF) still remains unclear about its etiology, pathophysiology, nomenclature and diagnostic criteria in the medical community. Traditional Chinese medicine (TCM) adopts a unique diagnostic method, namely ‘bian zheng lun zhi’ or syndrome differentiation, to diagnose the CF with a set of syndrome factors, which can be regarded as the Multi-Label Learning (MLL) problem in the machine learning literature. To obtain an effective and reliable diagnostic tool, we use Conformal Predictor (CP), Random Forest (RF) and Problem Transformation method (PT) for the syndrome differentiation of CF.
Methods and Materials
In this work, using PT method, CP-RF is extended to handle MLL problem. CP-RF applies RF to measure the confidence level (p-value) of each label being the true label, and then selects multiple labels whose p-values are larger than the pre-defined significance level as the region prediction. In this paper, we compare the proposed CP-RF with typical CP-NBC(Naïve Bayes Classifier), CP-KNN(K-Nearest Neighbors) and ML-KNN on CF dataset, which consists of 736 cases. Specifically, 95 symptoms are used to identify CF, and four syndrome factors are employed in the syndrome differentiation, including ‘spleen deficiency’, ‘heart deficiency’, ‘liver stagnation’ and ‘qi deficiency’.
The Results
CP-RF demonstrates an outstanding performance beyond CP-NBC, CP-KNN and ML-KNN under the general metrics of subset accuracy, hamming loss, one-error, coverage, ranking loss and average precision. Furthermore, the performance of CP-RF remains steady at the large scale of confidence levels from 80% to 100%, which indicates its robustness to the threshold determination. In addition, the confidence evaluation provided by CP is valid and well-calibrated.
CP-RF not only offers outstanding performance but also provides valid confidence evaluation for the CF syndrome differentiation. It would be well applicable to TCM practitioners and facilitate the utilities of objective, effective and reliable computer-based diagnosis tool.
PMCID: PMC4053362  PMID: 24918430
10.  Sclerostin is a direct target of osteoblast-specific transcription factor osterix 
Osterix (Osx) is an osteoblast-specific transcription factor required for osteoblast differentiation and bone formation. Osx knock-out mice lack bone completely. Recent findings that Osx inhibits Wnt signaling provide a feedback control mechanism involved in bone formation. Mechanisms of Osx inhibition on Wnt signaling are not fully understood. Our results in this study revealed that the expression of a Wnt antagonist Sclerostin (Sost) was downregulated in Osx-null calvaria. Overexpression of Osx in stable C2C12 mesenchymal cell line resulted in Sost upregulation. Transient transfection assay showed that Osx activated 1 kb Sost promoter reporter activity in a dose-dependent manner. To define Sost promoter activated by Osx, we made a series of deletion mutants of Sost constructs, and narrowed down the minimal region to the proximal 260 bp. Gel shift assay indicated that Osx bound to GC-rich site within this minimal region, and that point mutations of this binding site disrupted Osx binding. Moreover, the same point mutations in 260 bp Sost promoter reporter disrupted the promoter activation by Osx, suggesting that the GC-rich binding site was responsible for Sost promoter activation by Osx. To further examine physical association of Osx with Sost promoter in vivo, Chromatin immunoprecipitation (ChIP) assays were performed using primary osteoblasts from mouse calvaria. Osx was found to associate with endogenous Sost promoter. Taken together, these findings support our hypothesis that Sost is a direct target of Osx. This provides a new additional mechanism through which Osx inhibits Wnt signaling during bone formation.
PMCID: PMC4041335  PMID: 20816666
Osx; Sost; Osteoblast; Wnt signaling; Bone formation
11.  Novel Henipa-like Virus, Mojiang Paramyxovirus, in Rats, China, 2012 
Emerging Infectious Diseases  2014;20(6):1064-1066.
PMCID: PMC4036791  PMID: 24865545
novel virus; henipa-like virus; henipavirus; paramyxovirus; Mojiang paramyxovirus; China; rats; Rattus flavipectus; viruses; zoonoses; rodents
12.  Venous thromboembolism is a product in proliferation of cancer cells 
The pathogenesis of venous thromboembolism (VTE) in patients with cancer is related to the destruction of small veins and the intravenous formation of filamentous mesh-like structure by fibrinogen. The filamentous mesh-like filter can block hematogenous metastasis of cancer cells and also can stagnate blood cells, leading to venous thrombosis. Cancer cells have characteristics of malignancy and fast proliferation, and ischemic necrosis frequently occurs, and small veins were invaded and damaged. The formation of filamentous mesh-like structure has defense function and also may cause the occurrence of VTE. VTE is a product of the proliferation process of malignant cells.
PMCID: PMC4073750  PMID: 24995089
Venous thromboembolism; cancer; filter
13.  Temperature-dependent Activation of Neurons by Continuous Near-infrared Laser 
Optical control of neuronal activity has a number of advantages over electrical methods and can be conveniently applied to intact individual neurons in vivo. In this study, we demonstrated an experimental approach in which a focused continuous near-infrared (CNI) laser beam was used to activate single rat hippocampal neurons by transiently elevating the local temperature. Reversible changes in the amplitude and kinetics of neuronal voltage-gated Na and K channel currents were recorded following irradiation with a single-mode 980 nm CNI-laser. Using single-channel recordings under controlled temperatures as a means of calibration, it was estimated that temperature at the neuron rose by 14°C in 500 ms. Computer simulation confirmed that small temperature changes of about 5°C were sufficient to produce significant changes in neuronal excitability. The method should be broadly applicable to studies of neuronal activity under physiological conditions, in particular studies of temperature-sensing neurons expressing thermoTRP channels.
PMCID: PMC4019448  PMID: 19034696
Voltage-dependent ion channels; Activation; Inactivation; Action potential; Laser; Temperature
14.  A Novel Berbamine Derivative Inhibits Cell Viability and Induces Apoptosis in Cancer Stem-Like Cells of Human Glioblastoma, via Up-Regulation of miRNA-4284 and JNK/AP-1 Signaling 
PLoS ONE  2014;9(4):e94443.
Glioblastoma (GBM) is the most common primary brain tumor, accounting for approximately 40% of all central nervous system malignancies. Despite standard treatment consisting of surgical resection, radiotherapy and/or chemotherapy, the prognosis for GBM is poor; with a median survival of 14.6 months. The cancer stem cell or cancer-initiating cell model has provided a new paradigm for understanding development and recurrence of GBM following treatment. Berbamine (BBM) is a natural compound derived from the Berberis amurensis plant, and along with its derivatives, has been shown to exhibit antitumor activity in several cancers. Here, we reported that a novel synthetic Berbamine derivative, BBMD3, inhibits cell viability and induces apoptosis of cancer stem-like cells (CSCs) in a time- and dose-dependent manner when the CSCs from four GBM patients (PBT003, PBT008, PBT022, and PBT030) were cultured. These CSCs grew in neurospheres and expressed CD133 and nestin as markers. Treatment with BBMD3 destroyed the neurosphere morphology, and led to the induction of apoptosis in the CSCs. Induction of apoptosis in these CSCs is dependent upon activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP). MicroRNA-4284 (miR-4284) was shown to be over-expressed about 4-fold in the CSCs following BBMD3 treatment. Furthermore, transfection of synthetic anti-sense oligonucleotide against human miR-4284 partially blocked the anticancer effects of BBMD3 on the GBM derived CSCs. BBMD3 also increased phosphorylation of the c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK), resulting in an increase expression of phosphorylated c-Jun and total c-Fos; the major components of transcriptional factor AP-1. The JNK-c-Jun/AP-1 signaling pathway plays an important role in the induction of apoptosis in response to UV irradiation and some drug treatments. Targeting glioblastoma stem-like cells with BBMD3 is therefore novel, and may have promise as an effective therapeutic strategy for treating GBM patients.
PMCID: PMC3986211  PMID: 24732116
15.  Zebrafish on a Chip: A Novel Platform for Real-Time Monitoring of Drug-Induced Developmental Toxicity 
PLoS ONE  2014;9(4):e94792.
Pharmaceutical safety testing requires a cheap, fast and highly efficient platform for real-time evaluation of drug toxicity and secondary effects. In this study, we have developed a microfluidic system for phenotype-based evaluation of toxic and teratogenic effects of drugs using zebrafish (Danio rerio) embryos and larvae as the model organism. The microfluidic chip is composed of two independent functional units, enabling the assessment of zebrafish embryos and larvae. Each unit consists of a fluidic concentration gradient generator and a row of seven culture chambers to accommodate zebrafish. To test the accuracy of this new chip platform, we examined the toxicity and teratogenicity of an anti-asthmatic agent-aminophylline (Apl) on 210 embryos and 210 larvae (10 individuals per chamber). The effect of Apl on zebrafish embryonic development was quantitatively assessed by recording a series of physiological indicators such as heart rate, survival rate, body length and hatch rate. Most importantly, a new index called clonic convulsion rate, combined with mortality was used to evaluate the toxicities of Apl on zebrafish larvae. We found that Apl can induce deformity and cardiovascular toxicity in both zebrafish embryos and larvae. This microdevice is a multiplexed testing apparatus that allows for the examination of indexes beyond toxicity and teratogenicity at the sub-organ and cellular levels and provides a potentially cost-effective and rapid pharmaceutical safety assessment tool.
PMCID: PMC3986246  PMID: 24733308
16.  The Future of Biologic Coatings for Orthopaedic Implants 
Biomaterials  2013;34(13):3174-3183.
Implants are widely used for othopaedic applications such as fixing fractures, repairing nonunions, obtaining a joint arthrodesis, total joint arthroplasty, spinal reconstruction, and soft tissue anchorage. Previously, orthopaedic implants were designed simply as mechanical devices; the biological aspects of the implant were a byproduct of stable internal/external fixation of the device to the surrounding bone or soft tissue. More recently, biologic coatings have been incorporated into orthopaedic implants in order to modulate the surrounding biological environment. This opinion article reviews current and potential future use of biologic coatings for orthopaedic implants to facilitate osseointegration and mitigate possible adverse tissue responses including the foreign body reaction and implant infection. While many of these coatings are still in the preclinical testing stage, bioengineers, material scientists and surgeons continue to explore surface coatings as a means of improving clinical outcome of patients undergoing orthopaedic surgery.
PMCID: PMC3582840  PMID: 23391496
implant coatings; orthopaedics; osseointegration; calcium phosphate coatings; biomolecule coatings; infection; foreign body reaction
17.  CD90 (Thy-1)-Positive Selection Enhances Osteogenic Capacity of Human Adipose-Derived Stromal Cells 
Tissue Engineering. Part A  2013;19(7-8):989-997.
Stem cell-based bone tissue engineering with adipose-derived stromal cells (ASCs) has shown great promise for revolutionizing treatment of large bone deficits. However, there is still a lack of consensus on cell surface markers identifying osteoprogenitors. Fluorescence-activated cell sorting has identified a subpopulation of CD105low cells with enhanced osteogenic differentiation. The purpose of the present study was to compare the ability of CD90 (Thy-1) to identify osteoprogenitors relative to CD105.
Unsorted cells, CD90+, CD90−, CD105high, and CD105low cells were treated with an osteogenic differentiation medium. For evaluation of in vitro osteogenesis, alkaline phosphatase (ALP) staining and alizarin red staining were performed at 7 days and 14 days, respectively. RNA was harvested after 7 and 14 days of differentiation, and osteogenic gene expression was examined by quantitative real-time polymerase chain reaction. For evaluation of in vivo osteogenesis, critical-sized (4-mm) calvarial defects in nude mice were treated with the hydroxyapatite-poly(lactic-co-glycolic acid) scaffold seeded with the above-mentioned subpopulations. Healing was followed using micro-CT scans for 8 weeks. Calvaria were harvested at 8 weeks postoperatively, and sections were stained with Movat's Pentachrome.
Transcriptional analysis revealed that the CD90+ subpopulation was enriched for a more osteogenic subtype relative to the CD105low subpopulation. Staining at day 7 for ALP was greatest in the CD90+ cells, followed by the CD105low cells. Staining at day 14 for alizarin red demonstrated the greatest amount of mineralized extracellular matrix in the CD90+ cells, again followed by the CD105low cells. Quantification of in vivo healing at 2, 4, 6, and 8weeks postoperatively demonstrated increased bone formation in defects treated with CD90+ ASCs relative to all other groups. On Movat's Pentachrome-stained sections, defects treated with CD90+ cells showed the most robust bony regeneration. Defects treated with CD90− cells, CD105high cells, and CD105low cells demonstrated some bone formation, but to a lesser degree when compared with the CD90+ group.
While CD105low cells have previously been shown to possess an enhanced osteogenic potential, we found that CD90+ cells are more capable of forming bone both in vitro and in vivo. These data therefore suggest that CD90 may be a more effective marker than CD105 to isolate a highly osteogenic subpopulation for bone tissue engineering.
PMCID: PMC3589870  PMID: 23216074
18.  MAGEC2, an epithelial-mesenchymal transition inducer, is associated with breast cancer metastasis 
MAGEC2 is a member of melanoma antigen (MAGE) family of cancer-testis antigens and associated with tumor relapse and metastasis. Here, we investigated the expression of MAGEC2 in patients with breast cancer and its clinical effects with underlying mechanisms. The expression levels of MAGEC2 were compared between 420 invasive ductal carcinoma (IDC) and 120 ductal carcinoma in situ of the breast. Correlations between MAGEC2 expression and clinico-pathologic factors or survival of patients with IDC were analyzed. In addition, MAGEC2 expression levels in tumor tissues dissected from the primary focus and matched tumor-invaded axillary lymph nodes were analyzed in 8 breast cancer patients. The functional effects of MAGEC2 overexpression were assessed in vitro using scratch assay and transwell chamber assay. MAGEC2 expression was increased in metastatic breast cancer in comparison to the non-metastatic. MAGEC2 expression was significantly associated with ER negative expression (P = 0.037), high tumor grade (P = 0.014) and stage (P = 0.002), high incidence of axillary lymph node metastasis (P = 0.013), and distant metastasis (P = 0.004). Patients with tumor with MAGEC2 positive expression have a worse prognosis and a shorter metastasis free interval. Multivariate analyses showed that MAGEC2 expression was an independent risk factor for patient overall survival and metastasis-free survival. Breast cancer cells that overexpressed MAGEC2 had stronger migratory and invasive potential than control-treated cells. Epithelial markers (E-cadherin and cytokeratin) were down-regulated in MAGEC2-overexpressing cells compared to controls, whereas mesenchymal markers (vimentin and fibronectin) were upregulated. Our results indicate that MAGEC2 has a role in breast cancer metastasis through inducing epithelial-mesenchymal transition. In addition, MAGEC2 is a novel independent poor prognostic factor in patients with IDC. Thus, targeting MAGEC2 may provide a novel therapeutic strategy for breast cancer treatment.
PMCID: PMC3984411  PMID: 24687377
MAGEC2; Breast cancer; Metastasis; Clinical outcome; Epithelial-to-mesenchymal transition
19.  Inhibition of Enterovirus 71 Replication by 7-Hydroxyflavone and Diisopropyl-Flavon7-yl Phosphate 
PLoS ONE  2014;9(3):e92565.
Enterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease, which has been continuously prevalent in Asia in recent years. In children, severe cases can lead to death, and no prophylactic or therapeutic measures against EV71 infection are available. The 3C proteases of EV71 play an important role in viral replication and are an ideal drug target. In previous work, we resolved the crystal structure for EV71 3Cpro. In this report, we took advantage of the automated docking program AutoDock 4.0 to simulate EV71 3Cpro-ligand conformation. 7-hydroxyflavone (HF) and its phosphate ester(FIP) were predicted to bind with EV71 3Cpro.In an in vitro protease inhibition assay, FIP inhibited EV71 3Cpro protease activity. Both flavones were highly active against EV71, protecting cells from EV71 infection. Replication of viral RNA and formation of EV71 plaque were all strongly inhibited in cells. These results indicated that HF and FIP may serve as potential protective agents in the treatment of patients with chronic EV71 infection.
PMCID: PMC3963929  PMID: 24664133
20.  Increased Plasma DPP4 Activity Is an Independent Predictor of the Onset of Metabolic Syndrome in Chinese over 4 Years: Result from the China National Diabetes and Metabolic Disorders Study 
PLoS ONE  2014;9(3):e92222.
To determine whether fasting plasma Dipeptidyl Peptidase 4 (DPP4) activity and active Glucagon-Like Peptide-1 (GLP-1) were predictive of the onset of metabolic syndrome.
A prospective cohort study was conducted of 2042 adults (863 men and 1,179 women) aged 18-70 years without metabolic syndrome examined in 2007(baseline) and 2011(follow-up). Baseline plasma DPP4 activity was determined as the rate of cleavage of 7-amino-4- methylcoumarin (AMC) from the synthetic substrate H-glycyl-prolyl-AMC and active GLP-1 was determined by enzymoimmunoassay.
During an average of 4 years of follow-up, 131 men (15.2%) and 174 women (14.8%) developed metabolic syndrome. In multiple linear regression analysis, baseline DPP4 activity was an independent predictor of an increase in insulin resistance over a 4-year period (P<0.01). In multivariable-adjusted models, the odds ratio (OR) for incident metabolic syndrome comparing the highest with the lowest quartiles of DPP4 activity and active GLP-1 were 2.82, 0.45 for men and 2.48, 0.36 for women respectively. Furthermore, plasma DPP4 activity significantly improved the area under the ROC curve for predicting new-onset metabolic syndrome based on information from metabolic syndrome components (Both P<0.01).
DPP4 activity is an important predictor of the onset of insulin resistance and metabolic syndrome in apparently healthy Chinese men and women. This finding may have important implications for understanding the aetiology of metabolic syndrome.
Trial Registration
#TR-CCH-Chi CTR-CCH-00000361
PMCID: PMC3960228  PMID: 24647445
21.  Delivery of Small Interfering RNA for Inhibition of Endothelial Cell Apoptosis by Hypoxia and Serum Deprivation 
RNA interference (RNAi) for anti-angiogenic or pro-apoptotic factors in endothelial cells (ECs) has great potential for the treatment of ischemic diseases by promoting angiogenesis or inhibiting apoptosis. Here, we report the utility of small interfering RNA (siRNA) in inhibiting EC apoptosis induced by tumor necrosis factor-α (TNF-α). siRNA was designed and synthesized targeting tumor necrosis factor-α receptor-1 (TNFR-1) and Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1). Human umbilical vein endothelial cells (HUVECs) were cultured under in vitro hypoxic and serum-deprived conditions to simulate in vivo ischemic conditions. Two days after liposomal delivery of siRNA targeting TNFR-1 and SHP-1, significant silencing of each target (TNFR-1; 76.5 % and SHP-1; 97.2 %) was detected. Under serum-deprived hypoxic (1% oxygen) conditions, TNF-α expression in HUVECs increased relative to normoxic (20% oxygen) and serum-containing conditions. Despite enhanced TNF-α expression, suppression of TNFR-1 or SHP-1 by siRNA delivery not only enhanced expression of angiogenic factors (KDR/Flk-1 and eNOS) and anti-apoptotic factor (Bcl-xL) but also reduced expression of a pro-apoptotic factor (Bax). Transfection of TNFR-1 or SHP-1 siRNA significantly decreased the HUVEC apoptosis while significantly enhancing HUVEC proliferation and capillary formation. The present study demonstrates that TNFR-1 and SHP-1 may be useful targets for the treatment of myocardial or hindlimb ischemia.
PMCID: PMC3957099  PMID: 18765230
RNA interference; Endothelial cell; Hypoxia; Serum Deprivation; Apoptosis
22.  Identification and Characterization of a Ste20-Like Kinase in Artemia and Its Role in the Developmental Regulation and Resistance to Environmental Stress 
PLoS ONE  2014;9(3):e92234.
To adapt to extreme environments, the crustacean Artemia has evolved two alternative reproductive pathways. During ovoviviparous (direct) development, nauplius larvae are produced. In contrast, Artemia females release encysted diapause embryos (cysts) via the oviparous pathway. To date, the cellular mechanisms that regulate stress resistance of Artemia remain largely unknown. Ste20-like kinase (SLK) participates in multiple biological processes, including stress responses, apoptosis, and cell cycle progression.
Principal Finding
We isolated and characterized a member of the SLK superfamily termed ArSLK from Artemia parthenogenetica. The ArSLK gene is transcribed throughout both ovoviviparous and oviparous development; however, the protein is located mainly in the nuclei of stress-resistant diapause cysts, unlike the nauplii and nauplius-destined embryos where it is cytoplasmic. Interestingly, exposure of nauplii to heat shock, acidic pH, and UV irradiation induced the translocation of ArSLK from cytoplasm to nucleus. This translocation was reversed following stress removal. Moreover, under physiologically-stressful conditions, the nauplius larvae produced by adults after gene knockdown of endogenous ArSLK by RNAi, lost the ability of free-swimming much earlier than those of control larvae from females injected with GFP dsRNA.
Taken together, this study demonstrated that trafficking of ArSLK between the cytoplasm and the nucleus participates in regulating the stress resistance of Artemia. Our findings may provide significant insight into the functions of members of the SLK superfamily.
PMCID: PMC3956927  PMID: 24637947
23.  Activation of circulated immune cells and inflammatory immune adherence are involved in the whole process of acute venous thrombosis 
Objective: To investigate localization and distribution of integrin subunit β1, β2 and β3 and morphological changes of ligand-recepter binding in thrombi of acute pulmonary embolism (PE) patients and explore activation of circulated immune cells, inflammatory immune adherence and coagulation response in acute venous thrombosis. Methods: Thrombi were collected from patients with acute PE. Immunohistochemistry was done to detect the expression and distribution of integrin β1, β2 and β3 in cells within thrombi, and ligands of integrin subunit β1, β2 and β3 were also determined by immunohistochemistry within the thrombi. Results: 1) Acute venous thrombi were red thrombi composed of skeletons and filamentous mesh containing large amounts of red blood cells and white blood cells; 2) Integrin subunit β1, β2 and β3 were expressed on lymphocytes, neutrophils and platelets; 3) No expression of integrin β1 ligands: Laminin, Fibronectin, Collagen I or Collagen-II on lymphocytes; integrin β2 ligands including ICAM, factor X and iC3b are distributed on neutrophils, and ligand fibrinogen bound to neutrophils; integrin β3 was expressed on platelets which form the skeleton of thrombi and bound to fibrinogen to construct mesh structure; 4) Factor Xa was expressed on the filamentous mesh; 5) Filamentous mesh was fully filled with red blood cell dominant blood cells. Conclusion: Acute venous thrombosis is an activation process of circulated lymphocytes, neutrophils and platelets mainly, and a whole process including integrin subunit β2 and β3 binding with their ligands. Activation of immune cells, inflammatory immune adherence and coagulation response are involved in the acute venous thrombosis.
PMCID: PMC3992394  PMID: 24753749
Pulmonary embolism; venous thrombosis; integrin
24.  Inverse Tone Mapping Based upon Retina Response 
The Scientific World Journal  2014;2014:168564.
The development of high dynamic range (HDR) display arouses the research of inverse tone mapping methods, which expand dynamic range of the low dynamic range (LDR) image to match that of HDR monitor. This paper proposed a novel physiological approach, which could avoid artifacts occurred in most existing algorithms. Inspired by the property of the human visual system (HVS), this dynamic range expansion scheme performs with a low computational complexity and a limited number of parameters and obtains high-quality HDR results. Comparisons with three recent algorithms in the literature also show that the proposed method reveals more important image details and produces less contrast loss and distortion.
PMCID: PMC3973007  PMID: 24744678
25.  Anti-Enterovirus 71 Effects of Chrysin and Its Phosphate Ester 
PLoS ONE  2014;9(3):e89668.
Enterovirus 71 (EV71) can cause severe disease and even lead to death in children, and an effective antiviral drug is currently unavailable. The anti-EV71 effect of chrysin (5,7-dihydroxyflavone), a natural flavonoid commonly found in many plants, was tested in this report. By using the predicting program Autodock 4.0 and an in vitro protease inhibition assay, we found that chrysin could suppress viral 3Cpro activity. Replication of viral RNA and production of viral capsid protein and the infectious virion were strongly inhibited by chrysin, without noticeable cytotoxicity. Cytopathic effects on cells were also prevented. Diisopropyl chrysin-7-yl phosphate (CPI), the phosphate ester for chrysin, was generated through a simplified Atheron-Todd reaction to achieve stronger anti-viral activity. CPI was also able to bind with and inhibit viral 3Cpro activity in vitro. As expected, CPI demonstrated more potent antiviral activity against EV71.
PMCID: PMC3943725  PMID: 24598537

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