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1.  The Endoparasitoid, Cotesia vestalis, Regulates Host Physiology by Reprogramming the Neuropeptide Transcriptional Network 
Scientific Reports  2015;5:8173.
Endoparasitoids develop inside another insect by regulating host immunity and development via maternal factors injected into hosts during oviposition. Prior results have provided insights into parasitism-induced immunosuppression, including the neuropeptide accumulation in parasitized insects. Nonetheless, our understanding of neuropeptide influence on host development and behavior is not yet complete. We posed the hypothesis that parasitization alters expression of genes encoding pro-neuropeptides and used larvae of Plutella xylostella and its endoparasitoid, Cotesia vestalis to test our hypothesis. We prepared transcriptomes from the larval P. xylostella brain-CC-CA complex and identified transcripts encoding 19 neuropeptides. All corresponding cDNAs were confirmed by RACE. Our results demonstrate that parasitism significantly down-regulated, or delayed, expression of genes encoding pro-neuropeptides within 48 h post-parasitization. Changing expression of these genes may account for the previously reported decreased feeding behavior, reduced growth rates and aborted development in the host larvae. In effect, parasitization may operate at the molecular level within the CNS to create global changes in larval host biology. The significance of our finding is that, in addition to the known effects on immunity, parasitoids influence host pro-neuropeptide gene transcription. This finding reveals a new mechanism operating in host-parasitoid relationships to the advantage of the parasitoid.
PMCID: PMC4313088  PMID: 25640113
2.  Cyclin-Dependent Kinase 5 Mediates Adult OPC Maturation and Myelin Repair through Modulation of Akt and GsK-3β Signaling 
The Journal of Neuroscience  2014;34(31):10415-10429.
Failure of remyelination in diseases, such as multiple sclerosis (MS), leads to permanent axonal damage and irreversible functional loss. The mechanisms controlling remyelination are currently poorly understood. Recent studies implicate the cyclin-dependent kinase 5 (Cdk5) in regulating oligodendrocyte (OL) development and myelination in CNS. In this study, we show that Cdk5 is also an important regulator of remyelination. Pharmacological inhibition of Cdk5 inhibits repair of lysolecithin lesions. This inhibition is a consequence of Cdk5 disruption in neural cells because remyelination in slice cultures is blocked by Cdk5 inhibitors, whereas specific deletion of Cdk5 in OLs inhibits myelin repair. In CNP-Cre;Cdk5fl/fl conditional knock-out mouse (Cdk5 cKO), myelin repair was delayed significantly in response to focal demyelinating lesions compared with wild-type animals. The lack of myelin repair was reflected in decreased expression of MBP and proteolipid protein and a reduction in the total number of myelinated axons in the lesion. The number of CC1+ cells in the lesion sites was significantly reduced in Cdk5 cKO compared with wild-type animals although the total number of oligodendrocyte lineage cells (Olig2+ cells) was increased, suggesting that Cdk5 loss perturbs the transition of early OL lineage cell into mature OL and subsequent remyelination. The failure of remyelination in Cdk5 cKO animals was associated with a reduction in signaling through the Akt pathway and an enhancement of Gsk-3β signaling pathways. Together, these data suggest that Cdk5 is critical in regulating the transition of adult oligodendrocyte precursor cells to mature OLs that is essential for myelin repair in adult CNS.
PMCID: PMC4115145  PMID: 25080600
cyclin-dependent kinase 5; demyelination; myelination; oligodendrocyte; remyelination
3.  Genetic characterization of Toxoplasma gondii in Yunnan black goats (Capra hircus) in southwest China by PCR-RFLP 
Parasites & Vectors  2015;8:57.
Toxoplasma gondii is a protozoan parasite that infects almost all warm-blooded animals and human beings. Goats are one of the susceptible animals to T. gondii. However, little is known of genetic diversity of T. gondii in Yunnan black goats in China. The objective of this present study was to determine the genotypes of T. gondii isolates from black goats in Yunnan province, southwest China.
Genomic DNA was extracted from liver (n = 403), lung (n = 403) and lymph nodes (n = 250) of Yunnan black goats and assayed for T. gondii infection by semi-nested PCR of B1 gene. Then, the positive DNA samples were typed at 10 genetic markers using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technology. These markers include 9 nuclear loci, namely, SAG1, SAG2 (5’-SAG2 and 3’-SAG2, alternative SAG2), SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and an apicoplast locus Apico.
Out of 403 tested samples, 20 (4.96%) DNA samples were T. gondii positive by amplification of B1 gene. Among them, 2 isolates were genotyped at all loci, and 6 isolates were genotyped for 8 or more loci. In total, seven samples belong to ToxoDB PCR-RFLP genotype#10 (Type I), and one belongs to genotype ToxoDB #9.
To our knowledge, this is the first report of ToxoDB#9 and ToxoDB#10 T. gondii in Yunnan black goats in China. These results revealed a wide distribution of these T. gondii in Yunnan black goats in China, which has important implications for public health.
PMCID: PMC4316756  PMID: 25622613
Toxoplasma gondii; Genotype; PCR-RFLP; Yunnan black goats; China
4.  Duration of complex-spikes grades Purkinje cell plasticity and cerebellar motor learning 
Nature  2014;510(7506):529-532.
Behavioral learning is mediated by cellular plasticity such as changes in the strength of synapses at specific sites in neural circuits. The theory of cerebellar motor learning1,2,3 relies on movement errors signaled by climbing-fiber inputs to cause long-term depression of synapses from parallel fibers to Purkinje cells4,5. Yet, a recent review6 has called into question the widely-held view that the climbing fiber input is an “all-or-none” event. In anesthetized animals, there is wide variation in the duration of the complex-spike (CS) caused in Purkinje cells by a climbing fiber input7. Further, the duration of electrically-controlled bursts in climbing fibers grades the amount of plasticity in Purkinje cells8,9. The duration of bursts depends on the “state” of the inferior olive and therefore could be correlated across climbing fibers8,10. Here, we provide a potential functional context for these mechanisms during motor learning in behaving monkeys. The magnitudes of both plasticity and motor learning depend on the duration of the CS responses. Further, the duration of CS responses appears to be a meaningful signal that is correlated across the Purkinje cell population during motor learning. We suggest that during learning, longer bursts in climbing fibers lead to longer duration CS responses in Purkinje cells, more calcium entry into Purkinje cells, larger synaptic depression, and stronger learning. The same graded impact of instructive signals for plasticity and learning could occur throughout the nervous system.
PMCID: PMC4132823  PMID: 24814344
5.  Epidemiological Characterization and Risk Factors of Allergic Rhinitis in the General Population in Guangzhou City in China 
PLoS ONE  2014;9(12):e114950.
The prevalence of allergic rhinitis (AR) in China has increased with an apparent geographic variation. The current study aims to investigate the AR prevalence/classification, diagnosis/treatment conditions, trigger factors, and risk factors in the general population of Guangzhou, the third biggest city in China. A cross-sectional survey was performed in the citizens in Guangzhou from December 2009 to March 2010 by using a stratified multistage cluster sampling method. All subjects were asked to complete a comprehensive questionnaire via a face to face interview. A total of 9,899 questionnaires were valid. The prevalence rate of AR in the general population of Guangzhou was 6.24%, with a significant higher prevalence in urban area (8.32%) versus rural area (3.43%). Among the AR subjects, most (87%) were diagnosed with intermittent AR and 87% suffered from moderate-severe symptoms. High percentages of the AR patients did not have previously physician-based diagnosis (34%) or specific medical treatment (55%). Morning time, winter season, and cold air were the most common trigger factors of AR. Family history of AR, current living place, living place during babyhood, smoking, home renovation, and pet ownership were the significant risk factors associated with AR prevalence in the population. The study demonstrated comprehensive epidemiological and clinical information about the AR in Guangzhou population. Change of living environment and lifestyles had strong impacts on the prevalence of AR. Public health policies should help the patients benefit from a proper diagnosis/treatment and specifically target the local risk factors, in order to control the AR incidence.
PMCID: PMC4267734  PMID: 25514026
6.  The cyclic AMP response element-binding protein antisense oligonucleotide induced anti-nociception and decreased the expression of KIF17 in spinal cord after peripheral nerve injury in mice 
Backgrounds: The cyclic AMP response element-binding protein (CREB) plays an important role in neuropathic pain. Kinesin superfamily motor protein 17 (KIF17) is involved in long-term memory formation. CREB could increase the level of KIF17 when activated by synaptic input. This study is to investigate the role and mechanism of CREB antisense oligonucleotide (ODN) in neuropathic pain induced by chronic constriction injury (CCI) in mice. Results: CCI surgery decreased thresholds of mechanical allodynia and thermal hyperalgesia whereas CREB antisense oligonucleotide ODN significantly attenuated these pain behaviors (P < 0.05). CCI significantly induced the protein expression of phosphorylated CREB (pCREB) and KIF17, but not KIF5B, in the spinal cord of CCI mice (P < 0.05). Additionally, the mRNA expression of CREB and KIF17 was significantly increased by CCI (P < 0.05). However, CREB antisense ODN significantly decreased the protein expression of pCREB and KIF17 (but not KIF5B), and the mRNA expression of CREB and KIF17 (P < 0.05). Conclusions: CREB antisense oligonucleotide ODN may reduce neuropathic pain through targeting CREB and decreasing the expression of pCREB and KIF17.
PMCID: PMC4307467  PMID: 25664020
Neuropathic pain; CREB; KIF17; antisense oligonucleotide
7.  The diagnosis of diabetic acute complications using the glucose-ketone meter in outpatients at endocrinology department 
Objective: To determine urine ketone and blood β-hydroxybutyrate acid (β-HBA) in outpatients of endocrinology department and to investigate the association between urine ketone or blood β-HBA and diabetic ketosis (DK) or diabetic ketoacidosis (DKA). Methods: Urine ketone, blood β-HBA, body mass index (BMI) and glycosylated hemoglobin (HbA1c) were determined in 134 patients with blood glucose ≥ 13.9 mmol/L. Results: In 134 patients with severe hyperglycemia, there were 30 patients (22.4%) with acute complications of diabetes, including 24 patients (17.9%) diagnosed with DK and 6 patients (4.5%) diagnosed with DKA. Among them, 6 patients (20%) were withdrawal, 2 (6.7%) were infected, and 19 (63.3%) were not treated. When there was a negative urine ketone, 10% patients would have had blood β-HBA ≥ 0.3 mmol/L. When there was a positive urine ketone (+ to +++), 22.62% patients would have had blood β-HBA < 0.3 mmol/L. Conclusions: Blood β-HBA had a positive correlation with blood glucose (r = 0.34, P < 0.001). Complications of severe hyperglycemia could be diagnosed quickly and accurately by analyzing blood β-HBA using the glucose-ketone meter.
PMCID: PMC4307541  PMID: 25664094
Diabetic ketoacidosis; urine ketone; β-hydroxybutyrate acid; glucose-ketone meter
8.  Short-Term Effects of Continuous Subcutaneous Insulin Infusion Therapy in Perioperative Patients with Diabetes Mellitus 
Diabetes Technology & Therapeutics  2013;15(12):1010-1018.
Background: Hyperglycemia is common and hard to control in surgical patients with diabetes. We retrospectively investigated short-term effects of continuous subcutaneous insulin infusion (CSII) in perioperative patients with diabetes.
Patients and Methods: Perioperative patients with diabetes discharged between January 1, 2006 and January 1, 2012 were included. Glucose control and postoperative outcomes were compared between the patients using CSII or non-CSII insulin therapy.
Results: We identified 108 pairs of patients matched by propensity and surgical category who were using CSII therapy (CSII group) or non-CSII insulin therapy (control group). The CSII group had significantly lower fasting glucose levels (on the first postoperative day, 9.06±3.09 mmol/L vs. 11.05±4.19 mmol/L; P=0.003) and lower mean glucose levels (on the operation day, 9.93±2.65 mmol/L vs. 12.05±3.86 mmol/L; P=0.001). The CSII group also had a lower incidence of fever (on the first postoperative day, 30.4% vs. 53.2%; P=0.005). Furthermore, patients in the CSII group experienced significantly shorter postoperative intervals for suture removal (P=0.02) and hospital discharge (P=0.03). No significant difference in the total medical expenditure was observed between the two groups (P=0.47). We also made a comparison between the 30 pairs of patients who were using CSII or multiple daily insulin injection therapy but observed no significant difference between these two therapies in glucose control or postoperative outcomes.
Conclusions: Compared with non-CSII insulin therapy, even short-term implementation of CSII can improve the postoperative control of glucose, reduce the incidence of postoperative fever, and shorten the time for suture removal and discharge in surgical patients with diabetes.
PMCID: PMC3868275  PMID: 23971526
9.  Molecular Magnetic Resonance Imaging of Pulmonary Fibrosis in Mice 
Idiopathic pulmonary fibrosis is a chronic, progressive, fibrosing interstitial pneumonia of unknown cause resulting in dyspnea and functional decline until death. There are currently no effective noninvasive tools to monitor disease progression and response to treatment. The objective of the present study was to determine whether molecular magnetic resonance imaging of the lung using a probe targeted to type I collagen could provide a direct, noninvasive method for assessment of pulmonary fibrosis in a mouse model. Pulmonary fibrosis was generated in mice by transtracheal instillation of bleomycin (BM). Six cohorts were imaged before and immediately after intravenous administration of molecular imaging probe: (1) BM plus collagen-targeted probe, EP-3533; (2) sham plus EP-3533; (3) BM plus nonbinding control probe, EP-3612; (4) sham plus EP-3612; (5) BM plus EP-3533 imaged early; and (6) BM plus EP-3533 imaged late. Signal-to-noise ratio (SNR) enhancement was quantified in the lungs and muscle. Lung tissue was subjected to pathologic scoring of fibrosis and analyzed for gadolinium and hydroxyproline. BM-treated mice had 35% higher lung collagen than sham mice (P < 0.0001). The SNR increase in the lungs of fibrotic mice after EP-3533 administration was twofold higher than in sham animals and twofold higher than in fibrotic or sham mice that received control probe, EP-3612 (P < 0.0001). The SNR increase in muscle was similar for all cohorts. For EP-3533, we observed a strong, positive, linear correlation between lung SNR increase and hydroxyproline levels (r = 0.72). Collagen-targeted probe EP-3533–enhanced magnetic resonance imaging specifically detects pulmonary fibrosis in a mouse model of disease.
PMCID: PMC3931113  PMID: 23927643
molecular imaging; gadolinium; type I collagen; bleomycin; EP-3533
10.  GSK-3β Inhibition Attenuates CLP-Induced Liver Injury by Reducing Inflammation and Hepatic Cell Apoptosis 
Mediators of Inflammation  2014;2014:629507.
Liver dysfunction has been known to occur frequently in cases of sepsis. Excessive inflammation and apoptosis are pathological features of acute liver failure. Recent studies suggest that activation of glycogen synthase kinase- (GSK-) 3β is involved in inflammation and apoptosis. We aimed to investigate the protective effects of GSK-3β inhibition on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP), and SB216763 was used to inhibit GSK-3β in C57BL/6 mice. GSK-3β was activated following CLP. Administration of SB216763 decreased mortality, ameliorated liver injury, and reduced hepatic apoptosis. The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release. Moreover, GSK-3β inhibition suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB) but enhanced the transcriptional activity of cAMP response element binding protein (CREB) in the liver. In in vitro studies, GSK-3β inhibition reduced inflammatory cytokine production via modulation of NF-κB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages. In conclusion, these findings suggest that GSK-3β blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-κB and CREB activity and suppression of hepatic apoptosis.
PMCID: PMC4265684  PMID: 25525303
11.  Pre-pregnancy cytogenetic analysis of general couples in eastern China 
Scientific Reports  2014;4:7224.
The aim of this study was to investigate the contribution of chromosomal anomalies and the frequency of particular types of aberrations in general couples preparing for pregnancy and make recommendations for pregnancy on the basis of the medical literature. A total of 6,198 general couples were included in the present study. The karyotypes were generated from the peripheral blood lymphocyte cultures and the cytogenetic analysis was performed using G-banding. In 12,396 cases, chromosomal anomalies were detected in 59 cases (0.48%, 59/12,396). Among of them, the frequency of translocation was 0.35% (n = 43). Sex chromosomal anomalies accounted for 0.07% (n = 9), including Klinefelter syndrome (KS) (n = 4), Turner syndrome (TS) (n = 4), and XYY syndrome (n = 1). The others, including inversions (n = 6) and deletion (n = 1), accounted for 0.06%. Our study indicates that clinically important chromosomal defects are present at a remarkable frequency in the general couples in eastern China, suggesting pre-pregnancy cytogenetic analysis should be routinely performed among general couples in this area so that informed decision can be made, which will help to improve the quality of the pregnancy.
PMCID: PMC4245518  PMID: 25428275
12.  Role of Plasticity at Different Sites across the Time Course of Cerebellar Motor Learning 
The Journal of Neuroscience  2014;34(21):7077-7090.
Learning comprises multiple components that probably involve cellular and synaptic plasticity at multiple sites. Different neural sites may play their largest roles at different times during behavioral learning. We have used motor learning in smooth pursuit eye movements of monkeys to determine how and when different components of learning occur in a known cerebellar circuit. The earliest learning occurs when one climbing-fiber response to a learning instruction causes simple-spike firing rate of Purkinje cells in the floccular complex of the cerebellum to be depressed transiently at the time of the instruction on the next trial. Trial-over-trial depression and the associated learning in eye movement are forgotten in <6 s, but facilitate long-term behavioral learning over a time scale of ∼5 min. During 100 repetitions of a learning instruction, simple-spike firing rate becomes progressively depressed in Purkinje cells that receive climbing-fiber inputs from the instruction. In Purkinje cells that prefer the opposite direction of pursuit and therefore do not receive climbing-fiber inputs related to the instruction, simple-spike responses undergo potentiation, but more weakly and more slowly. Analysis of the relationship between the learned changes in simple-spike firing and learning in eye velocity suggests an orderly progression of plasticity: first on Purkinje cells with complex-spike (CS) responses to the instruction, later on Purkinje cells with CS responses to the opposite direction of instruction, and last in sites outside the cerebellar cortex. Climbing-fiber inputs appear to play a fast and primary, but nonexclusive, role in pursuit learning.
PMCID: PMC4028490  PMID: 24849344
climbing fibers; floccular complex; long-term depression; smooth pursuit eye movement; synaptic plasticity; trial-over-trial learning
13.  Evaluation of Gridded Precipitation Data for Driving SWAT Model in Area Upstream of Three Gorges Reservoir 
PLoS ONE  2014;9(11):e112725.
Gridded precipitation data are becoming an important source for driving hydrologic models to achieve stable and valid simulation results in different regions. Thus, evaluating different sources of precipitation data is important for improving the applicability of gridded data. In this study, we used three gridded rainfall datasets: 1) National Centers for Environmental Prediction - Climate Forecast System Reanalysis (NCEP-CFSR); 2) Asian Precipitation - Highly-Resolved Observational Data Integration Towards Evaluation (APHRODITE); and 3) China trend - surface reanalysis (trend surface) data. These are compared with monitoring precipitation data for driving the Soil and Water Assessment Tool in two basins upstream of Three Gorges Reservoir (TGR) in China. The results of one test basin with significant topographic influence indicates that all the gridded data have poor abilities in reproducing hydrologic processes with the topographic influence on precipitation quantity and distribution. However, in a relatively flat test basin, the APHRODITE and trend surface data can give stable and desirable results. The results of this study suggest that precipitation data for future applications should be considered comprehensively in the TGR area, including the influence of data density and topography.
PMCID: PMC4237342  PMID: 25409467
14.  Paxillin regulates vascular endothelial growth factor A-induced in vitro angiogenesis of human umbilical vein endothelial cells 
Molecular Medicine Reports  2014;11(3):1784-1792.
The purpose of the present study was to investigate the role of paxillin in the vascular endothelial growth factor A (VEGF-A)-induced adhesion, proliferation, migration and capillary formation of endothelial cells (ECs) in vitro. Human umbilical vein ECs (HUVECs) were used to evaluate these four processes in vitro. The HUVECs were either mock-transfected (control), transfected with scramble small interference RNA (siRNA) or transfected with siRNA specifically targeting paxillin. VEGF-A (20 ng/ml) was used to stimulate angiogenesis. The VEGF-A treatment significantly increased the adhesion, proliferation, migration and tube formation of the HUVECs in the control and scramble siRNA groups, whereas the siRNA-mediated knockdown of paxillin inhibited these VEGF-A-induced effects. Paxillin is essential for VEGF-A-mediated angiogenesis in ECs and its inhibition may be a potential target for antiangiogenic therapies.
PMCID: PMC4270338  PMID: 25405379
paxillin; vascular endothelial growth factor; endothelium; angiogenesis
15.  20(S)-Protopanaxadiol Inhibition of Progression and Growth of Castration-Resistant Prostate Cancer 
PLoS ONE  2014;9(11):e111201.
Castration-resistant progression of prostate cancer after androgen deprivation therapies remains the most critical challenge in the clinical management of prostate cancer. Resurgent androgen receptor (AR) activity is an established driver of castration-resistant progression, and upregulation of the full-length AR (AR-FL) and constitutively-active AR splice variants (AR-Vs) has been implicated to contribute to the resurgent AR activity. We reported previously that ginsenoside 20(S)-protopanaxadiol-aglycone (PPD) can reduce the abundance of both AR-FL and AR-Vs. In the present study, we further showed that the effect of PPD on AR expression and target genes was independent of androgen. PPD treatment resulted in a suppression of ligand-independent AR transactivation. Moreover, PPD delayed castration-resistant regrowth of LNCaP xenograft tumors after androgen deprivation and inhibited the growth of castration-resistant 22Rv1 xenograft tumors with endogenous expression of AR-FL and AR-Vs. This was accompanied by a decline in serum prostate-specific antigen levels as well as a decrease in AR levels and mitoses in the tumors. Notably, the 22Rv1 xenograft tumors were resistant to growth inhibition by the next-generation anti-androgen enzalutamide. The present study represents the first to show the preclinical efficacy of PPD in inhibiting castration-resistant progression and growth of prostate cancer. The findings provide a rationale for further developing PPD or its analogues for prostate cancer therapy.
PMCID: PMC4222907  PMID: 25375370
16.  Molecular MRI of Collagen to Diagnose and Stage Liver Fibrosis 
Journal of hepatology  2013;59(5):992-998.
Background & Aims
The gold standard in assessing liver fibrosis is biopsy despite limitations like invasiveness and sampling error and complications including morbidity and mortality. Therefore, there is a major unmet medical need to quantify fibrosis noninvasively to facilitate early diagnosis of chronic liver disease and provide a means to monitor disease progression. The goal of this study was to evaluate the ability of several magnetic resonance imaging (MRI) techniques to stage liver fibrosis.
A gadolinium (Gd)-based MRI probe targeted to type I collagen (termed EP-3533) was utilized to noninvasively stage liver fibrosis in a carbon tetrachloride (CCl4) mouse model and the results were compared to other MRI techniques including relaxation times, diffusion and magnetization transfer measurements.
The most sensitive MR biomarker was the change in liver:muscle contrast to noise ratio (ΔCNR) after EP-3533 injection. We observed a strong positive linear correlation between ΔCNR and liver hydroxyproline (i.e. collagen) levels (r=0.89) as well as ΔCNR and conventional Ishak fibrosis scoring. In addition, the area under the receiver operating curve (AUR0C) for distinguishing early (Ishak ≤3) from late (Ishak ≥ 4) fibrosis was 0.942±0.052 (p<0.001). By comparison, other MRI techniques were not as sensitive to changes in fibrosis in this model.
We have developed a MRI technique using a collagen-specific probe for diagnosing and staging liver fibrosis, and validated it in the CCl4 mouse model. This approach should provide a better means to monitor disease progression in patients.
PMCID: PMC3805694  PMID: 23838178
fibrosis; MRI; molecular imaging; type 1 collagen; noninvasive; gadolinium; EP-3533; CCl4
17.  Prognostic role of SPARC expression in gastric cancer: a meta-analysis 
Archives of Medical Science : AMS  2014;10(5):863-869.
Secreted protein acidic and rich in cysteine (SPARC) is involved in regulating cell adhesion, proliferation, migration, and tissue remodeling. We performed a meta-analysis to evaluate the association between SPARC expression and the clinicopathologic features and outcomes of gastric cancer patients.
Material and methods
Publications that assessed the clinical or prognostic significance of SPARC in gastric cancer up to October 2013 were identified. A meta-analysis was performed to clarify the association between SPARC expression and clinical outcomes.
Ten studies, including 1417 cases, met the inclusion criteria. The data were analyzed and the results show that SPARC is not significantly associated with the depth of gastric cancer invasion (odds ratio (OR) = 1.17, 95% confidence interval (CI): 0.60–2.29, Z = 0.47, p = 0.64) or tumor differentiation (OR = 0.59, 95% CI: 0.22–1.58, Z = 1.06, p = 0.29). Moreover, SPARC was not significantly correlated with lymph node metastasis (OR = 0.72, 95% CI: 0.37–1.41, Z = 0.96, p = 0.34). However, SPARC overexpression was highly correlated with reduced overall survival (relative risk (RR) = 1.78, 95% CI: 1.52–2.09, Z = 7.10, p = 0.43).
The SPARC may play an important role in the progression of gastric cancer, and SPARC overexpression is closely correlated with poor patient survival. The SPARC is a potential clinical marker for the survival of gastric cancer patients; however, well-designed prospective studies are needed to confirm these findings.
PMCID: PMC4223132  PMID: 25395936
secreted protein acidic and rich in cysteine; tumor progression; gastric cancer; prognosis
18.  Effect of Inlet and Outlet Flow Conditions on Natural Gas Parameters in Supersonic Separation Process 
PLoS ONE  2014;9(10):e110313.
A supersonic separator has been introduced to remove water vapour from natural gas. The mechanisms of the upstream and downstream influences are not well understood for various flow conditions from the wellhead and the back pipelines. We used a computational model to investigate the effect of the inlet and outlet flow conditions on the supersonic separation process. We found that the shock wave was sensitive to the inlet or back pressure compared to the inlet temperature. The shock position shifted forward with a higher inlet or back pressure. It indicated that an increasing inlet pressure declined the pressure recovery capacity. Furthermore, the shock wave moved out of the diffuser when the ratio of the back pressure to the inlet one was greater than 0.75, in which the state of the low pressure and temperature was destroyed, resulting in the re-evaporation of the condensed liquids. Natural gas would be the subsonic flows in the whole supersonic separator, if the mass flow rate was less than the design value, and it could not reach the low pressure and temperature for the condensation and separation of the water vapor. These results suggested a guidance mechanism for natural gas supersonic separation in various flow conditions.
PMCID: PMC4206423  PMID: 25338207
19.  Non-Genetic Direct Reprogramming and Biomimetic Platforms in a Preliminary Study for Adipose-Derived Stem Cells into Corneal Endothelia-Like Cells 
PLoS ONE  2014;9(10):e109856.
Cell fate and function can be regulated and reprogrammed by intrinsic genetic program, extrinsic factors and niche microenvironment. Direct reprogramming has shown many advantages in the field of cellular reprogramming. Here we tried the possibility to generate corneal endothelia (CE) -like cells from human adipose-derived stem cells (ADSCs) by the non-genetic direct reprogramming of recombinant cell-penetrating proteins Oct4/Klf4/Sox2 (PTD-OKS) and small molecules (purmorphamine, RG108 and other reprogramming chemical reagents), as well as biomimetic platforms of simulate microgravity (SMG) bioreactor. Co-cultured with corneal cells and decellularized corneal ECM, Reprogrammed ADSCs revealed spherical growth and positively expressing Nanog for RT-PCR analysis and CD34 for immunofluorescence staining after 7 days-treatment of both purmorphamine and PTD-OKS (P-OKS) and in SMG culture. ADSCs changed to CEC polygonal morphology from spindle shape after the sequential non-genetic direct reprogramming and biomimetic platforms. At the same time, induced cells converted to weakly express CD31, AQP-1 and ZO-1. These findings demonstrated that the treatments were able to promote the stem-cell reprogramming for human ADSCs. Our study also indicates for the first time that SMG rotary cell culture system can be used as a non-genetic means to promote direct reprogramming. Our methods of reprogramming provide an alternative strategy for engineering patient-specific multipotent cells for cellular plasticity research and future autologous CEC replacement therapy that avoids complications associated with the use of human pluripotent stem cells.
PMCID: PMC4198143  PMID: 25333522
20.  In vivo magnetic resonance imaging tracking of transplanted superparamagnetic iron oxide-labeled bone marrow mesenchymal stem cells in rats with myocardial infarction 
Molecular Medicine Reports  2014;11(1):113-120.
Superparamagnetic iron oxide (SPIO) nanoparticles generate superparamagnetism, thereby resulting in an inhomogeneous local magnetic field, which shortens the T2 value on magnetic resonance imaging (MRI). The purpose of the present study was to use MRI to track bone marrow mesenchymal stem cells (BMSCs) labeled with SPIO in a rat model of myocardial infarction. The BMSCs were isolated from rats and labeled with SPIO. The anterior descending branch of the coronary artery was ligated under anesthesia. Two weeks later, the rats received, at random, 5×107 SPIO-labeled BMSCs, 5×107 unlabeled BMSCs or a vehicle (100 μl phosphate-buffered saline) via direct injection into the ischemic area (20 animals/group). MRI was used to track the SPIO-labeled BMSCs and the rats were then sacrificed to verify the presence of BMSCs using immunohistochemistry with an anti-CD90 antibody. The procedure labeled 99% of the BMSCs with SPIO, which exhibited low-intensity signals on T2 and T2* MRI imaging. At 24 h post-BMSC transplantation, low-intensity MRI signals were detected on the T2 and T2* sequences at the infarction margins. After 3 weeks following transplantation, low-intensity signals started to appear within the infarcted area; however, the signal intensity subsequently decreased and became indistinct. Immunohistochemistry revealed that the SPIO-labeled BMSCs migrated from the margin into the infarcted region. In conclusion, the BMSCs were readily labeled with SPIO and in vivo and MRI tracking demonstrated that the SPIO-labeled BMSCs established and grew in the infarcted myocardium.
PMCID: PMC4237077  PMID: 25323652
superparamagnetic iron oxide; bone marrow mesenchymal stem cells; myocardial infarction; magentic resonance imaging
21.  Value of fine needle aspiration cell blocks in the diagnosis and classification of lymphoma 
Fine needle aspiration biopsy (FNAB) is a simple yet accurate diagnostic procedure. However, the role of FNAB in lymphoma diagnosis and classification remains controversial. This study aimed to evaluate the value of FNAB cell blocks in the diagnosis and classification of lymphoma using our patented aspirator in a pencil-grip operation manner and a simplified cell block preparation method. We retrospectively reviewed 177 cases of lymph node and extranodal lymphoproliferative disorders that were diagnosed with cytomorphology, morphology, and immunohistochemistry of cell blocks. Of these, 83 were primary lymphoma; 14 were recurrent lymphoma; 8 were suspected as lymphoma, and 72 were benign reactive hyperplasia (BRH). Our analysis indicated 99.0% sensitivity, 95.9% specificity, 97.1% positive predictive value, and 98.6% negative predictive value in discriminating among primary/recurrent lymphoma and BRH. The diagnostic accuracy for sub-classification of lymphoma was 86.6% (84/97), with 77.8% (7/9) for classical Hodgkin’s lymphoma and 87.5% (77/88) for non-Hodgkin’s lymphoma. Our results implicated cell blocks as a reliable and useful adjunct to FNAB for the diagnosis and classification of lymphoma. Cytomorphology, morphology, and immunohistochemical studies of cell blocks offered very high accuracy in the diagnosis of lymphoma and allowed further sub-classification in many cases. Thus, patients with a definitive diagnosis and classification might avoid invasive and expensive surgical biopsy procedures.
PMCID: PMC4270562  PMID: 25550808
Fine needle aspiration biopsy; cell block; lymphoma; accuracy; immunohistochemistry
22.  Characteristics and clinical outcome of nonsteroidal anti-inflammatory drug-induced acute hepato-nephrotoxicity among Chinese patients 
World Journal of Gastroenterology : WJG  2014;20(38):13956-13965.
AIM: To determine the clinicopathological characteristics of nonsteroidal anti-inflammatory drug (NSAID)-induced acute hepato-nephrotoxicity among Chinese patients.
METHODS: We conducted a retrospective chart review of patients using the International Classification of Diseases, Ninth Revision diagnosis code for acute kidney injury (AKI) (584.5 or 584.9) and for acute liver injury (ALI) (570.0 or 573.3) from January 2004 to December 2013. Medical records were reviewed to confirm the diagnosis of AKI and ALI and to quantify NSAID administration.
RESULTS: Seven of 59 patients (11.8%) were identified with acute hepato-nephrotoxicity induced by NSAIDs. Five patients (71.4%) received over the recommended NSAIDs dose. Compared with NSAIDs-associated mere AKI, the risk factors of NSAIDs-induced acute hepato-nephrotoxicity are age older than 60 years (57.1%), a high prevalence of alcohol use (71.4%) and positive hepatitis B virus (HBV) markers (85.7%). Compared with NSAIDs-associated mere ALI, the risk factors of NSAIDs-induced acute hepato-nephrotoxicity are age older than 60 years (57.1%), increased extracellular volume depletion (71.4%), and renin-angiotensin-aldosterone system (RAAS) inhibitor combined use (57.1%). Acute interstitial nephritis and acute tubulointerstitial disease were apparent in three out of six (42.9%) kidney biopsy patients, respectively. Acute hepatitis was found in four out of six (66.7%) liver biopsy patients. Overall complete recovery occurred in four patients within a mean of 118.25 ± 55.42 d.
CONCLUSION: The injury typically occurred after an overdose of NSAIDs. The risk factors include age older than 60 years, alcohol use, positive HBV markers, extracellular volume depletion and RAAS inhibitor combined use.
PMCID: PMC4194579  PMID: 25320533
Nonsteroidal anti-inflammatory drug; Hepato-nephrotoxicity; Acute interstitial nephritis; Acute hepatitis; Cholestasis
23.  Epidermal growth factor upregulates serotonin transporter and its association with visceral hypersensitivity in irritable bowel syndrome 
World Journal of Gastroenterology : WJG  2014;20(37):13521-13529.
AIM: To investigate the role of epidermal growth factor (EGF) in visceral hypersensitivity and its effect on the serotonin transporter (SERT).
METHODS: A rat model for visceral hypersensitivity was established by intra-colonic infusion of 0.5% acetic acid in 10-d-old Sprague-Dawley rats. The visceral sensitivity was assessed by observing the abdominal withdrawal reflex and recording electromyographic activity of the external oblique muscle in response to colorectal distension. An enzyme-linked immunosorbent assay was used to measure the EGF levels in plasma and colonic tissues. SERT mRNA expression was detected by real-time PCR while protein level was determined by Western blot. The correlation between EGF and SERT levels in colon tissues was analyzed by Pearson’s correlation analysis. SERT function was examined by tritiated serotonin (5-HT) uptake experiments. Rat intestinal epithelial cells (IEC-6) were used to examine the EGF regulatory effect on SERT expression and function via the EGF receptor (EGFR).
RESULTS: EGF levels were significantly lower in the rats with visceral hypersensitivity as measured in plasma (2.639 ± 0.107 ng/mL vs 4.066 ± 0.573 ng/mL, P < 0.01) and in colonic tissue (3.244 ± 0.135 ng/100 mg vs 3.582 ± 0.197 ng/100 mg colon tissue, P < 0.01) compared with controls. Moreover, the EGF levels were positively correlated with SERT levels (r = 0.820, P < 0.01). EGF displayed dose- and time-dependent increased SERT gene expressions in IEC-6 cells. An EGFR kinase inhibitor inhibited the effect of EGF on SERT gene upregulation. SERT activity was enhanced following treatment with EGF (592.908 ± 31.515 fmol/min per milligram vs 316.789 ± 85.652 fmol/min per milligram protein, P < 0.05) and blocked by the EGFR kinase inhibitor in IEC-6 cells (590.274 ± 25.954 fmol/min per milligram vs 367.834 ± 120.307 fmol/min per milligram protein, P < 0.05).
CONCLUSION: A decrease in EGF levels may contribute to the formation of visceral hypersensitivity through downregulation of SERT-mediated 5-HT uptake into enterocytes.
PMCID: PMC4188903  PMID: 25309082
Epidermal growth factor; Visceral hypersensitivity; Rat models; Serotonin transporter; Rat small intestinal epithelial cells; Intestinal epithelial cells; Irritable bowel syndrome
24.  Stress-Induced Hyperglycemia After Hip Fracture and the Increased Risk of Acute Myocardial Infarction in Nondiabetic Patients 
Diabetes Care  2013;36(10):3328-3332.
To investigate the risk of acute myocardial infarction (AMI) following stress hyperglycemia after hip fracture.
From February 2007 to February 2012, we carried out a prospective observational analysis of 1,257 consecutive patients with no history of diabetes who suffered hip fractures. Fasting blood glucose (FBG) and glycosylated hemoglobin tests as well as electrocardiography, ultrasonic cardiography, and chest X-ray examinations were performed after admission. All selected hip fracture patients were divided into stress hyperglycemia and non-hyperglycemia groups according to their FBG, and the incidence of AMI was monitored.
Among the patients enrolled, the frequency of stress hyperglycemia was 47.89% (602/1,257) and that of AMI was 9.31% (117/1,257), and the occurrence of AMI in the stress hyperglycemia group was higher than in the non-hyperglycemia group (12.46 vs. 6.41%, P < 0.05). In the stress hyperglycemia patients, FBG reached maximum levels at 2–3 days after hip fractures and then decreased gradually. The AMI incidence (62.67% [47/75]) of the stress hyperglycemia group was highest in the initial 3 days after hip fracture, significantly coinciding with the FBG peak time (P < 0.05). In all patients with AMI, non–ST-segment elevation myocardial infarction occurred more often than ST-segment elevation myocardial infarction (62.39% [73/117] vs. 37.61% [44/117]).
Stress-induced hyperglycemia after hip fracture increased the risk of AMI.
PMCID: PMC3781495  PMID: 23846813
25.  Activation of Liver X Receptor Alleviates Ocular Inflammation in Experimental Autoimmune Uveitis 
To investigate whether a synthetic LXR agonist TO901317 (TO90) ameliorates ocular inflammation in a mouse model of experimental autoimmune uveitis (EAU) and to explore its underlying mechanism.
EAU was induced with subcutaneous injection of IRBP161–180 peptide (SGIPYIISYLHPGNTILHVD) in B10.RIII mice. TO90 (50 mg/kg/d) or vehicle was administrated orally for successive 16 days or 8 days as prevention or effector phase, respectively. The severity of EAU was evaluated with clinical and histological scores. The levels of LXRs, NF-κB subunit p65, and an LXR target gene ABCA1 in the retina were detected with real-time PCR and Western blotting. The expressions of proinflammatory genes, including TNF-α, IL-1β, IL-6, MCP-1, IFN-γ, and IL-17, were detected by real-time PCR. IRBP-specific lymphocyte proliferation was detected by MTT. Intracellular IFN-γ and IL-17 in CD4+ T cells were measured by flow cytometry.
We found both LXRα and LXRβ were expressed in mouse retina. After administering TO90 orally to B10.RIII mice, the expression of LXRα but not LXRβ was upregulated in the naïve mice. Compared with naïve mice, LXRα expression was increased in vehicle and TO90-treated EAU mice, but the LXRβ expression was unchanged. The protein level of ABCA1 was enhanced in TO90-treated naïve and EAU mice but was unchanged in vehicle-treated EAU mice, suggesting activation of LXRα by TO90 is ligand dependent. TO90-mediated activation of LXRα improved the clinical and morphological scores in EAU mice. Meanwhile, activation of LXRα decreased the expressions of proinflammatory cytokines, including TNF-α, IL-1β, IL-6, MCP-1, IFN-γ, and IL-17 in the retina. TO90 treatment inhibited IRBP-specific immune responses. The proportions of Th1 and Th17 expressing IFN-γ and IL-17 were reduced in TO90-treated EAU mice in both prevention and effector phases. Furthermore, TO90 significantly downregulated the expressions of an NF-κB subunit p65 at the protein and mRNA levels.
TO90 activates LXRα and potently attenuates ocular inflammation in EAU. Alleviation of ocular inflammation could partially result from inhibition of the NF-κB signaling pathway. TO90 reduces IFN-γ and IL-17 expression in both prevention and treatment scenarios. Our data suggest that the LXR agonist may become a novel class of therapeutic agent for autoimmune uveitis.
Both LXRα and LXRβ were expressed in mouse retina. An LXR agonist, TO901317, activated LXRα and its target gene ABCA1. Activation of LXRα inhibited intraocular inflammation and downregulated NF-κB p65. TO90 suppressed the production of IFN-γ and IL-17 in both prevention and effector phases in EAU, suggesting LXR agonists may become a novel category of therapeutic agents for uveitis.
PMCID: PMC4004425  PMID: 24699378
LXR; uveitis; retina; EAU; NF-κB

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