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1.  Poor Sleep Quality of Third-Trimester Pregnancy is a Risk Factor for Postpartum Depression 
The aim of this study was to investigate whether poor sleep quality of third-trimester pregnancy is a risk factor for postpartum depression.
Third-trimester pregnant women (T0, n=293) were tested using the first socio-demographic, Pittsburgh Sleep Quality Index, and Edinburgh Postnatal Depression Scale assessments, and received a diagnosis of depression. Three months (T1, n=223) after delivery, scale filling was finished and the structured interview was performed again.
We found that 73 persons (32.7%) were low income, 84 persons (37.7%) were middle-income, and 66 persons (29.6%) were higher income. The overall prevalence of postpartum depression was 9.4% (21 persons). After controlling for other factors, age, household income, marital satisfaction, and sleep quality were significantly related to postpartum depression, in which age and sleep quality scores (a higher score was associated with poorer sleep quality) were positively related to postpartum depression, and household income and marital satisfaction were negatively related to postpartum depression. Moreover, third-trimester sleep quality score was positively related to postpartum depressive symptoms.
Poor third-trimester subjective sleep quality is a risk factor for postpartum depression.
PMCID: PMC4280053  PMID: 25526703
Depression, Postpartum; Pregnancy Trimester, Third; Risk Factors
2.  Ice crystals growth driving assembly of porous nitrogen-doped graphene for catalyzing oxygen reduction probed by in situ fluorescence electrochemistry 
Scientific Reports  2014;4:6723.
In recent years, doped carbonaceous materials as alternative catalysts for oxygen reduction reaction (ORR) have received considerable attention due to the low cost and high CO tolerance capability. Different theoretical studies have suggested that oxygen is reduced in a rapid sequence intermediated by diverse oxygen-containing reactive intermediates (ORI). However, due to the short lifetimes of the possible ORI, direct experimental evidence is very difficult to be obtained. Here, we report the synthesis of an ultralight and porous nitrogen-doped graphene (NG) by annealing graphite oxide (GO)-melamine scaffold shaped in ice template. The resultant NG exhibits excellent electrocatalytic activity toward 4e-reduction of oxygen with the onset potential as low as −0.05 V vs. Ag/AgCl in alkaline media. Using this material as model study, sensitive in situ fluorescence spectroelectrochemistry is applied to demonstrate the presence the reactive ORI. The global ORR pathway is unraveled as stepwise electron transfer involving hydroxyl radical as the important intermediate via both inner- and outer-sphere process. This result would likely provide a new insight into the further understanding of ORR mechanism on those intrinsic carbonaceous materials.
PMCID: PMC4205891  PMID: 25335571
3.  Thioredoxin-Like Protein 2 Is Overexpressed in Colon Cancer and Promotes Cancer Cell Metastasis by Interaction with Ran 
Antioxidants & Redox Signaling  2013;19(9):899-911.
Aims: Our previous work identified thioredoxin-like protein 2 (Txl-2) as the target of the monoclonal antibody MC3 associated with colon cancer, but its underlying mechanisms remain poorly understood. Txl-2, a novel thioredoxin (Trx) and nucleoside diphosphate kinase family member, is alternatively spliced and gives rise to three different Txl-2 isoforms. In this study, Txl-2 expression in colon cancer, differential functions for Txl-2 isoforms in cell invasion and metastasis, and the downstream signaling were investigated. Results: Txl-2 expression was elevated in colon cancer tissues compared to normal colonic tissues, with a high correlation between the histological grade and prognosis. Knockdown of Txl-2 expression significantly inhibited cancer cell motility, and the invasive and metastatic abilities of colon cancer cells. Interestingly, Txl-2 isoforms showed differential effects on cancer cell invasion and metastasis. Cell invasion and metastasis were significantly promoted by Txl-2b but inhibited by Txl-2c, while no obvious effect was observed for Txl-2a. Furthermore, a direct interaction was identified between Txl-2b and Ran, a Ras-related protein, by yeast two-hybrid assay and coimmunoprecipitation. PI3K pathway was found to be a major pathway mediating Txl-2b induced tumor invasion and metastasis. Innovation: The current study provides a novel biomarker and target molecule for the diagnosis and treatment of colon cancer and provides a novel paradigm to understand how alternative splicing functions in human cancer. Conclusion: Our findings demonstrate an elevated Txl-2 expression in colon cancer and that Txl-2b promotes cell invasion and metastasis through interaction with Ran and PI3K signaling pathway. Antioxid. Redox Signal. 19, 899–911.
PMCID: PMC3763228  PMID: 23311631
4.  Spontaneous Genomic Alterations in a Chimeric Model of Colorectal Cancer Enable Metastasis and Guide Effective Combinatorial Therapy 
PLoS ONE  2014;9(8):e105886.
Colon cancer is the second most common cause of cancer mortality in the Western world with metastasis commonly present at the time of diagnosis. Screening for propagation and metastatic behavior in a novel chimeric-mouse colon cancer model, driven by mutant p53 and β-Catenin, led to the identification of a unique, invasive adenocarcinoma. Comparison of the genome of this tumor, CB42, with genomes from non-propagating tumors by array CGH and sequencing revealed an amplicon on chromosome five containing CDK6 and CDK14, and a KRAS mutation, respectively. Single agent small molecule inhibition of either CDK6 or MEK, a kinase downstream of KRAS, led to tumor growth inhibition in vivo whereas combination therapy not only led to regression of the subcutaneous tumors, but also near complete inhibition of lung metastasis; thus, genomic analysis of this tumor led to effective, individualized treatment.
PMCID: PMC4146580  PMID: 25162504
5.  Effects of Formaldehyde on Lymphocyte Subsets and Cytokines in the Peripheral Blood of Exposed Workers 
PLoS ONE  2014;9(8):e104069.
Formaldehyde (FA) is a well-known irritant, and it is suggested to increase the risk of immune diseases and cancer. The present study aimed to evaluate the distribution of major lymphocyte subsets and cytokine expression profiles in the peripheral blood of FA-exposed workers. A total of 118 FA-exposed workers and 79 controls were enrolled in the study. High performance liquid chromatography, flow cytometry, and cytometric bead array were used to analyze FA in air sample and formic acid in urine, blood lymphocyte subpopulations, and serum cytokines, respectively. The FA-exposed workers were divided into low and high exposure groups according to their exposure levels. The results showed that both the low and high FA-exposed groups had a significant increase of formic acid in urine when compared to the controls. Both the low and high exposure groups had a significant increase in the percentage of B cells (CD19+) compared to the control group (p<0.01). A significant increase in the percentage of the natural killer (NK) cells (CD56+) was observed in the low exposure group compared to the control (p = 0.013). Moreover, the FA-exposed workers in both exposure groups showed a significant higher level of IL-10 but lower level of IL-8 than the control (p<0.01). Subjects in the high exposure group had a higher level of IL-4 but a lower level of IFN-γ than the control (p<0.05). Finally, there is a significant correlation between the levels of IL-10, IL-4, and IL-8 and formic acid (p<0.05). The findings from the present study may explain, at least in part, the association between FA exposure and immune diseases and cancer.
PMCID: PMC4144836  PMID: 25157974
6.  Hepatic ERK activity plays a role in energy metabolism 
Mitogen activated protein kinases (MAPKs), such as c-Jun N-terminal kinase (JNK) and P38, have been reported to play important roles in energy homeostasis. In this study, we show that the activity of extracellular signal-regulated kinase (ERK) is increased in the livers of diet induced and genetically obese mice. Activation of ERK in the livers of lean mice by over-expressing the constitutively active MAPK kinase 1 (MEK CA) results in decreased energy expenditure, lowered expression of genes involved in fatty acid oxidation, increases fasting hyperglycemia and causes systemic insulin resistance. Interestingly, hepatic glycogen content is markedly increased and expression of G6Pase gene is decreased in mice over-expressing MEK CA compared to control mice expressing green fluorescent protein (GFP), therefore hepatic glucose output is not likely the major contributor of hyperglycemia. One potential mechanism of decreased expression of G6Pase gene by MEK CA is likely due to ERK mediated phosphorylation and cytosolic retention of FOXO1. Adipocytes isolated from MEK CA mice display increased lipolysis. Circulating levels of free fatty acids (FFAs) in these mice are also increased, which possibly contribute to systemic insulin resistance and subsequent hyperglycemia. Consistent with these results, knocking down ERK expression in the liver of diet induced obese (DIO) mice improves systemic insulin sensitivity and glucose tolerance. These results indicate that increased hepatic ERK activity in DIO mice may contribute to rincreased liver glycogen content and decreased energy expenditure in obesity.
PMCID: PMC3733366  PMID: 23732116
7.  Identification of Sucrose Non-Fermenting–Related Kinase (SNRK) as a Suppressor of Adipocyte Inflammation 
Diabetes  2013;62(7):2396-2409.
In this study, the role of sucrose non-fermenting–related kinase (SNRK) in white adipocyte biology was investigated. SNRK is abundantly expressed in adipose tissue, and the expression level is decreased in obese mice. SNRK expression is repressed by inflammatory signals but increased by insulin sensitizer in cultured adipocytes. In vivo, adipose tissue SNRK expression can be decreased by lipid injection but enhanced by macrophage ablation. Knocking down SNRK in cultured adipocytes activates both JNK and IKKβ pathways as well as promotes lipolysis. Insulin-stimulated Akt phosphorylation and glucose uptake are impaired in SNRK knockdown adipocytes. Phosphoproteomic analysis with SNRK knockdown adipocytes revealed significantly decreased phosphorylation of 49 proteins by 25% or more, which are involved in various aspects of adipocyte function with a clear indication of attenuated mTORC1 signaling. Phosphorylation of 43 proteins is significantly increased by onefold or higher, among which several proteins are known to be involved in inflammatory pathways. The inflammatory responses in SNRK knockdown adipocytes can be partially attributable to defective mTORC1 signaling, since rapamycin treatment activates IKKβ and induces lipolysis in adipocytes. In summary, SNRK may act as a suppressor of adipocyte inflammation and its presence is necessary for maintaining normal adipocyte function.
PMCID: PMC3712026  PMID: 23520131
8.  Value of 18F-FDG PET-CT in surveillance of postoperative colorectal cancer patients with various carcinoembryonic antigen concentrations 
AIM: To evaluate the value of positron emission tomography (PET)/computerized tomography (CT) in surveillance of colorectal cancer (CRC) patients with different carcinoembryonic antigen (CEA) concentrations.
METHODS: One hundred and six postoperative CRC patients who had suspected recurrence or metastasis and received fluorodeoxyglucose (FDG) PET/CT within one week were included in this study. The final diagnosis was confirmed by histological examination or clinical follow-up over at least six months.
RESULTS: The sensitivity, specificity, and accuracy of FDG PET/CT were 95.2%, 82.6%, and 92.5%, and 94.8%, 81.4% and 92.8%, respectively, in the case- and lesion-based analyses. The sensitivity and accuracy of FDG PET/CT significantly differed from CT in both analyses (χ2 = 8.186, P = 0.004; χ2 =6.201, P = 0.013; χ2 =13.445, P = 0.000; χ2 =11.194, P = 0.001). In the lesion-based analysis, the sensitivity, specificity, and accuracy of FDG PET/CT in the abnormal CEA group were 97.8%, 82.6%, and 95.6%, compared with 81.3%, 80%, and 80.6% for patients with normal CEA levels. In case-based analysis, the sensitivity, specificity, and accuracy of FDG PET/CT were 97.2%, 77.8%, and 95% in abnormal CEA group. Only in lesion-based analysis, the sensitivity and accuracy of FDG PET/CT in the abnormal CEA group were significantly superior to those in the normal CEA group (χ2 =6.432, P = 0.011; χ2 =7.837, P = 0.005). FDG PET/CT changed the management in 45.8% of patients with positive scans.
CONCLUSION: FDG PET/CT showed superior diagnostic value and is an advisable option in surveillance of postoperative CRC patients with a vague diagnosis.
PMCID: PMC4047348  PMID: 24914384
Colorectal cancer; Carcinoembryonic antigen; Fluorodeoxyglucose positron emission tomography/computed tomography; Recurrence; Metastasis
9.  Human adipose dynamics and metabolic health 
The two types of adipose tissue in humans, white and brown, have distinct developmental origins and functions. Human white adipose tissue plays a pivotal role in maintaining whole body energy homeostasis by storing triglycerides when energy is in surplus, releasing free fatty acids as a fuel during energy shortage and secreting adipokines that are important for regulating lipid and glucose metabolism. The size of white adipose mass needs to be kept at a proper set point. Dramatic expansion of white fat mass causes obesity, which has now become a global epidemic disease, and increases the risk for the development of many life threatening diseases. Absence of white adipose tissue or abnormal white adipose tissue re-distribution leads to lipodystrophy, a condition often associated with metabolic disorders. Brown adipose tissue is a thermogenic organ, and its mass is inversely correlated with body mass index and age. Therapeutic approaches targeting adipose tissue have been proved to be effective in improving obesity-related metabolic disorders and promising new therapies could be developed in the near future.
PMCID: PMC3618577  PMID: 23317303
WAT; BAT; obesity; lipodystrophy
10.  A cross-sectional study on perception of stigma by Chinese schizophrenia patients 
In this cross-sectional study, we sought to assess the extent of internalized stigma among inpatients and outpatients with schizophrenia in the People’s Republic of China and to investigate whether education level correlated with the experience of stigma.
Schizophrenia patients were evaluated using the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions-Severity of Illness (CGI-S) scale and the Stigma Scale for Mental Illness (SSMI-C). Patients were categorized into high education and low education groups, according to their educational levels.
One hundred thirty-three subjects were included in the study. Their mean course of illness was 4.32±6.14 years (range: 1 month to 15 years). Their mean BPRS score was 19.87±5.46, their mean PANSS score was 44.11±13.1, and their mean CGI-S score was 2.22±0.81. In addition, their mean SSMI-C score was 6.49±0.9. The mean SSMI-C score of patients who have received high school education or above was 7.15±0.98, which was markedly higher than that of patients who have received middle school education or below, which was 5.75±0.79 (P<0.05). Before the study most patients (92.5%, 123/133) took atypical drugs.
Education level impacts on the perception of stigma by schizophrenia patients, and more psychoeducation should be undertaken to improve patients’ knowledge about schizophrenia.
PMCID: PMC3971935  PMID: 24707179
schizophrenia; stigma; Brief Psychiatric Rating Scale (BPRS); Positive and Negative Syndrome Scale (PANSS); Clinical Global Impression-Severity (CGI-S) scale; Stigma Scale for Mental Illness (SSMI-C)
11.  Activation of guanylate cyclase-C attenuates stretch responses and sensitization of mouse colorectal afferents 
Irritable bowel syndrome (IBS) is characterized by altered bowel habits, persistent pain and discomfort, and typically colorectal hypersensitivity. Linaclotide, a peripherally-restricted 14-amino acid peptide approved for the treatment of IBS with constipation, relieves constipation and reduces IBS-associated pain in these patients presumably by activation of guanylate cyclase-C (GC-C), which stimulates production and release of cyclic guanosine monophosphate (cGMP) from intestinal epithelial cells. We investigated whether activation of GC-C by the endogenous agonist uroguanylin or the primary downstream effector of that activation, cGMP, directly modulates responses and sensitization of mechanosensitive colorectal primary afferents. The distal 2 cm of mouse colorectum with attached pelvic nerve was harvested, pinned flat mucosal side up for in vitro single-fiber recordings and the encoding properties of mechanosensitive afferents (serosal, mucosal, muscular and muscular-mucosal) to probing and circumferential stretch studied. Both cGMP (10–300μM) and uroguanylin (1–1000nM) applied directly to colorectal receptive endings significantly reduced responses of muscular and muscular-mucosal afferents to stretch; serosal and mucosal afferents were not affected. Sensitized responses (i.e., increased responses to stretch) of muscular and muscular-mucosal afferents were reversed by cGMP, returning responses to stretch to control. Blocking the transport of cGMP from colorectal epithelia by probenecid, a mechanism validated by studies in cultured intestinal T84 cells, abolished the inhibitory effect of uroguanylin on muscular-mucosal afferents. These results suggest that GC-C agonists like linaclotide alleviate colorectal pain and hypersensitivity by dampening stretch-sensitive afferent mechanosensitivity and normalizing afferent sensitization.
PMCID: PMC3739058  PMID: 23739979
12.  RhoE Promotes Metastasis in Gastric Cancer through a Mechanism Dependent on Enhanced Expression of CXCR4 
PLoS ONE  2013;8(11):e81709.
RhoE, a novel member of the Rho protein family, is a key regulator of the cytoskeleton and cell migration. Our group has previously shown that RhoE as a direct target for HIF-1α and mediates hypoxia-induced epithelial to mesenchymal transition in gastric cancer cells. Therefore, we assumed that RhoE might play an important role in gastric cancer metastasis. In the present study, we have explored the role of RhoE expression in gastric cancer, cell invasion and metastasis, and the influence of RhoE on regulating the potential expression of down-stream genes. RhoE expression was elevated in gastric cancer tissues as compared with normal gastric tissues. We also found a close correlation between the histological grade and the diagnosis of the patient. Up-regulation of RhoE significantly enhanced the migratory and invasive abilities of gastric cancer cells both in vitro and in vivo. Moreover, down-regulation of RhoE diminished the metastatic potential of cancer cells. PCR array and subsequent transwell assay showed that the regulation of gastric cancer metastasis by RhoE was partially mediated by CXCR4. This observation suggested that CXCR4 might be a downstream effector for RhoE. In summary, our study identified RhoE as a novel prognostic biomarker and metastatic-promoting gene of gastric cancer.
PMCID: PMC3843694  PMID: 24312338
13.  Translation and Psychometric Evaluation of the Chinese Version of Functional Digestive Disorders Quality of Life Questionnaire 
Digestive Diseases and Sciences  2013;59(2):390-420.
Few useful patient-reported outcomes scales for functional dyspepsia exist in China.
The purpose of this work was to translate and cross-culturally adapt the Functional Digestive Disorders Quality of Life Questionnaire (FDDQL) from the English version to Chinese (in Mandarin).
The following steps were performed: forward translations, synthesis of the translations, backward translations, pre-testing and field testing of FDDQL. Reliability, validity, responsiveness, confirmatory factor analysis, item response theory and differential item functioning of the scale were analyzed.
A total of 300 functional dyspepsia patients and 100 healthy people were included. The total Cronbach’s alpha was 0.932, and split-half reliability coefficient was 0.823 with all test–retest coefficients greater than 0.9 except Coping With Disease domain. In construct validity analysis, every item correlated higher with its own domain than others. The comparative fit index of FDDQL was 0.902 and root mean square error of approximation was 0.076. Functional dyspepsia patients and healthy people had significant differences in all domains. After treatment, all domains had significant improvements except diet. Item response theory analysis showed the Person separation index of 0.920 and the threshold estimator of items was normally distributed with a mean of 0 and standard deviation of 1.27. The residuals of each item were between −2.5 and 2.5, without statistical significance. Differential item functioning analysis found that items had neither uniform nor non-uniform differential item functioning in different genders and age groups.
The Chinese version of FDDQL has good psychometric properties and is suitable for measuring the health status of Chinese patients with functional dyspepsia.
PMCID: PMC3924031  PMID: 24202648
Functional dyspepsia; Quality of life; Translations; Validation studies; Cross-cultural comparison; Health outcomes
14.  Applicability of the Chinese Version of the Hypomania Symptom Checklist (HCL-32) Scale for Outpatients of Psychiatric Departments in General Hospitals 
PLoS ONE  2013;8(10):e75631.
This study aimed to determine the suitability of the Chinese version of the Hypomania Symptom Checklist (HCL-32) scale for psychiatric department outpatients with mood disorders in Chinese general hospitals, and provide a theoretical basis for the application of the HCL-32 scale.
Outpatients with mood disorders receiving continuous treatment in the psychiatric medicine department of three top-ranking general hospitals in three cities completed scoring the HCL-32 scale.
A total of 1010 patients were recruited. 417 were diagnosed with bipolar disorder (236 for type I and 181 for type II) and 593 were depression. Four factors with eigenvalues >1 were considered. Factor 1 with an eigenvalue of 5.5 was labeled “active/cheerful”. Factor 2 with an eigenvalue of 2.7 was labeled “adventurous/irritable.” The coefficient of internal consistency reliability of the HCL-32 total scale was 0.84, and the coefficients for factors 1 and 2 were 0.84 and 0.88, respectively. With the total score of HCL-32≥14 as positive standard, the sensitivity of HCL-32 was calculated at 69.30% and the specificity was 97.81%.
Results showed that HCL-32 had a preferable reliability and validity and was suitable as auxiliary means for bipolar disorder screening in general hospitals.
PMCID: PMC3792138  PMID: 24116062
15.  MEK/ERK pathway mediates insulin-promoted degradation of MKP-3 protein in liver cells 
Molecular and cellular endocrinology  2012;361(1-2):116-123.
MAP kinase Phosphatase 3 (MKP-3) was recently identified as an important regulator of glucose homeostasis in the liver and its expression can be repressed by insulin at post transcriptional level. In this study, the mechanism underlying insulin promoted decrease of MKP-3 protein was investigated by studying MKP-3 protein stability via immunoblot analysis in the presence of cycloheximide using cultured liver cells. Several pathways were examined and activation of the MEK/ERK pathway was found to mediate reduction of MKP-3 protein expression in response to insulin. MEK inhibitor markedly slowed down MKP-3 protein degradation. Mutation of two ERK phosphorylation sites on MKP-3 rendered it resistant to insulin and constitutively active MEK-induced MKP-3 protein degradation. To understand the biological effect of MKP-3 protein stability on liver cell glucose output, expression level of G6Pase gene, which encodes the key enzyme controlling the last step of de novo glucose synthesis in liver cells, was examined by real time PCR analysis upon manipulation of MEK signaling. Activation of MEK pathway in Fao cells resulted in decreased expression of G6Pase gene and lowered glucose output. Consistent with this result, MEK inhibitor increased expression of G6Pase gene and glucose output in Fao cells. In conclusion, insulin likely promotes MKP-3 protein degradation through activation of MEK/ERK pathway in liver cells and MKP-3 protein level affects the capability of Fao cells to output glucose.
PMCID: PMC3407345  PMID: 22521266
MAP kinase phosphatase; glucose output; protein degradation
16.  Theranostic Protein Targeting ErbB2 for Bioluminescence Imaging and Therapy for Cancer 
PLoS ONE  2013;8(9):e75288.
A combination of molecular-targeted cancer imaging and therapy is an emerging strategy to improve cancer diagnosis and minimize the side effects of conventional treatments. Here, we generated a recombinant protein, EC1-GLuc-p53C, by fusing EC1 peptide, an artificial ligand of ErbB2, with Gaussia luciferase (GLuc) and a p53-activating peptide, p53C. EC1-GLuc-p53C was expressed and purified from E. coli BL21. In vitro experiments showed that EC1-GLuc-p53c was stable in luminescent activity and selectively targeted ErbB2-overexpressing BT474 cells for bioluminescence imaging. Moreover, the internalized EC1-GLuc-p53C in BT474 cells exerted its function to reactivate p53 and significantly inhibited cellular proliferation. In tumor-bearing mice, the ErbB2-targeted bioluminescence imaging and therapeutic effect of EC1-GLuc-p53C were also observed specifically in BT474 tumors but not in MCF7 tumors, which does not overexpress ErbB2. Thus, the present study demonstrates EC1-GLuc-p53C to be an effective theranostic reagent targeting ErbB2 for bioluminescence imaging and cancer therapy.
PMCID: PMC3775930  PMID: 24069396
17.  Molecular Identification and Analysis of Human Enteroviruses Isolated from Healthy Children in Shenzhen, China from 2010 to 2011 
PLoS ONE  2013;8(6):e64889.
To determine the prevalence and distribution of human enteroviruses (HEVs) among healthy children in Shenzhen, China.
Clinical specimens were obtained from 320 healthy children under 5 years old in Shenzhen, China from 2010 to 2011. The specimens were evaluated using real-time PCR and cell cultures. The positive specimens were further tested using reverse transcription-seminested PCR (RT-snPCR). Molecular typing and phylogenetic analysis were based on the sequence determined.
Among the 320 samples, 34 were tested positive for HEVs (10.6%) and 22 different serotypes were identified using RT-snPCR. PV1 and PV2 were also detected. The predominant serotype observed was EV71 (17.6%), followed by CV-B4 (14.7%). HEV-B was detected most frequently, with an overall prevalence of 47.1%. HEV-A and HEV-C were found in 32.3% and 20.6% of the samples, respectively. No HEV-D was identified. Molecular phylogeny indicated that all EV71 strains were of C4 genotype.
Although a variety of HEVs was detected in healthy children, HEV-B was relatively more prevalent than other HEV species. Considering HEV-A is more prevalent than HEV-B among patients with hand-foot-mouth disease, additional long-term surveillance of HEV is warranted in both asymptomatic and symptomatic populations.
PMCID: PMC3675095  PMID: 23762262
18.  Excessive Astrocyte-Derived Neurotrophin-3 Contributes to the Abnormal Neuronal Dendritic Development in a Mouse Model of Fragile X Syndrome 
PLoS Genetics  2012;8(12):e1003172.
Fragile X syndrome (FXS) is a form of inherited mental retardation in humans that results from expansion of a CGG repeat in the Fmr1 gene. Recent studies suggest a role of astrocytes in neuronal development. However, the mechanisms involved in the regulation process of astrocytes from FXS remain unclear. In this study, we found that astrocytes derived from a Fragile X model, the Fmr1 knockout (KO) mouse which lacks FMRP expression, inhibited the proper elaboration of dendritic processes of neurons in vitro. Furthermore, astrocytic conditioned medium (ACM) from KO astrocytes inhibited proper dendritic growth of both wild-type (WT) and KO neurons. Inducing expression of FMRP by transfection of FMRP vectors in KO astrocytes restored dendritic morphology and levels of synaptic proteins. Further experiments revealed elevated levels of the neurotrophin-3 (NT-3) in KO ACM and the prefrontal cortex of Fmr1 KO mice. However, the levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF) were normal. FMRP has multiple RNA–binding motifs and is involved in translational regulation. RNA–binding protein immunoprecipitation (RIP) showed the NT-3 mRNA interacted with FMRP in WT astrocytes. Addition of high concentrations of exogenous NT-3 to culture medium reduced the dendrites of neurons and synaptic protein levels, whereas these measures were ameliorated by neutralizing antibody to NT-3 or knockdown of NT-3 expression in KO astrocytes through short hairpin RNAs (shRNAs). Prefrontal cortex microinjection of WT astrocytes or NT-3 shRNA infected KO astrocytes rescued the deficit of trace fear memory in KO mice, concomitantly decreased the NT-3 levels in the prefrontal cortex. This study indicates that excessive NT-3 from astrocytes contributes to the abnormal neuronal dendritic development and that astrocytes could be a potential therapeutic target for FXS.
Author Summary
Fragile X syndrome is a form of inherited mental retardation in humans that results from expansion of a CGG repeat in the Fmr1 gene. Recent studies suggest that astrocytes play a role in neuronal growth. In this study, we find that astrocytes derived from a Fragile X model, the Fmr1 knockout (KO) mouse, inhibit the proper elaboration of dendritic processes of neurons in vitro. Excessive neurotrophin-3 (NT-3) is released in the astrocytes from Fmr1 KO mice. Blockage of NT-3 by neutralizing antibodies and knockdown of NT-3 by using short hairpin RNAs (shRNAs) in Fmr1 KO astrocytes can rescue the neuronal dendritic development. In vivo experiments show that prefrontal cortex microinjection of WT astrocytes or NT-3 shRNA–infected KO astrocytes rescues the deficit of trace fear memory in KO mice. This study provides the evidence that a lack of FMRP leads to an overexpression of NT-3, which reduces dendritic growth in neurons.
PMCID: PMC3531466  PMID: 23300470
19.  Coronin 3 promotes gastric cancer metastasis via the up-regulation of MMP-9 and cathepsin K 
Molecular Cancer  2012;11:67.
Coronins are a family of highly evolutionary conserved proteins reportedly involved in the regulation of actin cytoskeletal dynamics, although only coronin 3 has been shown to be related to cancer cell migration. In glioblastoma cells, the knockdown of coronin 3 inhibits cell proliferation and invasion. Coronin 3 is also associated with the aggression and metastasis of hepatocellular carcinoma. In this paper, we analyze the migration, invasion and metastasis abilities of gastric cancer cells after up- or down-regulation of coronin 3, and explore the mechanism of coronin 3 in the process of gastric cancer metastasis.
The expression of coronin 3 was higher in the highly metastatic sub-cell line MKN28-M, which we established in our laboratory. We also demonstrated that the expression of coronin 3 was remarkably higher in lymph lode metastases than in primary gastric cancer tissues, and over-expression of coronin 3 was correlated with the increased clinical stage and lymph lode metastasis. Recombinant lentiviral vectors encoding shRNAs were designed to down-regulate coronin 3 expression in gastric cancer cell lines. Stable knockdown of coronin 3 by this lentiviral vector could efficiently inhibit the migration and invasion of MKN45 gastric cancer cells. In contrast, up-regulation of coronin 3 significantly enhanced migration and invasion of MKN28-NM cells. In addition, knockdown of coronin 3 significantly reduced liver metastasis in mice after tail vein injection of gastric cancer cells. The Human Tumor Metastasis PCR Array was used to screen the metastasis-associated genes identified by the down-regulation of coronin 3, and the results suggested that, following the knockdown of coronin 3, the tumor cell migration and invasion were inhibited by the reduced expression of MMP-9 and cathepsin K.
Coronin 3 is highly expressed in gastric cancer metastases and can promote the metastatic behaviors of gastric cancer cells, including their migration and invasion.
PMCID: PMC3522055  PMID: 22974233
Coronin 3; Gastric cancer; Metastasis; MMP-9; Cathepsin K
20.  Mapping MKP-3/FOXO1 Interaction and Evaluating the Effect on Gluconeogenesis 
PLoS ONE  2012;7(7):e41168.
MAP kinase phosphatase 3 (MKP-3) is known to attenuate the ERK signaling pathway. It has been recently demonstrated that MKP-3 is also a player in promoting hepatic glucose output in obese state by interacting and activating FOXO1. Reduction of hepatic MKP-3 expression is sufficient to reduce blood glucose levels in both diet-induced and genetically obese mice.
Methodology/Principal Findings
In current study, the mechanism of MKP-3/FOXO1 interaction and the effects on transcription of gluconeogenic gene and glucose output was investigated in Fao hepatoma cells by using mutated MKP-3 and FOXO1 adenoviral constructs. The results indicate that MKP-3 phosphatase activity is not required for MKP-3/FOXO1 interaction but is essential for FOXO1 nuclear translocation and MKP-3 promoted gluconeogenesis. Compared to GFP control (1±0.38), MKP-3 increased G6Pase gene expression by 242% (3.42±0.62) while inactive MKP-3 does not change G6Pase expression (0.98±0.17). The residues 200–260 of MKP-3 and the residues 360–456 of FOXO1 are essential for mediating MKP-3/FOXO1 interaction. Interestingly, ERK phosphorylation deficient but not Akt phosphorylation deficient FOXO1 mutant lost interaction with MKP-3. Furthermore, in vivo experiments showed that Akt phosphorylation resistant FOXO1 3A mutant is sufficient to rescue the hypoglycemia caused by MKP-3 knock down in the liver of lean mice (from 141±6.78 to 209±14.64 mg/dL).
1) Critical residues mediating MKP-3/FOXO1 interaction have been identified; 2) ERK phosphorylation deficient FOXO1 mutant is as potent as Akt phosphorylation deficient FOXO1 mutant in activating transcription of gluconeogenic genes; 3) Constitutively active FOXO1 can rescue the hypoglycemic effect caused by reduced hepatic MKP-3 expression in vivo.
PMCID: PMC3405053  PMID: 22848439
21.  Glucocorticoid Receptor and Sequential P53 Activation by Dexamethasone Mediates Apoptosis and Cell Cycle Arrest of Osteoblastic MC3T3-E1 Cells 
PLoS ONE  2012;7(6):e37030.
Glucocorticoids play a pivotal role in the proliferation of osteoblasts, but the underlying mechanism has not been successfully elucidated. In this report, we have investigated the molecular mechanism which elucidates the inhibitory effects of dexamethasone on murine osteoblastic MC3T3-E1 cells. It was found that the inhibitory effects were largely attributed to apoptosis and G1 phase arrest. Both the cell cycle arrest and apoptosis were dependent on glucocorticoid receptor (GR), as they were abolished by GR blocker RU486 pre-treatment and GR interference. G1 phase arrest and apoptosis were accompanied with a p53-dependent up-regulation of p21 and pro-apoptotic genes NOXA and PUMA. We also proved that dexamethasone can’t induce apoptosis and cell cycle arrest when p53 was inhibited by p53 RNA interference. These data demonstrate that proliferation of MC3T3-E1 cell was significantly and directly inhibited by dexamethasone treatment via aberrant GR activation and subsequently P53 activation.
PMCID: PMC3375272  PMID: 22719835
22.  Group I mGluR antagonist rescues the deficit of D1-induced LTP in a mouse model of fragile X syndrome 
Fragile X syndrome (FXS) is caused by the absence of the mRNA-binding protein Fragile X mental retardation protein (FMRP), encoded by the Fmr1 gene. Overactive signaling by group 1 metabotropic glutamate receptor (Grp1 mGluR) could contribute to slowed synaptic development and other symptoms of FXS. Our previous study has identified that facilitation of synaptic long-term potentiation (LTP) by D1 receptor is impaired in Fmr1 knockout (KO) mice. However, the contribution of Grp1 mGluR to the facilitation of synaptic plasticity by D1 receptor stimulation in the prefrontal cortex has been less extensively studied.
Here we demonstrated that DL-AP3, a Grp1 mGluR antagonist, rescued LTP facilitation by D1 receptor agonist SKF81297 in Fmr1KO mice. Grp1 mGluR inhibition restored the GluR1-subtype AMPA receptors surface insertion by D1 activation in the cultured Fmr1KO neurons. Simultaneous treatment of Grp1 mGluR antagonist with D1 agonist recovered the D1 receptor signaling by reversing the subcellular redistribution of G protein-coupled receptor kinase 2 (GRK2) in the Fmr1KO neurons. Treatment of SKF81297 alone failed to increase the phosphorylation of NR2B-containing N-methyl D-aspartate receptors (NMDARs) at Tyr-1472 (p-NR2B-Tyr1472) in the cultures from KO mice. However, simultaneous treatment of DL-AP3 could rescue the level of p-NR2B-Tyr1472 by SKF81297 in the cultures from KO mice. Furthermore, behavioral tests indicated that simultaneous treatment of Grp1 mGluR antagonist with D1 agonist inhibited hyperactivity and improved the learning ability in the Fmr1KO mice.
The findings demonstrate that mGluR1 inhibition is a useful strategy to recover D1 receptor signaling in the Fmr1KO mice, and combination of Grp1 mGluR antagonist and D1 agonist is a potential drug therapy for the FXS.
PMCID: PMC3467183  PMID: 22640474
Group I mGluRs; Dopamine; Long-term potentiation prefrontal cortex
23.  Transmission Dynamics of the Recently-Identified BYD Virus Causing Duck Egg-Drop Syndrome 
PLoS ONE  2012;7(4):e35161.
Baiyangdian (BYD) virus is a recently-identified mosquito-borne flavivirus that causes severe disease in ducks, with extremely rapid transmission, up to 15% mortality within 10 days and 90% reduction in egg production on duck farms within 5 days of infection. Because of the zoonotic nature of flaviviruses, the characterization of BYD virus and its epidemiology are important public health concerns. Here, we develop a mathematical model for the transmission dynamics of this novel virus. We validate the model against BYD outbreak data collected from duck farms in Southeast China, as well as experimental data obtained from an animal facility. Based on our model, the basic reproductive number of BYD virus is high (R0 = 21) indicating that this virus is highly transmissible, consistent with the dramatic epidemiology observed in BYDV-affected duck farms. Our results indicate that younger ducks are more vulnerable to BYD disease and that ducks infected with BYD virus reduce egg production (to about 33% on average) for about 3 days post-infection; after 3 days infected ducks are no longer able to produce eggs. Using our model, we predict that control measures which reduce contact between mosquitoes and ducks such as mosquito nets are more effective than insecticides.
PMCID: PMC3329443  PMID: 22529985
24.  Clodronate Liposomes Improve Metabolic Profile and Reduce Visceral Adipose Macrophage Content in Diet-Induced Obese Mice 
PLoS ONE  2011;6(9):e24358.
Obesity-related adipose inflammation has been thought to be a causal factor for the development of insulin resistance and type 2 diabetes. Infiltrated macrophages in adipose tissue of obese animals and humans are an important source for inflammatory cytokines. Clodronate liposomes can ablate macrophages by inducing apoptosis. In this study, we aim to determine whether peritoneal injection of clodronate liposomes has any beneficial effect on systemic glucose homeostasis/insulin sensitivity and whether macrophage content in visceral adipose tissue will be reduced in diet-induced obese (DIO) mice.
Methodology/Principal Findings
Clodronate liposomes were used to deplete macrophages in lean and DIO mice. Macrophage content in visceral adipose tissue, metabolic parameters, glucose and insulin tolerance, adipose and liver histology, adipokine and cytokine production were examined. Hyperinsulinemic-euglycemic clamp study was also performed to assess systemic insulin sensitivity. Peritoneal injection of clodronate liposomes significantly reduced blood glucose and insulin levels in DIO mice. Systemic glucose tolerance and insulin sensitivity were mildly improved in both lean and DIO mice treated with clodronate liposomes by intraperitoneal (ip) injection. Hepatosteatosis was dramatically alleviated and suppression of hepatic glucose output was markedly increased in DIO mice treated with clodronate liposomes. Macrophage content in visceral adipose tissue of DIO mice was effectively decreased without affecting subcutaneous adipose tissue. Interestingly, levels of insulin sensitizing hormone adiponectin, including the high molecular weight form, were significantly elevated in circulation.
Intraperitoneal injection of clodronate liposomes reduces visceral adipose tissue macrophages, improves systemic glucose homeostasis and insulin sensitivity in DIO mice, which can be partially attributable to increased adiponectin levels.
PMCID: PMC3171445  PMID: 21931688
25.  Peripheral and central P2X3 receptor contributions to colon mechanosensitivity and hypersensitivity in the mouse 
Gastroenterology  2009;137(6):2096-2104.
Background & Aims
Irritable bowel syndrome is characterized by altered sensory qualities, namely discomfort/pain and colorectal hypersensitivity. In mice, we examined the role of P2X3 receptors in colon mechanosensitivity and intracolonic zymosan-produced hypersensitivity, a model of persistent colon hypersensitivity without colon inflammation.
The visceromotor response (VMR) to colon distension (15 – 60 mmHg) was determined before and after intracolonic saline or zymosan (30 mg/mL, 0.1 mL, daily for 3 days) treatment. Colon pathology and intracolonic ATP release was assessed in parallel experiments. To examine P2X3 receptor contributions to colon mechanosensation and hypersensitivity, electrophysiological experiments were performed using an in vitro colon-pelvic nerve preparation.
VMRs to distension were significantly reduced in P2X3+/−and P2X3−/− mice relative to wildtype mice. Colon hypersensitivity produced by zymosan was virtually absent in P2X3−/− relative to wildtype or P2X3+/− mice. Intralumenal release of the endogenous P2X receptor ligand ATP did not differ between wildtype and P2X3−/− mice or change after intracolonic zymosan treatment. Responses of muscular and muscular-mucosal pelvic nerve afferents to mechanical stretch did not differ between P2X3−/− and wildtype mice. Both muscular and muscular-mucosal afferents in wildtype mice sensitized to application of an inflammatory soup, whereas only muscular-mucosal afferents did so in P2X3−/− mice.
These results suggest differential roles for peripheral and central P2X3 receptors in colon mechanosensory transduction and hypersensitivity.
PMCID: PMC2789894  PMID: 19549524

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