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1.  In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model 
Cell stem cell  2013;14(2):188-202.
Summary
Loss of neurons after brain injury and in neurodegenerative disease is often accompanied by reactive gliosis and scarring, which are difficult to reverse with existing treatment approaches. Here, we show that reactive glial cells in the cortex of stab-injured or Alzheimer’s disease (AD) model mice can be directly reprogrammed into functional neurons in vivo using retroviral expression of a single neural transcription factor, NeuroD1. Following expression of NeuroD1, astrocytes were reprogrammed into glutamatergic neurons, while NG2 cells were reprogrammed into glutamatergic and GABAergic neurons. Cortical slice recordings revealed both spontaneous and evoked synaptic responses in NeuroD1-converted neurons, suggesting that they integrated into local neural circuits. NeuroD1 expression was also able to reprogram cultured human cortical astrocytes into functional neurons. Our studies therefore suggest that direct reprogramming of reactive glial cells into functional neurons in vivo could provide an alternative approach for repair of injured or diseased brain.
doi:10.1016/j.stem.2013.12.001
PMCID: PMC3967760  PMID: 24360883
NeuroD1; reactive astrocytes; NG2 cells; reprogram; in vivo; Alzheimer’s disease; brain injury; cortex; neurons
2.  Efficacy and Safety of Transcutaneous Electrical Acupoint Stimulation to Treat Muscle Spasticity following Brain Injury: A Double-Blinded, Multicenter, Randomized Controlled Trial 
PLoS ONE  2015;10(2):e0116976.
Objective
This study was aimed at evaluating the clinical efficacy and safety of transcutaneous electrical acupoint stimulation (TEAS) to treat muscle spasticity after brain injury (Chinese Clinical Trial Registry: ChiCTR-TRC-11001310).
Methods
A total of 60 patients with muscle spasticity after brain injury were randomized to the following 3 groups: 100, 2, and 0 Hz (sham) TEAS. The acupoints Hegu (LI4)—Yuji (LU10) and Zusanli (ST36)—Chengshan (BL57) on the injured side were stimulated at 0, 2, or 100 Hz, 5 times per week for 4 weeks. The patients were followed up for 1 and 2 months after the treatments. The effects of the treatments on muscle spasticity at the wrist, thumb, the other 4 fingers, elbow, shoulder, knee, and ankle were evaluated by the Modified Ashworth Scale, and the effects on disability were assessed by the Disability Assessment Scale. The walking capability was evaluated by the Holden functional ambulation classification score. The overall performance was assessed by the Global Assessment Scale score and the improved Barthel Index. The safety of the treatments administered was also monitored.
Results
The wrist spasticity was significantly reduced from baseline at weeks 2, 3, and 4 of treatment and at the 1- and 2-month follow-up visits in the 100 Hz group (P < 0.01). Compared with 2 Hz or sham TEAS, 100 Hz TEAS decreased wrist spasticity at weeks 2, 3, and 4 of treatment and 1 month after treatment (P < 0.001). The other endpoints were not affected by the treatments. No treatment-emergent adverse events were reported during treatments and follow-up visits.
Conclusions
TEAS appears to be a safe and effective therapy to relieve muscle spasticity after brain injury, although large-scale studies are required to further verify the findings.
Trial Registration
Chinese Clinical Trial Registry ChiCTR-TRC-11001310 http://www.chictr.org
doi:10.1371/journal.pone.0116976
PMCID: PMC4314074  PMID: 25643051
3.  Differentially co-expressed genes in postmortem prefrontal cortex of individuals with alcohol use disorders: Influence on alcohol metabolism-related pathways 
Human genetics  2014;133(11):1383-1394.
Chronic alcohol consumption may induce gene expression alterations in brain reward regions such as the prefrontal cortex (PFC), modulating the risk of alcohol use disorders (AUDs). Transcriptome profiles of 23 AUD cases and 23 matched controls (16 pairs of males and 7 pairs of females) in postmortem PFC were generated using Illumina’s HumanHT-12 v4 Expression BeadChip. Probe-level differentially expressed genes and gene modules in AUD subjects were identified using multiple linear regression and weighted gene co-expression network analyses. The enrichment of differentially co-expressed genes in alcohol dependence-associated genes identified by genome-wide association studies (GWAS) was examined using gene set enrichment analysis. Biological pathways overrepresented by differentially co-expressed genes were uncovered using DAVID bioinformatics resources. Three AUD-associated gene modules in males [Module 1 (561 probes mapping to 505 genes): r=0.42, Pcorrelation=0.020; Module 2 (815 probes mapping to 713 genes): r=0.41, Pcorrelation=0.020; Module 3 (1,446 probes mapping to 1,305 genes): r=−0.38, Pcorrelation=0.030] and one AUD-associated gene module in females [Module 4 (683 probes mapping to 652 genes): r=0.64, Pcorrelation=0.010] were identified. Differentially expressed genes mapped by significant expression probes (Pnominal≤0.05) clustered in Modules 1 and 2 were enriched in GWAS-identified alcohol dependence-associated genes [Module 1 (134 genes): P=0.028; Module 2 (243 genes): P=0.004]. These differentially expressed genes, including ALDH2, ALDH7A1, and ALDH9A1, are involved in cellular functions such as aldehyde detoxification, mitochondrial function, and fatty acid metabolism. Our study revealed differentially co-expressed genes in postmortem PFC of AUD subjects and demonstrated that some of these differentially co-expressed genes participate in alcohol metabolism.
doi:10.1007/s00439-014-1473-x
PMCID: PMC4185230  PMID: 25073604
Alcohol use disorders; postmortem prefrontal cortex; genome-wide gene expression; co-expression; gene set enrichment analysis; biological pathways
4.  QT dynamics during treatment with sertindole 
Objectives:
Sertindole is a nonsedating atypical antipsychotic drug with low propensity to cause extrapyramidal side effects but it has been associated with a 20 ms QTc prolongation and increased risk of cardiac events. It is uncertain whether this drug-induced increase in cardiac risk might also be revealed by dynamic measures of the QT interval such as the ratio of QT variability to heart rate variability (variability ratio [VR]). The aim of this study was to investigate the effect of sertindole on QT dynamics.
Methods:
QTc and the VR were assessed in an observational study using 24-hour Holter monitoring at baseline and after 3 weeks of treatment with sertindole 16 mg. The VR was calculated by dividing the standard deviation of QT intervals with the standard deviation of heart rates. Outcome measures were compared using paired t-test.
Results:
A total of 18 patients participated in the study, two were excluded from further analysis due to low amplitude of the T-wave. When patients were shifted to sertindole, the VR increased from 0.192 (SD 0.045) to 0.223 (SD 0.061), p = 0.02. The QTcF interval increased from 388 (SD 16) to 403 ms (SD 14), p = 0.002. There was no difference in heart rate 78 bpm (SD 8) versus 80 bpm (SD 10), p = 0.3 or heart rate variability (SDNN) 127 (SD 40) versus 115 ms (SD 45), p = 0.4.
Conclusion:
Sertindole was associated with 19 ms QTc prolongation and an increased ratio of QT variability to heart rate variability. Both measures may contribute to the increased cardiovascular mortality found with sertindole.
doi:10.1177/2045125314560738
PMCID: PMC4315672  PMID: 25653828
cardiac safety; heart rate variability; QT dynamics; QT interval variability; QTc; SDNN; sertindole; variability ratio
5.  Combination therapy of ursodeoxycholic acid and budesonide for PBC–AIH overlap syndrome: a meta-analysis 
In this study, a meta-analysis of randomized controlled trials comparing ursodeoxycholic acid (UDCA) monotherapy with combination therapies utilizing UDCA and budesonide was performed. We found that combination therapy with UDCA and budesonide was more effective than UDCA monotherapy for primary biliary cirrhosis–autoimmune hepatitis overlap syndrome. Moreover, compared to prednisone, budesonide has fewer side effects.
doi:10.2147/DDDT.S74515
PMCID: PMC4304592  PMID: 25632224
meta-analysis; UDCA; budesonide; combination therapy; PBC–AIH overlap syndrome
6.  Meta-analysis of the efficacy of probiotics in Helicobacter pylori eradication therapy 
World Journal of Gastroenterology : WJG  2014;20(47):18013-18021.
AIM: To evaluate the role of probiotics in the standard triple Helicobacter pylori therapy.
METHODS: In this meta-analysis, we investigated the efficacy of probiotics in a standard triple H. pylori therapy in adults. Searches were mainly conducted in MEDLINE/PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. Fourteen studies met our criteria, and the quality of these studies was assessed using the Jadad scale. We used STATA version 12.0 to extract data and to calculate the odds ratios (ORs), which are presented with the corresponding 95% confidence intervals (CIs). The data are presented as forest plots.
RESULTS: The pooled ORs for the eradication rates calculated by intention-to-treat analysis and per-protocol analysis in the probiotic group vs the control group were 1.67 (95%CI: 1.38-2.02) and 1.68 (95%CI: 1.35-2.08), respectively, using the fixed-effects model. The sensitivity of the Asian studies was greater than that of the Caucasian studies (Asian: OR = 1.78, 95%CI: 1.40-2.26; Caucasian: OR = 1.48, 95%CI: 1.06-2.05). The pooled OR for the incidence of total adverse effects was significantly lower in the probiotic group (OR = 0.49, 95%CI: 0.26-0.94), using the random effects model, with significant heterogeneity (I2 = 85.7%). The incidence of diarrhea was significantly reduced in the probiotic group (OR = 0.21, 95%CI: 0.06-0.74), whereas the incidence of taste disorders, metallic taste, vomiting, nausea, and epigastric pain did not differ significantly between the probiotic group and the control group.
CONCLUSION: Supplementary probiotic preparations during standard triple H. pylori therapy may improve the eradication rate, particularly in Asian patients, and the incidence of total adverse effects.
doi:10.3748/wjg.v20.i47.18013
PMCID: PMC4273153  PMID: 25548501
Helicobacter pylori; Eradication; Probiotics; Meta-analysis; Adult
7.  Dual-color labeled anti-mucin 1 antibody for imaging of ovarian cancer: A preliminary animal study 
Oncology Letters  2014;9(3):1231-1235.
To investigate the feasibility of the anti-mucin 1 (anti-MUC1/CD227) antibody in the fluorescent imaging of ovarian cancer, the CD227 antibody and a control IgG antibody were labeled with a near-infrared dye [Cy5.5-N-hydroxysuccinimide (NHS)] and a green dye (fluorescein-NHS). In vivo fluorescence images were obtained at 4, 12 and 36 h after injection of the probes into OVCAR3 tumor-bearing mice. The tumor to background ratios were calculated for both probes. Ex vivo fluorescence images were obtained following sacrifice at 36 h. After conjugation to Cy5.5 and fluorescein, the dual-color labeled CD227 probe (Ab-FL-Cy5.5) could be visualized by both green and near-infrared fluorescence. Uptake by the tumors was higher for the Ab-FL-Cy5.5 than for the IgG-Cy5.5 probe. All tumors could be visualized by in vivo imaging with an acceptable tumor to background ratio. Ex vivo studies demonstrated the advantages of using green fluorescence imaging to guide the resection of tumor tissues. These preliminary data indicate that the Ab-FL-Cy5.5 probe is promising for further tumor imaging applications and clinical translation.
doi:10.3892/ol.2014.2807
PMCID: PMC4315008  PMID: 25663888
fluorescence imaging; ovarian cancer; mucin 1 antibody; CD227 antibody; near-infrared fluorescence
8.  Concerns of and coping strategies by parents of pediatric liver transplant recipients: a qualitative study from China 
Parents of liver transplant recipient children have to face complicated health issues of their children. Coping strategies of parents as major care providers not only impacts on their handling of stresses on themselves but also on the recipients’ quality of life. In this study, we sought to investigate the coping strategies of parents of Chinese pediatric liver transplant recipients at a single tertiary care institution in China. Twenty-five parents of liver transplant recipients were selected by the purposive sampling method and data was collected using qualitative semi-structured interview. Interviews were conducted until thematic saturation was achieved. We extracted 5 major themes: 1) guilt and self-blame for not giving a happy life to the sick child; 2) seeking social support for helping to treat the sick child; 3) standing firm by not giving up on treating the sick child; 4) cautious caretaking; 5) compromise: a helpless acceptance of truth. In summary, parents of transplant recipients present 5 major coping strategies. Proper assessment of stresses on parents of liver transplant recipient children and their coping strategies may help the medical staff and social services to provide more targeted support, and help and promote the balance of the family function.
PMCID: PMC4307545  PMID: 25664098
Liver transplant; children; parents; coping; qualitative study
9.  Modeling TMJD pain in the laboratory mouse: role of TRP ion channels 
Molecular Pain  2014;10(Suppl 1):O8.
doi:10.1186/1744-8069-10-S1-O8
PMCID: PMC4304387
12.  Differential Expression of miR-130a in Postmortem Prefrontal Cortex of Subjects with Alcohol Use Disorders 
Background
Emerging evidence suggests that neuroadaptations to alcohol may result from chronic alcohol consumption-induced expression changes of microRNAs (miRNAs) and their target genes. Studies with animal or cell culture models have demonstrated that ethanol exposure leads to miRNA expression alterations. However, there is limited information on miRNA expression in the brains of subjects with alcohol use disorders (AUDs). The present study aimed to analyze expression changes of miRNAs and their target genes in postmortem prefrontal cortex (PFC) of AUD subjects.
Methods
Genome-wide miRNA and mRNA expression was examined in postmortem PFC of 23 European Australia AUD cases and 23 matched controls using the Illumina HumanHT-12 v4 Expression BeadChip array, which targets 43,270 coding transcripts and 3,961 non-coding transcripts (including 574 miRNA transcripts). Multiple linear regression analysis and permutation test were performed to identify differentially expressed miRNAs and their target mRNAs. Target gene prediction, Gene Set Enrichment Analysis (GESA), and DAVID functional annotation clustering analysis were applied to identify AUD-associated gene sets and biological modules.
Results
Two miRNAs and 787 coding genes were differentially expressed in the PFC of AUD cases [miR-130a (downregulated): Ppermutation=0.023, miR-604 (upregulated): Ppermutation=0.019, coding genes: 1.6×10−5≤Ppermutation≤0.05; but all P values did not survive multiple-testing correction]. GESA showed that the 202 predicted target genes of miR-130a were highly enriched in differentially expressed genes (Pnominal<0.001), but not the 116 predicted target genes of miR-604 (Pnominal=0.404). DAVID functional clustering further revealed that the hub target genes (e.g., ITPR2 and ATP1A2) of miRNA130a were mainly responsible for regulating ion channel function.
Conclusion
This study provides evidence that downregulation of miR-130a may lead to altered expression of a number of genes in the PFC of AUD subjects. Further studies are warranted to confirm these findings in replication samples and other reward-related brain regions.
doi:10.4172/2155-6105.1000155
PMCID: PMC4221234  PMID: 25383235
microRNA; alcohol use disorders; postmortem prefrontal cortex; expression microarray
13.  Improving heart function by modulating myocardiocyte autophagy: a possible novel mechanism for cardiovascular protection of high-density lipoprotein 
Background
High-density lipoprotein (HDL) has been shown to confer cardiovascular protection in clinical and epidemiologic studies. Emerging evidence suggests that many of the cardioprotective functions of HDL may be due to the phospholipid sphingosine-1-phosphate (S1P).
Presentation of the hypothesis
HDL-S1P binds to S1P receptors in the heart, activating PI3K/Akt signaling and myocyte survival. PI3K/Akt is a classic signaling modulator of autophagy. Excessive autophagy due to cell death and cardiomyocyte loss may contribute to impaired heart function during pressure overload-induced heart failure. Therefore, we hypothesize that HDL-S1P may suppress excessive autophagy of cardiomyocytes through activation of PI3K/Akt signaling. Further, reconstituted HDL (including S1P) may protect heart function during pressure overload-induced heart failure.
Testing the hypothesis
We will design the following experiments to test this hypothesis. (1) We will treat cells and mice with PI-3 kinase inhibitors to examine if HDL-S1P downregulates expression of Autophagy-related genes (ATGs) and proteins via activation of PI3K/Akt signaling. (2) We will use siRNA against S1P receptors or inhibitors of S1P receptors to determine which types of S1P receptors participate in this mechanism. (3) We will also examine if reconstituted HDL (including S1P) improves heart function during pressure overload-induced heart failure by suppressing excessive autophagy of cardiomyocytes through activation of PI3K/Akt signaling.
Implications of the hypothesis
Understanding the autophagy signaling pathway modulated by HDL-S1P will make a major contribution to the field by identifying a novel mechanism for cardiovascular protection of high-density lipoprotein. Further, using reconstituted HDL to improve heart function would provide a novel therapeutic approach for pressure overload–induced heart failure.
doi:10.1186/1476-511X-13-163
PMCID: PMC4216853  PMID: 25339382
Autophagy; Reconstituted high-density lipoprotein; Sphingosine-1-phosphate; Heart function
14.  Effects of Hypoxanthine Substitution in Peptide Nucleic Acids Targeting KRAS2 Oncogenic mRNA Molecules: Theory and Experiment 
The journal of physical chemistry. B  2013;117(39):11584-11595.
Genetic disorders can arise from single base substitutions in a single gene. A single base substitution for wild type guanine in the twelfth codon of KRAS2 mRNA occurs frequently to initiate lung, pancreatic, and colon cancer. We have observed single base mismatch specificity in radioimaging of mutant KRAS2 mRNA in tumors in mice by in vivo hybridization with radiolabeled peptide nucleic acid (PNA) dodecamers. We hypothesized that multi-mutant specificity could be achieved with a PNA dodecamer incorporating hypoxanthine, which can form Watson-Crick basepairs with adenine, cytosine, thymine, and uracil. Using molecular dynamics simulations and free energy calculations, we show that hypoxanthine substitutions in PNAs are tolerated in KRAS2 RNA-PNA duplexes where wild type guanine is replaced by mutant uracil or adenine in RNA. To validate our predictions, we synthesized PNA dodecamers with hypoxanthine, and then measured the thermal stability of RNA-PNA duplexes. Circular dichroism thermal melting results showed that hypoxanthine-containing PNAs are more stable in duplexes where hypoxanthine-adenine and hypoxanthine-uracil base pairs are formed than single mismatch duplexes or duplexes containing hypoxanthine-guanine opposition.
doi:10.1021/jp4064966
PMCID: PMC3946533  PMID: 23972113
hypoxanthine; oligonucleotides; peptide nucleic acid; accelerated molecular dynamics; KRAS2
15.  N-Acetylcysteine Attenuates Ischemia-Reperfusion-Induced Apoptosis and Autophagy in Mouse Liver via Regulation of the ROS/JNK/Bcl-2 Pathway 
PLoS ONE  2014;9(9):e108855.
Background
Hepatic ischemia–reperfusion injury (HIRI) remains a pivotal clinical problem after hemorrhagic shock, transplantation, and some types of toxic hepatic injury. Apoptosis and autophagy play important roles in cell death during HIRI. It is also known that N-acetylcysteine (NAC) has significant pharmacologic effects on HIRI including elimination of reactive oxygen species (ROS) and attenuation of hepatic apoptosis. However, the effects of NAC on HIRI-induced autophagy have not been reported. In this study, we evaluated the effects of NAC on autophagy and apoptosis in HIRI, and explored the possible mechanism involved.
Methods
A mouse model of segmental (70%) hepatic warm ischemia was adopted to determine hepatic injury. NAC (150 mg/kg), a hepatoprotection agent, was administered before surgery. We hypothesized that the mechanism of NAC may involve the ROS/JNK/Bcl-2 pathway. We evaluated the expression of JNK, P-JNK, Bcl-2, Beclin 1 and LC3 by western blotting and immunohistochemical staining. Autophagosomes were evaluated by transmission electron microscopy (TEM).
Results
We found that ALT, AST and pathological changes were significantly improved in the NAC group. Western blotting analysis showed that the expression levels of Beclin 1 and LC3 were significantly decreased in NAC-treated mice. In addition, JNK, p-JNK, Bax, TNF-α, NF-κB, IL2, IL6 and levels were also decreased in NAC-treated mice.
Conclusion
NAC can prevent HIRI-induced autophagy and apoptosis by influencing the JNK signal pathway. The mechanism is likely to involve attenuation of JNK and p-JNK via scavenged ROS, an indirect increase in Bcl-2 level, and finally an alteration in the balance of Beclin 1 and Bcl-2.
doi:10.1371/journal.pone.0108855
PMCID: PMC4181678  PMID: 25264893
16.  Hydrogen sulfide, a potential novel drug, attenuates concanavalin A-induced hepatitis 
Background
Hydrogen sulfide (H2S) is known to exert anti-inflammatory properties. Apoptosis and autophagy play important roles in concanavalin A (Con A)-induced acute hepatitis. The purpose of this study was to explore both the effect and mechanism of H2S on Con A-induced acute hepatitis.
Methods
BALB/c mice were randomized into sham group, Con A-injection group, and 14 μmol/kg of sodium hydrosulfide (NaHS, an H2S donor) pretreatment group.
Results
Aspartate aminotransferase, alanine aminotransferase, and pathological damage were significantly ameliorated by NaHS pretreatment. NaHS pretreatment significantly reduced the levels of interleukin-6 and tumor necrosis factor-α compared with those of the Con A group. The expression of Bcl-2, Bax, Beclin-1, and LC3-2, which play important roles in the apoptosis and autophagy pathways, were also clearly affected by NaHS. Furthermore, NaHS affected the p-mTOR and p-AKT.
Conclusion
H2S attenuates Con A-induced acute hepatitis by inhibiting apoptosis and autophagy, in part, through activation of the PtdIns3K-AKT1 signaling pathway.
doi:10.2147/DDDT.S66573
PMCID: PMC4166909  PMID: 25246769
NaHS; apoptosis; PtdIns3K-AKT; autophagy
17.  CpG Island Methylator Phenotype and Prognosis of Colorectal Cancer in Northeast China 
BioMed Research International  2014;2014:236361.
Purpose. To investigate the association between CpG island methylator phenotype (CIMP) and the overall survival of sporadic colorectal cancer (CRC) in Northeast China. Methods. 282 sporadic CRC patients were recruited in this study. We selected MLH1, MGMT, p16, APC, MINT1, MINT31, and RUNX3 as the CIMP panel markers. The promoter methylation was assessed by methylation sensitive high resolution melting (MS-HRM). Proportional hazards-regression models were fitted with computing hazard ratios (HR) and the corresponding 95% confidence intervals (95% CI). Results. 12.77% (36/282) of patients were CIMP-0, 74.1% (209/282) of patients were CIMP-L, and 13.12% (37/282) of patients were CIMP-H. The five-year survival of the 282 CRC patients was 58%. There was significant association between APC gene promoter methylation and CRC overall survival (HR = 1.61; 95% CI: 1.05–2.46; P = 0.03). CIMP-H was significantly associated with worse prognosis compared to CIMP-0 (HR = 3.06; 95% CI: 1.19–7.89; P = 0.02) and CIMP-L (HR = 1.97; 95% CI: 1.11–3.48; P = 0.02), respectively. While comparing with the combine of CIMP-L and CIMP-0 (CIMP-L/0), CIMP-H also presented a worse prognosis (HR = 2.31; 95% CI: 1.02–5.24; P = 0.04). Conclusion. CIMP-H may be a predictor of a poor prognosis of CRC in Northeast China patients.
doi:10.1155/2014/236361
PMCID: PMC4163374  PMID: 25243122
18.  More than a rhythm of life: Breathing as a binder of orofacial sensation 
Nature neuroscience  2014;17(5):647-651.
When rodents engage in the exploration of novel stimuli, breathing occurs at an accelerated rate that is synchronous with whisking. We review the recently observed relationships between breathing and the sensations of smell and vibrissa-based touch. We consider the hypothesis that the breathing rhythm serves not only as a motor drive signal but also as a common clock that binds these two senses into a common percept. This possibility may be extended to include taste through the coordination of licking with breathing. The status of experimental evidence that pertains to this hypothesis is evaluated.
doi:10.1038/nn.3693
PMCID: PMC4140942  PMID: 24762718
19.  Preeclampsia induced by cadmium in rats is related to abnormal local glucocorticoid synthesis in placenta 
Background
Cadmium (Cd) is a major environmental pollutant that causes multiple adverse health effects in humans and animals. In this study, we investigated Cd-mediated toxic effects in rats during pregnancy and endocrine intervention in the placenta.
Methods
We exposed pregnant rats to intraperitoneal Cd (CdCl2) at various doses (0, 0.25, and 0.5 mg/kg BW/day) from days 5 to 19 of pregnancy and evaluated the maternal-placental-fetal parameters linked to preeclampsia. We measured the corticosterone level in rat serum and placental tissue by sensitive ELISA and also analyzed the expression of glucocorticoid synthesis enzymes in the placenta.
Results
Key features of preeclampsia (PE), including hypertension, proteinuria, glomerular endotheliosis, placental abnormalities and small fetal size, appeared in pregnant rats after injection with 0.5 mg/kg BW/day Cd. The placental corticosterone production and maternal and fetal plasma corticosterone levels were increased in rats treated with 0.5 mg/kg BW/day Cd (P <0.01). The expression of 21-hydroxylase (CYP21) and 11beta-hydroxylase (CYP11B1), enzymes essential for corticosteroid synthesis, were increased in Cd-exposed placenta (P <0.01). 11beta-hydroxysteroid dehydrogenase (11beta-HSD2), a dominant negative regulator of local glucocorticoid levels, was decreased in Cd-exposed placenta (P <0.01).
Conclusions
Our study demonstrates for the first time that changes in placental glucocorticoid synthesis induced by Cd exposure during pregnancy could contribute to preeclamptic conditions in rats.
doi:10.1186/1477-7827-12-77
PMCID: PMC4249735  PMID: 25108313
Cadmium; Preeclampsia; Glucocorticoid synthesis; Placenta; Rat
20.  Survival outcomes and progonostic factors of extrahepatic cholangiocarcinoma patients following surgical resection: Adjuvant therapy is a favorable prognostic factor 
Molecular and Clinical Oncology  2014;2(6):1069-1075.
This study was conducted to investigate survival and prognostic factors for extrahepatic cholangiocarcinoma (ECC) following surgical resection and evaluate the effects of postoperative adjuvant therapy (AT) on overall survival (OS). We retrospectively collected clinical and pathological data between March, 2008 and December, 2013. The Kaplan-Meier method and the COX regression model were used to evaluate the OS and prognostic factors of 105 postoperative ECC patients, of whom 32 had received AT. The patients were stratified into seven risk subgroups and the survival rates were compared within each subgroup between patients who received AT and those who did not. The results demonstrated a median OS of 17.6 months, with 1- and 3-year survival rates of 67.9 and 19.5%, respectively, for the entire cohort. On univariate analysis, preoperative cholangitis, non-R0 surgical margins, poor differentiation grade, stage 3/4 and lymphatic metastasis were identified as adverse prognostic factors. AT was not significantly associated with improved OS. However, the subgroup analysis revealed that the effect of AT was significant only in the lymphatic metastasis group (median OS, 21.6 vs. 10.4 months; and 3-year OS, 16.6 vs. 0%, respectively; P=0.02). The survival curves of the AT and non-AT groups were significantly different only for node-positive patients. The COX regression model identified lymphatic metastasis, surgical margins and AT as independent prognostic factors for ECC. A negative resection margin may reduce the mortality rate following surgery by 47%. By contrast, lymph node metastasis was associated with a 2.18-fold higher mortality rate for ECC patients. Postoperative AT contributed to a 0.45-fold mortality rate compared to non-AT ECC patients. Therefore, we concluded that AT is a favorable prognostic factor for ECC patients and it may prolong the survival of patients with lymphatic metastasis. Our data suggest that postoperative AT should be recommended for node-positive ECC patients.
doi:10.3892/mco.2014.377
PMCID: PMC4179817  PMID: 25279199
adjuvant therapy; extrahepatic cholangiocarcinoma; prognosis; survival
21.  MiR-124 suppresses tumor growth and metastasis by targeting Foxq1 in nasopharyngeal carcinoma 
Molecular Cancer  2014;13(1):186.
Background
The molecular mechanisms underlying dysregulation of microRNAs have been documented in nasopharyngeal carcinoma (NPC). Our previous study demonstrated that plasma miR-124 was down-regulated in NPC using microarray analysis and quantitative PCR validation. Though growing studies showed that down-regulated miR-124 was closely related to tumourigenesis in various types of cancers, the role of miR-124 in NPC remains largely unknown.
Methods
The expression level of miR-124 was evaluated in NPC cell lines and patient specimens using quantitative reverse transcription-PCR (Real-time qPCR). The clinicopathological significance of the resultant data was later analyzed. Then, we explored the role of miR-124 in NPC tumorigenesis by in vitro and in vivo experiments. Homo sapiens forkhead box Q1 (Foxq1) was confirmed as a novel direct target gene of miR-124 by the dual-luciferase assay and western bolt.
Results
We found that miR-124 was commonly down-regulated in NPC specimens and NPC cell lines. The expression of miR-124 was inversely correlation with clinical stages and marked on T stages. Then, the ectopic expression of miR-124 dramatically inhibited cell proliferation, colony formation, migration and invasion in vitro, as well as tumor growth and metastasis in vivo. Furthermore, we identified Foxq1 as a novel direct target of miR-124. Functional studies showed that knockdown of Foxq1 inhibited cell growth, migration and invasion, whereas Foxq1 overexpression partially rescued the suppressive effect of miR-124 in NPC. In clinical specimens, Foxq1 was commonly up-regulated in NPC, and the level increased with clinical stages and T stages. Additionally, the level of Foxq1 was inversely correlated with miR-124.
Conclusions
Our results demonstrate that miR-124 functions as a tumor-suppressive microRNA in NPC, and that its suppressive effects are mediated chiefly by repressing Foxq1 expression. MiR-124 could serve as an independent biomarker to identify patients with different clinical characteristics. Therefore, our findings provide valuable clues toward the understanding the of mechanisms of NPC pathogenesis and provide an opportunity to develop new effective clinical therapies in the future.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-4598-13-186) contains supplementary material, which is available to authorized users.
doi:10.1186/1476-4598-13-186
PMCID: PMC4267157  PMID: 25098939
MicroRNA-124; Tumor growth; Metastasis; Nasopharyngeal carcinoma; Foxq1
22.  Diagnostic Performance of Des-γ-carboxy Prothrombin for Hepatocellular Carcinoma: A Meta-Analysis 
Background. There have been many reports on des-γ-carboxy prothrombin (DCP) as a promising serum marker in the diagnosis of hepatocellular carcinoma (HCC); however, the results are inconsistent and even conflicting. Methods. This meta-analysis was performed to investigate the performance of DCP in the diagnosis of HCC. Following a systematic review of relevant studies, Meta-DiSc 1.4 software was used to extract data and to calculate the overall sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). Data are presented as forest plots and summary receiver operating characteristic curve (SROC) analysis was used to summarize the overall test performance. Results. Twelve studies were included in our meta-analysis. The overall sensitivity, specificity, PLR, and NLR of DCP for the detection of HCC in the studies included were 71% (95%CI: 68%–73%), 84% (95%CI: 83%–86%), 6.48 (95%CI: 4.22–9.93), and 0.33 (95%CI: 0.25–0.43), respectively. The area under the SROC curve was 0.8930 and the Q index was 0.8238. Significant heterogeneity was found. Conclusion. This meta-analysis indicated that DCP had moderate diagnostic accuracy in HCC. Further studies with rigorous design, large sample size, and mmultiregional cooperation are needed in the future.
doi:10.1155/2014/529314
PMCID: PMC4140125  PMID: 25165471
23.  Temporomandibular joint pain: A critical role for Trpv4 in the trigeminal ganglion 
Pain  2013;154(8):1295-1304.
Temporomandibular joint disorder (TMJD) is known for its mastication-associated pain. TMJD is medically relevant because of its prevalence, severity, chronicity, and “therapy-refractoriness” of its pain, and its largely elusive pathogenesis. Against this background we sought to investigate pathogenetic contributions of the calcium-permeable TRPV4 ion channel, robustly expressed in the trigeminal ganglion sensory neurons, to TMJ inflammation and pain behavior. We demonstrate here that TRPV4 is critical for TMJ-inflammation evoked pain behavior in mice, and that trigeminal ganglion pro-nociceptive changes are Trpv4-dependent. As a quantitative metric, bite force was recorded as evidence of masticatory sensitization, in keeping with human translational studies. In Trpv4−/− mice with TMJ-inflammation, attenuation of bite force was significantly less than in WT mice. Similar effects were seen with systemic application of a specific TRPV4 inhibitor. TMJ-inflammation and mandibular bony changes were apparent after CFA injections, but remarkably independent of Trpv4 genotype. Intriguingly, as a result of TMJ-inflammation, WT mice exhibited significant up-regulation of TRPV4 and phosphorylated ERK in TMJ-innervating trigeminal sensory neurons, absent in Trpv4−/− mice. Mice with genetically-impaired MEK/ERK phosphorylation in neurons showed a similar resistance to reduction of bite-force as Trpv4−/− mice. Thus, TRPV4 is necessary for masticatory sensitization in TMJ-inflammation, and likely functions up-stream of MEK/ERK phosphorylation in trigeminal ganglion sensory neurons in-vivo. TRPV4 therefore represents a novel pro-nociceptive target in TMJ inflammation, and should be considered a target-of-interest in human TMJD.
doi:10.1016/j.pain.2013.04.004
PMCID: PMC3722361  PMID: 23726674
24.  Sonic Hedgehog-Gli1 Signaling Pathway Regulates the Epithelial Mesenchymal Transition (EMT) by Mediating a New Target Gene, S100A4, in Pancreatic Cancer Cells 
PLoS ONE  2014;9(7):e96441.
Aims
The hedgehog signaling pathway plays an important role in EMT of pancreatic cancer cells, but the precise mechanisms remain elusive. Because S100A4 as a key EMT moleculer marker was found to be upregulated upon Gli1 in pancreatic cancer cells, we focused on the relationship between Shh-Gli1 signals and S100 genes family.
Methods
On the base of cDNA microarray data, we investigated regulating mechanism of Gli1 to some members of S100A genes family in pancreatic cancer cell lines firstly. Then, the regulation of Gli1 to S100A4 gene was studied by molecular biology assays and the pro-metastasis effection of Gli1-dependent S100A4 was investigated in vitro. Finally, the expressions of Shh, Gli1, S100A4 and E-cadherin in pancreatic cancer tissues were studied by using immunohistochemistry assays.
Results
Five members of the S100 genes family, S100A2, S100A4, S100A6, S100A11, and S100A14 were found to be downregulated significantly upon Gli1 knockdown. Gli1 enhancer prediction combining with in vitro data demonstrated that Gli1 primarily regulates S100A family members via cis-acting elements. Indeed, the data indicate S100A4 and vimentin genes were upregulated significantly by Shh/Gli1-expression increasing and E-cadherin was significantly reduced at the same time. Migration of PC cells was increased significantly in a dose-dependent manner of Gli1 expression (P<0.05) and siS100A4 significantly reversed the response of PC cells induced by L-Shh transduction (P<0.01).
Conclusion
Our data establish a novel connection between Shh-Gli1 signaling and S100A4 regulation, which imply that S100A4 might be one of the key factors in EMT mediated by Shh-Gli1 signaling in pancreatic cancer.
doi:10.1371/journal.pone.0096441
PMCID: PMC4114558  PMID: 25072505
25.  K-ras Mutational Status in Cytohistological Tissue as a Molecular Marker for the Diagnosis of Pancreatic Cancer: A Systematic Review and Meta-Analysis 
Disease Markers  2014;2014:573783.
Background. More clinically meaningful diagnostic tests are needed in pancreatic cancer (PC). K-ras mutations are the most frequently acquired genetic alteration. Methods. Original research articles involving the diagnostic accuracy of K-ras mutation detection in PC were selected. Data were presented as forest plots and summary receiver operating characteristic (SROC) curve analysis was used to summarize the overall test performance. Results. We assessed 19 studies from 16 published articles. The reports were divided into three groups according to the process used to obtain the test material. The summary estimates for detecting K-ras status using an invasive method (fine needle aspiration (FNA), endoscopic retrograde cholangiopancreatography (ERCP), or surgery) were better than cytology: the pooled sensitivity was 77% (95% confidence interval (CI): 74–80%) versus 54% (95% CI: 47–61%); specificity was 88% (95% CI: 85–91%) versus 91% (95% CI: 83–96%); and diagnostic odds ratio (DOR) was 20.26 (11.40–36.03) versus 7.52 (95% CI: 2.80–20.18), respectively. When two procedures were combined, the diagnostic accuracy was markedly improved. Conclusions. The analysis of K-ras mutations in pancreatic tissue has a promising diagnostic significance in PC. Further valuable studies are needed.
doi:10.1155/2014/573783
PMCID: PMC4124783  PMID: 25301978

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