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1.  Expression of BMP4 in myocardium and vascular tissue of obese mice 
Background
Obesity is regarded as a risk factor for cardiovascular disease. Bone morphogenetic protein 4 (BMP4) is a proinflammatory and profibrotic factor, and the reduced expression of this molecule in obese mice seems to be inconsistent with the known proinflammatory effects of obesity. Therefore, we studied BMP4 expression and inflammation in the myocardial tissue and aortas of obese mice.
Methods and Results
Four-week-old ob/ob mice were used as the experimental group, and C57BL/6 mice comprised the control group. Animals were sacrificed after a 12-week full diet, and then the blood, heart, abdominal aorta, and inguinal adipose tissue were collected. The expression of BMP4 mRNA and protein in the heart and aorta was significantly higher in the experimental group than in the control group, but expression was lower in adipose tissue. Inflammation measured by the expression of IL-1β and IL-9 mRNA and protein and Smad1 and phosphorylated Smad1/5/8 protein in the heart and aorta was higher in the experimental group than in the control group. In addition, the expression of BMP4 in the serum was significantly higher in the experimental group than in the control group.
Conclusion
BMP4 is significantly overexpressed in the myocardial tissue and aortas of obese mice, and mediates local inflammatory responses.
doi:10.1186/s12950-015-0047-6
PMCID: PMC4326186
BMP4; Obesity; Inflammation; Cardiovascular disease
2.  Rapid Identification of α-Glucosidase Inhibitors from Phlomis tuberosa by Sepbox Chromatography and Thin-Layer Chromatography Bioautography 
PLoS ONE  2015;10(2):e0116922.
Alpha-glucosidase inhibitors currently form an important basis for developing novel drugs for diabetes treatment. In our preliminary tests, the ethyl acetate fraction of Phlomis tuberosa extracts showed significant α-glucosidase inhibitory activity (IC₅₀ = 100 μg/mL). In the present study, a combined method using Sepbox chromatography and thin-layer chromatography (TLC) bioautography was developed to probe α-glucosidase inhibitors further. The ethyl acetate fraction of P. tuberosa extracts was separated into 150 individual subfractions within 20 h using Sepbox chromatography. Then, under the guidance of TLC bioautography, 20 compounds were successfully isolated from these fractions, including four new diterpenoids [14-hydroxyabieta-8,11,13-triene-11-carbaldehyde-18-oic-12-carboxy-13-(1-hydroxy-1-methylethyl)-lactone (1), 14-hydroxyabieta-8,11,13-triene-17-oic-12-carboxy-13-(1-hydroxy-1-methylethyl)-lactone (2), 14,16-dihydroxyabieta-8,11,13-triene-15,17-dioic acid (3), and phlomisol (15,16-eposy-8,13(16),14-labdatrien-19-ol) (4)], and 16 known compounds. Activity estimation indicated that 15 compounds showed more potent α-glucosidase inhibitory effects (with IC50 values in the range 0.067–1.203 mM) than the positive control, acarbose (IC50 = 3.72 ± 0.113 mM). This is the first report of separation of α-glucosidase inhibitors from P. tuberosa.
doi:10.1371/journal.pone.0116922
PMCID: PMC4319760  PMID: 25658100
3.  Deferoxamine attenuates lipopolysaccharide-induced neuroinflammation and memory impairment in mice 
Background
Neuroinflammation often results in enduring cognitive impairment and is a risk factor for postoperative cognitive dysfunction. There are currently no effective treatments for infection-induced cognitive impairment. Previous studies have shown that the iron chelator deferoxamine (DFO) can increase the resistance of neurons to injury and disease by stimulating adaptive cellular stress responses. However, the impact of DFO on the cognitive sequelae of neuroinflammation is unknown.
Methods
A mouse model of lipopolysaccharide (LPS)-induced cognitive impairment was established to evaluate the neuroprotective effects of DFO against LPS-induced memory deficits and neuroinflammation. Adult C57BL/6 mice were treated with 0.5 μg of DFO 3 days prior to intracerebroventricular microinjection of 2 μg of LPS. Cognitive function was assessed using a Morris water maze from post-injection days 1 to 3. Animal behavioral tests, as well as pathological and biochemical assays were performed to evaluate the LPS-induced hippocampal damage and the neuroprotective effect of DFO.
Results
Treatment of mice with LPS resulted in deficits in cognitive performance in the Morris water maze without changing locomotor activity, which were ameliorated by pretreatment with DFO. DFO prevented LPS-induced microglial activation and elevations of IL-1β and TNF-α levels in the hippocampus. Moreover, DFO attenuated elevated expression of caspase-3, modulated GSK3β activity, and prevented LPS-induced increases of MDA and SOD levels in the hippocampus. DFO also significantly blocked LPS-induced iron accumulation and altered expression of proteins related to iron metabolism in the hippocampus.
Conclusions
Our results suggest that DFO may possess a neuroprotective effect against LPS-induced neuroinflammation and cognitive deficits via mechanisms involving maintenance of less brain iron, prevention of neuroinflammation, and alleviation of oxidative stress and apoptosis.
doi:10.1186/s12974-015-0238-3
PMCID: PMC4323121  PMID: 25644393
Deferoxamine; Neuroinflammation; Iron; Memory impairment; Oxidative stress; Apoptosis
5.  Biological mechanism analysis of acute renal allograft rejection: integrated of mRNA and microRNA expression profiles 
Objectives: Renal transplantation is the preferred method for most patients with end-stage renal disease, however, acute renal allograft rejection is still a major risk factor for recipients leading to renal injury. To improve the early diagnosis and treatment of acute rejection, study on the molecular mechanism of it is urgent. Methods: MicroRNA (miRNA) expression profile and mRNA expression profile of acute renal allograft rejection and well-functioning allograft downloaded from ArrayExpress database were applied to identify differentially expressed (DE) miRNAs and DE mRNAs. DE miRNAs targets were predicted by combining five algorithm. By overlapping the DE mRNAs and DE miRNAs targets, common genes were obtained. Differentially co-expressed genes (DCGs) were identified by differential co-expression profile (DCp) and differential co-expression enrichment (DCe) methods in Differentially Co-expressed Genes and Links (DCGL) package. Then, co-expression network of DCGs and the cluster analysis were performed. Functional enrichment analysis for DCGs was undergone. Results: A total of 1270 miRNA targets were predicted and 698 DE mRNAs were obtained. While overlapping miRNA targets and DE mRNAs, 59 common genes were gained. We obtained 103 DCGs and 5 transcription factors (TFs) based on regulatory impact factors (RIF), then built the regulation network of miRNA targets and DE mRNAs. By clustering the co-expression network, 5 modules were obtained. Thereinto, module 1 had the highest degree and module 2 showed the most number of DCGs and common genes. TF CEBPB and several common genes, such as RXRA, BASP1 and AKAP10, were mapped on the co-expression network. C1R showed the highest degree in the network. These genes might be associated with human acute renal allograft rejection. Conclusions: We conducted biological analysis on integration of DE mRNA and DE miRNA in acute renal allograft rejection, displayed gene expression patterns and screened out genes and TFs that may be related to acute renal allograft rejection.
PMCID: PMC4307466  PMID: 25664019
Renal transplantation; acute rejection; microRNA; mRNA; transcription factor
6.  Blue rubber bleb nevus syndrome: A case report and literature review 
World Journal of Gastroenterology : WJG  2014;20(45):17254-17259.
Blue rubber bleb nevus syndrome (BRBNS) is a rare disease characterized by multiple venous malformations and hemangiomas in the skin and visceral organs. The lesions often involve the cutaneous and gastrointestinal systems. Other organs can also be involved, such as the central nervous system, liver, and muscles. The most common symptoms are gastrointestinal bleeding and secondary iron deficiency anemia. The syndrome may also present with severe complications such as rupture, intestinal torsion, and intussusception, and can even cause death. Cutaneous malformations are usually asymptomatic and do not require treatment. The treatment of gastrointestinal lesions is determined by the extent of intestinal involvement and severity of the disease. Most patients respond to supportive therapy, such as iron supplementation and blood transfusion. For more significant hemorrhages or severe complications, surgical resection, endoscopic sclerosis, and laser photocoagulation have been proposed. Here we present a case of BRBNS in a 45-year-old woman involving 16 sites including the scalp, eyelid, orbit, lip, tongue, face, back, upper and lower limbs, buttocks, root of neck, clavicle area, superior mediastinum, glottis, esophagus, colon, and anus, with secondary severe anemia. In addition, we summarize the epidemiology, clinical manifestations, diagnosis, differential diagnosis and therapies of this disease by analyzing all previously reported cases to enhance the awareness of this syndrome.
doi:10.3748/wjg.v20.i45.17254
PMCID: PMC4258599  PMID: 25493043
Anemia; Blue rubber bleb nevus syndrome; Hemangioma; Vascular malformations; Gastrointestinal bleeding
7.  Preliminary Extraction and Identification of the 44.5 kDa Outer Membrane Proteins Isolated from Bovine Fusobacterium necrophorum (AB) 
Indian Journal of Microbiology  2013;53(4):395-399.
Fusobacterium necrophorum (AB) in the pharynx, respiratory tract, female reproductive tract or urinary system is the causative agent of footrot and hepatic abscesses in animals and acute Lemierre’s syndrome in humans. Current methods do not effectively protect animals and humans against F. necrophorum (AB). The outer membrane proteins (OMP) of F. necrophorum (AB) can be used as new material to protect against the diseases induced by F. necrophorum (AB). The aim of this study was to extract OMP and examine the immunogenic response of OMP. The preliminary extraction of OMP of F. necrophorum (AB) was identified by SDS-PAGE and stained by Coomassie Brilliant Blue R-250 (CB B R-250) and silver staining methods. The results showed that only a major band of 44.5 kDa was observed when staining the gel using CB B R-250. This band represented the target protein. In contrast, many small bands were observed by the silver staining method. The OMP also exhibited immune biological activities according to western blot analysis. The brightest band among the multi-banding observed was the OMP. Thus, the OMP was obtained and had immunogenic activity. The results provide a new direction to protect animals and humans against F. necrophorum (AB) in the clinical setting.
doi:10.1007/s12088-013-0388-x
PMCID: PMC3779297  PMID: 24426142
Preliminary extraction; 44.5 kDa; Fusobacterium necrophorum (AB); Outer membrane proteins
8.  Impact of dose calculation algorithm on radiation therapy 
World Journal of Radiology  2014;6(11):874-880.
The quality of radiation therapy depends on the ability to maximize the tumor control probability while minimize the normal tissue complication probability. Both of these two quantities are directly related to the accuracy of dose distributions calculated by treatment planning systems. The commonly used dose calculation algorithms in the treatment planning systems are reviewed in this work. The accuracy comparisons among these algorithms are illustrated by summarizing the highly cited research papers on this topic. Further, the correlation between the algorithms and tumor control probability/normal tissue complication probability values are manifested by several recent studies from different groups. All the cases demonstrate that dose calculation algorithms play a vital role in radiation therapy.
PMCID: PMC4241494  PMID: 25431642
Dose calculation; Algorithm; Radiation therapy; Tumor control probability; Normal tissue complication probability
9.  Malignant gangliocytic paraganglioma of the duodenum with distant metastases and a lethal course 
World Journal of Gastroenterology : WJG  2014;20(41):15454-15461.
Gangliocytic paraganglioma (GP) is rare and has been regarded as benign in general with a good prognosis. We present a patient with duodenal GP showing a malignant and lethal clinical course. A 47-year-old male patient was found to have a duodenal tumor and enlarged regional lymph nodes. The patient initially underwent a pancreaticoduodenectomy to resect the tumor and involved lymph nodes completely. Histological and immunohistochemical analyses showed findings typical of GP. However, the distant metastatic lesions in the liver and pelvic cavity were rapidly observed after surgery. The patient underwent chemotherapy and radiotherapy, as well as a second surgery to partly remove the metastatic mass in the pelvic cavity. The histological examination revealed no significant difference in histological features between the primary duodenal tumor and the metastatic pelvic mass. However, the patient finally died of the tumor due to the recurrence of the residual pelvic lesion and increased liver mass. To our knowledge, this is the first report of lethal GP with multifocal metastases. Our case confirms that GP should be regarded as a malignant potential tumor with behavior code of “1”, rather than a benign tumor of “0”.
doi:10.3748/wjg.v20.i41.15454
PMCID: PMC4223280  PMID: 25386095
Duodenal neoplasms; Gangliocytic neoplasms; Paraganglioma; Lymphatic metastasis; Treatment outcome
11.  Association between Helicobacter pylori infection and migraine: A meta-analysis 
World Journal of Gastroenterology : WJG  2014;20(40):14965-14972.
AIM: To quantify the association between Helicobacter pylori (H. pylori) infection and migraine.
METHODS: A systematic literature search of PubMed and EMBASE was conducted from inception to December 2013. Studies that provided data dealing with H. pylori infection in patients with migraine, as well as healthy controls, were selected. Meta-analysis was carried out using the odds ratio (OR) with a fixed or random effects model, and a 95%CI for the OR was calculated. An unconditional logistic regression model was used to analyze potential parameters related to H. pylori prevalence. Subgroup analyses were conducted as methods of detection and evidence grade.
RESULTS: Five case-control studies published between 2000 and 2013 were finally identified, involving 903 patients, with a total H. pylori infection rate of 39.31%. The prevalence of H. pylori infection was significantly greater in migraineurs than in controls (44.97% vs 33.26%, OR = 1.92, 95%CI: 1.05-3.51, P = 0.001). A sensitivity test indicated that no single study dominated the combined results. Univariate regression analysis found that publication year, geographical distribution and evidence grade were relevant to the results and were the main reason for the heterogeneity. Subgroup analysis found a significantly greater infection rate of H. pylori in Asian patients with migraine, but no statistically significant infection rate in European patients. The ORs were 3.48 (95%CI: 2.09-5.81, P = 0.000) and 1.19 (95%CI: 0.86-1.65, P = 0.288), respectively.
CONCLUSION: The pooled data suggest a trend of more frequent H. pylori infections in patients with migraine.
doi:10.3748/wjg.v20.i40.14965
PMCID: PMC4209561  PMID: 25356058
Helicobacter pylori; Migraine; Meta-analysis; Odds ratio; Subgroup analysis
12.  Effect of A disintegrin and metalloproteinase 10 gene silencing on the proliferation, invasion and migration of the human tongue squamous cell carcinoma cell line TCA8113 
Molecular Medicine Reports  2014;11(1):212-218.
The present study aimed to investigate the effect of A disintegrin and metalloproteinase 10 (ADAM10) gene silencing on the proliferation, migration and invasion of the human tongue squamous cell carcinoma cell line TCA8113. RNA interference was used to knock down the expression of ADAM10 in the TCA8113 cell line and the proliferation, migration and invasive ability of the treated cells were observed in vitro. The expression levels of epidermal growth factor receptor (EGFR) and E-cadherin in the treated cells were determined by western blot analysis. The proliferation, migration and invasion abilities of cells in the ADAM10 siRNA-treated group were significantly lower than those in the control groups (P<0.05). In addition, compared with the control groups, the expression levels of EGFR and E-cadherin in the ADAM10 siRNA-treated cells were significantly decreased (P<0.05) and increased (P<0.05), respectively. These results suggested that ADAM10 is important in regulating the proliferation, invasion and migration of the human tongue squamous cell carcinoma cell line TCA8113 and that the mechanism may, at least in part, be associated with the upregulation of EGFR and the downregulation of E-cadherin.
doi:10.3892/mmr.2014.2717
PMCID: PMC4237091  PMID: 25333745
TCA8113; A disintegrin and metalloproteinase 10; proliferation; migration; invasion
13.  RANKL Promotes Migration and Invasion of Hepatocellular Carcinoma Cells via NF-κB-Mediated Epithelial-Mesenchymal Transition 
PLoS ONE  2014;9(9):e108507.
Background
Metastasis accounts for the most deaths in patients with hepatocellular carcinoma (HCC). Receptor activator of nuclear factor kappa B ligand (RANKL) is associated with cancer metastasis, while its role in HCC remains largely unknown.
Methods
Immunohistochemistry was performed to determine the expression of RANK in HCC tissue (n = 398). Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to examine the expression of RANK, E-cadherin, N-cadherin, vimentin, Snail, Slug, Twist and MMPs in HCC cells. Wound healing and Transwell assays were used to evaluate cell migration and invasion ability.
Results
We found that expression of RANK, the receptor of RANKL, was significantly higher in HCC tumor tissues than in peritumor liver tissues (p<0.001). Constitutive expression of RANK was detected in HCC cell lines, which can be up-regulated when HCC cells were stimulated with RANKL. Notably, in vitro experiments showed that activation of RANKL-RANK axis significantly promoted migration and invasion ability of HCC cells. In addition, RANKL stimulation increased the expression levels of N-cadherin, Snail, and Twist, while decreased the expression of E-cadherin, with concomitant activation of NF-κB signaling pathway. Moreover, administration of the NF-κB inhibitor attenuated RANKL-induced migration, invasion and epithelial-mesenchymal transition of HCC cells.
Conclusions
RANKL could potentiate migration and invasion ability of RANK-positive HCC cells through NF-κB pathway-mediated epithelial-mesenchymal transition, which means that RANKL-RANK axis could be a potential target for HCC therapy.
doi:10.1371/journal.pone.0108507
PMCID: PMC4182493  PMID: 25268581
14.  Measurement Properties of the Chinese Version of the Youth Quality of Life Instrument–Weight Module (YQOL-W) 
PLoS ONE  2014;9(9):e109221.
Background
Childhood obesity is a growing public health concern in China. It not only compromises physical health, but also has negative impacts on psychosocial well-being. As obesity rates increase, finding out what the perceptions of Chinese youth are regarding their weight is important for intervention planning and evaluation. However, there is a paucity of available obesity-specific instruments for children and adolescents in China and youth weight-specific quality of life (QOL) has been little reported. This study aimed to evaluate the measurement properties of the Chinese version of the Youth Quality of Life Instrument – Weight Module (YQOL-W).
Methods
The Chinese version of the YQOL-W was administered to 840 youth aged 11–18 from nine schools. Measurement properties including measurement model, reliability, validity and burden were evaluated.
Results
Confirmatory factor analysis showed that a three-factor model had acceptable model fit. The instrument had robust internal consistency reliability with Cronbach's α ranging from 0.84 to 0.96 and acceptable test-retest reliability with the intraclass correlation coefficients (ICCs) all higher than 0.7. The standard error of measurement (SEM) values for the Self, Social and Environment factors and total score were 10.352, 9.526, 12.086 and 8.425, respectively. The small real differences (SRDs) for the Self, Social and Environment factors and total score were 28.675, 26.387, 33.478, and 23.337, respectively. The Pearson's correlation coefficients between the YQOL-W and the PedsQL4.0 General Core Scales were stronger between comparable dimensions than those between less comparable dimensions, demonstrating convergent and discriminant evidence of construct validity. Significant differences were found in subscale and total scores across weight status, age and genders (P<0.01), supporting the known-groups validity of the instrument.
Conclusion
The Chinese version of the YQOL-W has acceptable measurement properties and can be used to assess the weight-specific QOL of children and adolescents in China.
doi:10.1371/journal.pone.0109221
PMCID: PMC4182632  PMID: 25268884
15.  Association of Gestational Diabetes Mellitus (GDM) with subclinical atherosclerosis: a systemic review and meta-analysis 
Background
Gestational diabetes mellitus (GDM) is associated with an elevated risk of adverse health outcomes such as type 2 diabetes and cardiovascular diseases. Carotid intima-media thickness (cIMT) is increasingly used as a noninvasive marker for subclinical atherosclerosis. Whether there is a direct correlation between GDM and elevated cIMT is still controversial.
Methods
PubMed, Embase and reference lists of relevant papers were reviewed. Studies assessing the relationship between GDM and cIMT were included. Weighted Mean Difference (WMD) of cIMT was calculated using random-effect models.
Results
Fifteen studies with a total of 2247 subjects were included in our analysis, giving a pooled WMD of 0.05 (95% confidence interval [CI] 0.03 –0.07). Furthermore, meta regression and subgroup analysis found that the association between GDM and larger cIMT already existed during pregnancy, and this relation was stronger in obese GDM patients.
Conclusions
GDM in and after pregnancy is associated with subclinical atherosclerosis. Weight control may be helpful to prevent cardiovascular diseases for GDM patients.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2261-14-132) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2261-14-132
PMCID: PMC4192280  PMID: 25266849
Gestational diabetes mellitus; Carotid intima-media thickness; Atherosclerosis
16.  MicroRNA-183 inhibits apoptosis and promotes proliferation and invasion of gastric cancer cells by targeting PDCD4 
MicroRNA plays an important role in multiple processes of cancer development. Aberrant expression of miR-183 has been frequently reported in a variety of cancer types; however, the roles and mechanisms of miR-183 in gastric cancer are largely unknown. Here, we report that miR-183 is significantly up-regulated in human gastric tumor tissues compared to the adjacent normal tissues. Up-regulation of miR-183 is associated with advanced clinical stage, positive lymph node, deep stromal invasion, and distant metastasis in gastric cancer patients. We further demonstrated that miR-183 promotes gastric cancer cell growth in vitro by inhibition of apoptosis. Moreover, overexpression of miR-183 enhances gastric cancer cell migration and invasion. Mechanistically, we demonstrated that overexpression of miR-183 decreased, and inhibition of miR-183 increased the expression of PDCD4, a tumor suppressor, at both mRNA and protein levels. Taken together, our results suggest that miR-183 may modulate progression and metastatic potential of gastric cancer through inhibition of PDCD4 expression. miR-183 could serve as a potential biomarker for gastric cancer progression and a novel therapeutic target for gastric cancer treatment.
PMCID: PMC4211755  PMID: 25356105
Gastric cancer; miR-183; PDCD4; metastasis
17.  Upregulation of 5-Hydroxytryptamine Receptor Signaling in Coronary Arteries after Organ Culture 
PLoS ONE  2014;9(9):e107128.
Background
5-Hydroxytryptamine (5-HT) is a powerful constrictor of coronary arteries and is considered to be involved in the pathophysiological mechanisms of coronary-artery spasm. However, the mechanism of enhancement of coronary-artery constriction to 5-HT during the development of coronary artery disease remains to be elucidated. Organ culture of intact blood-vessel segments has been suggested as a model for the phenotypic changes of smooth muscle cells in cardiovascular disease.
Methodology/Principal Findings
We wished to characterize 5-HT receptor-induced vasoconstriction and quantify expression of 5-HT receptor signaling in cultured rat coronary arteries. Cumulative application of 5-HT produced a concentration-dependent vasoconstriction in fresh and 24 h-cultured rat coronary arteries without endothelia. 5-HT induced greater constriction in cultured coronary arteries than in fresh coronary arteries. U46619- and CaCl2-induced constriction in the two groups was comparable. 5-HT stimulates the 5-HT2A receptor and cascade of phospholipase C to induce coronary vasoconstriction. Calcium influx through L-type calcium channels and non-L-type calcium channels contributed to the coronary-artery constrictions induced by 5-HT. The contractions mediated by non-L-type calcium channels were significantly enhanced in cultured coronary arteries compared with fresh coronary arteries. The vasoconstriction induced by thapsigargin was also augmented in cultured coronary arteries. The decrease in Orai1 expression significantly inhibited 5-HT-evoked entry of Ca2+ in coronary artery cells. Expression of the 5-HT2A receptor, Orai1 and STIM1 were augmented in cultured coronary arteries compared with fresh coronary arteries.
Conclusions
An increased contraction in response to 5-HT was mediated by the upregulation of 5-HT2A receptors and downstream signaling in cultured coronary arteries.
doi:10.1371/journal.pone.0107128
PMCID: PMC4159325  PMID: 25202989
18.  Anesthetic manipulation in extreme airway stenosis: a case report 
Introduction
Anesthetic management with airway stenosis is challenging. Techniques for maintaining spontaneous respiration are required under sedative and analgesic conditions.
Case presentation
A 35-year-old Chinese woman presented to our hospital with difficulty breathing. Computerized tomography showed a tumor in the frontal area of her neck, which was causing extreme narrowing of her trachea. She was immediately scheduled for emergency surgery to remove the tumor. Fiberscopic intubation was carefully performed with dexmedetomidine sedation and remifentanil analgesia. Spontaneous respiration was successfully maintained.
Conclusion
In cases of extreme airway stenosis, intubation can be safely achieved with dexmedetomidine sedation and remifentanil analgesia.
doi:10.1186/1752-1947-8-292
PMCID: PMC4158769  PMID: 25186092
19.  Neddylation pathway is up-regulated in human intrahepatic cholangiocarcinoma and serves as a potential therapeutic target 
Oncotarget  2014;5(17):7820-7832.
Therapeutic intervention in neddylation pathway is an emerging area for cancer treatment. Herein, we evaluated the clinical relevance and therapeutic potential of targeting this pathway in intrahepatic cholangiocarcinoma (ICC). Immunohistochemistry of neddylation pathway components in a cohort of 322 cases showed that E1 (NAE1 and UBA3) and E2 (UBC12) enzymes, as well as global NEDD8 conjugation, were upregulated in over 2/3 of human ICC. Notably, NAE1 was identified as an independent prognosticator for postoperative recurrence (P=0.009) and a combination of NEDD8 and NAE1 provided a better power for predicting patient clinical outcomes. In vitro treatment with MLN4924, a small-molecule NEDD8-activating enzyme inhibitor, led to a dose-dependent decrease of viability in both established and primary cholangiocarcinoma cell lines. Additionally, MLN4924 exhibited at least additive effect when combined with cisplatin. By blocking cullins neddylation, MLN4924 inactivated Cullin-Ring ligase (CRL) and caused the accumulation of CRL substrates that triggered cell cycle arrest, senescence or apoptosis. Meanwhile, MLN4924 was well-tolerated and significantly inhibited tumor growth in xenograft model of cholangiocarcinoma. Taken together, our findings indicated that upregulated neddylation pathway was involved in ICC progression and interference in this pathway could be a promising target for ICC therapy.
PMCID: PMC4202163  PMID: 25229838
Intrahepatic cholangiocarcinoma; Neddylation; NEDD8; MLN4924; Cullin-Ring ligase
20.  Interaction of DNA repair gene polymorphisms and aflatoxin B1 in the risk of hepatocellular carcinoma 
Aflatoxin B1 (AFB1) is an important environmental carcinogen and can induce DNA damage and involve in the carcinogenesis of hepatocellular carcinoma (HCC). The deficiency of DNA repair capacity related to the polymorphisms of DNA repair genes might play a central role in the process of HCC tumorigenesis. However, the interaction of DNA repair gene polymorphisms and AFB1 in the risk of hepatocellular carcinoma has not been elucidated. In this study, we investigated whether six polymorphisms (including rs25487, rs861539, rs7003908, rs28383151, rs13181, and rs2228001) in DNA repair genes (XPC, XRCC4, XRCC1, XRCC4, XPD, XRCC7, and XRCC3) interacted with AFB1, and the gene-environmental interactive role in the risk of HCC using hospital-based case-control study (including 1486 HCC cases and 1996 controls). Genotypes of DNA repair genes were tested using TaqMan-PCR technique. Higher AFB1 exposure was observed among HCC patients versus the control group [odds ratio (OR) = 2.08 for medium AFB1 exposure level and OR = 6.52 for high AFB1 exposure level]. Increasing risk of HCC was also observed in these with the mutants of DNA repair genes (risk values were from 1.57 to 5.86). Furthermore, these risk roles would be more noticeable under the conditions of two variables, and positive interactive effects were proved in the followed multiplicative interaction analysis. These results suggested that DNA repair risk genotypes might interact with AFB1 in the risk of HCC.
PMCID: PMC4203246  PMID: 25337275
Aflatoxin B1; DNA repair gene; interaction effect; polymorphism; hepatocellular carcinoma
21.  Definition of the To Be Named Ligament and Vertebrodural Ligament and Their Possible Effects on the Circulation of CSF 
PLoS ONE  2014;9(8):e103451.
Few studies have been conducted specifically on the dense connective tissue located in the posterior medial part of the cervical epidural space. This study was undertaken to examine the presence of this connection between the cervical dura mater and the posterior wall of spinal canal at the level of C1–C2. 30 head-neck specimens of Chinese adults were used. Gross dissection was performed on the suboccipital regions of the 20 specimens. Having been treated with the P45 plastination method, 10 specimens were sliced (9 sagittal and 1 horizontal sections). As a result, a dense fibrous band was identified in the nuchal ligament of 29 specimens (except for one horizontal section case). This fascial structure arose from the tissue of the posterior border of the nuchal ligament and then projected anteriorly and superiorly to enter the atlantoaxial interspace. It was termed as to be named ligament (TBNL). In all 30 specimens the existence of a fibrous connection was found between the posterior aspect of the cervical dura mater and the posterior wall of the spinal canal at the level of the atlas to the axis. This fibrous connection was identified as vertebrodural ligament (VDL). The VDL was mainly subdivided into three parts, and five variations of VDL were identified. These two structures, TBNL and VDL, firmly link the posterior aspect of cervical dura mater to the rear of the atlas-axis and the nuchal region. According to these findings, the authors speculated that the movements of the head and neck are likely to affect the shape of the cervical dural sleeve via the TBNL and VDL. It is hypothesized that the muscles directly associated with the cervical dural sleeve, in the suboccipital region, may work as a pump providing an important force required to move the CSF in the spinal canal.
doi:10.1371/journal.pone.0103451
PMCID: PMC4118883  PMID: 25084162
22.  Development of a Freeze-Dried Fungal Wettable Powder Preparation Able to Biodegrade Chlorpyrifos on Vegetables 
PLoS ONE  2014;9(7):e103558.
Continuous use of the pesticide chlorpyrifos has resulted in harmful contaminations in environment and species. Based on a chlorpyrifos-degrading fungus Cladosporium cladosporioides strain Hu-01 (collection number: CCTCC M 20711), a fungal wettable powder preparation was developed aiming to efficiently remove chlorpyrifos residues from vegetables. The formula was determined to be 11.0% of carboxymethyl cellulose-Na, 9.0% of polyethylene glycol 6000, 5.0% of primary alcohol ethoxylate, 2.5% of glycine, 5.0% of fucose, 27.5% of kaolin and 40% of freeze dried fungi by response surface methodology (RSM). The results of quality inspection indicated that the fungal preparation could reach manufacturing standards. Finally, the degradation of chlorpyrifos by this fungal preparation was determined on pre-harvest cabbage. Compared to the controls without fungal preparation, the degradation of chlorpyrifos on cabbages, which was sprayed with the fungal preparation, was up to 91% after 7 d. These results suggested this freeze-dried fungal wettable powder may possess potential for biodegradation of chlorpyrifos residues on vegetables and provide a potential strategy for food and environment safety against pesticide residues.
doi:10.1371/journal.pone.0103558
PMCID: PMC4111614  PMID: 25061758
23.  Synthesized Attributes of Water Use by Regional Vegetation: A Key to Cognition of “Water Pump” Viewpoint 
The Scientific World Journal  2014;2014:954849.
Recently, the frequent seasonal drought in Southwest China has brought considerable concerns and continuous heated arguments on the “water pump” viewpoint (i.e., the water demand from Hevea spp. and Eucalyptus spp. can be treated as a water pump) once again. However, such viewpoint just focused on water consumption from vegetation transpiration and its ecoenvironment impacts, which had not considered other attributes of vegetation, namely, water saving and drought resistance, and hydrological regulation (water conservation) into consideration. Thus, in this paper, the synthesized attributes of regional vegetation water use had been mainly discussed. The results showed that the study on such aspects as the characters of water consumption from vegetation transpiration, the potential of water saving and drought resistance, and the effects of hydrological regulation in Southwest China lagged far behind, let alone the report on synthesized attributes of water utilization with the organic combination of the three aspects above or the paralleled analysis. Accordingly, in this paper, the study on the synthesized attributes of water use by regional vegetation in Southwest China was suggested, and the objectives of such a special study were clarified, targeting the following aspects: (i) characters of water consumption from transpiration of regional typical artificial vegetation; (ii) potential of water saving and drought resistance of regional typical artificial vegetation; (iii) effects of hydrological regulation of regional typical artificial vegetation; (iv) synthesized attributes of water use by regional typical artificial vegetation. It is expected to provide a new idea for the scientific assessment on the regional vegetation ecoenvironment effects and theoretical guidance for the regional vegetation reconstruction and ecological restoration.
doi:10.1155/2014/954849
PMCID: PMC4181508  PMID: 25302337
24.  Can Serum Levels of Alkaline Phosphatase and Phosphate Predict Cardiovascular Diseases and Total Mortality in Individuals with Preserved Renal Function? A Systemic Review and Meta-Analysis 
PLoS ONE  2014;9(7):e102276.
Background
It is demonstrated that elevated serum levels of alkaline phosphatase (ALP) and phosphate indicate a higher risks of cardiovascular disease (CVD) and total mortality in population with chronic kidney disease (CKD), but it remains unclear whether this association exists in people with normal or preserved renal function.
Method
Clinical trials were searched from Embase and PubMed from inception to 2013 December using the keywords “ALP”, “phosphate”, “CVD”, “mortality” and so on, and finally 24 trials with a total of 147634 patients were included in this study. Dose-response and semi-parametric meta-analyses were performed.
Results
A linear association of serum levels of ALP and phosphate with risks of coronary heart disease (CHD) events, CVD events and deaths was identified. The relative risk(RR)of ALP for CVD deaths was 1.02 (95% confidence interval [CI], 1.01–1.04). The RR of phosphate for CVD deaths and events was 1.05 (95% CI, 1.02–1.09) and 1.04 (95% CI: 1.03–1.06), respectively. A non-linear association of ALP and phosphate with total mortality was identified. Compared with the reference category of ALP and phosphate, the pooled RR of ALP for total mortality was 1.57 (95% CI, 1.27–1.95) for the high ALP group, while the RR of phosphate for total mortality was 1.33 (95% CI, 1.21–1.46) for the high phosphate group. It was observed in subgroup analysis that higher levels of serum ALP and phosphate seemed to indicate a higher mortality rate in diabetic patients and those having previous CVD. The higher total mortality rate was more obvious in the men and Asians with high ALP.
Conclusion
A non-linear relationship exists between serum levels of ALP and phosphate and risk of total mortality. There appears to be a positive association of serum levels of ALP/phosphate with total mortality in people with normal or preserved renal function, while the relationship between ALP and CVD is still ambiguous.
doi:10.1371/journal.pone.0102276
PMCID: PMC4102523  PMID: 25033287
25.  Cationic star-shaped polymer as an siRNA carrier for reducing MMP-9 expression in skin fibroblast cells and promoting wound healing in diabetic rats 
Background
Excessive expression of matrix metalloproteinase-9 (MMP-9) is deleterious to the cutaneous wound-healing process in the context of diabetes. The aim of the present study was to explore whether a cationic star-shaped polymer consisting of β-cyclodextrin (β-CD) core and poly(amidoamine) dendron arms (β-CD-[D3]7) could be used as the gene carrier of small interfering RNA (siRNA) to reduce MMP-9 expression for enhanced diabetic wound healing.
Methods
The cytotoxicity of β-CD-(D3)7 was investigated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MMT) method in the rat CRL1213 skin fibroblast cell line. The transfection efficiency of β-CD-(D3)7/MMP-9-small interfering RNA (siRNA) complexes was determined by confocal microscopy and flow cytometry. Quantitative real time (RT) polymerase chain reaction was performed to measure the gene expression of MMP-9 after the transfection by β-CD-(D3)7/MMP-9-siRNA complexes. The β-CD-(D3)7/MMP-9-siRNA complexes were injected on the wounds of streptozocin-induced diabetic rats. Wound closure was measured on days 4 and 7 post-wounding.
Results
β-CD-(D3)7 exhibited low cytotoxicity in fibroblast cells, and easily formed the complexes with MMP-9-siRNA. The β-CD-(D3)7/MMP-9-siRNA complexes were readily taken up by fibroblast cells, resulting in the downregulation of MMP-9 gene expression (P<0.01). Animal experiments revealed that the treatment by β-CD-(D3)7/MMP-9-siRNA complexes enhanced wound closure in diabetic rats on day 7 post-wounding (P<0.05).
Conclusion
β-CD-(D3)7 may be used as an efficient carrier for the delivery of MMP-9-siRNA to reduce MMP-9 expression in skin fibroblast cells and promote wound healing in diabetic rats.
doi:10.2147/IJN.S66368
PMCID: PMC4106967  PMID: 25075185
gene carrier; small interfering RNAs; matrix metalloproteinase-9; diabetic foot ulceration

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