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1.  Bone marrow mesenchymal stem cells promote osteosarcoma cell proliferation and invasion 
Background
Bone marrow-derived stem cells (BMSCs) are locally adjacent to the tumor tissues and may interact with tumor cells directly. The purpose of this study was to explore the effects of BMSCs on the proliferation and invasion of osteosarcoma cells in vitro and the possible mechanism involved.
Methods
BMSCs were co-cultured with osteosarcoma cells, and CCK-8 assay was used to measure cell proliferation. The ELISA method was used to determine the concentration of stromal cell-derived factor-1 (SDF-1) in the supernatants. Reverse transcription polymerase chain reaction (RT-PCR) was performed to detect the expression of CXCR4 in osteosarcoma cells and BMSCs. Matrigel invasion assay was performed to measure tumor cell invasion.
Results
SDF-1 was detected in the supernatants of BMSCs, but not in osteosarcoma cells. Higher CXCR4 mRNA levels were detected in the osteosarcoma cell lines compared to BMSCs. In addition, conditioned medium from BMSCs can promote the proliferation and invasion of osteosarcoma cells, and AMD3100, an antagonist for CXCR4, can significantly downregulate these growth-promoting effects.
Conclusions
BMSCs can promote the proliferation and invasion of osteosarcoma cells, which may involve the SDF-1/CXCR4 axis.
doi:10.1186/s12957-015-0465-1
PMCID: PMC4334855
Bone marrow mesenchymal stem cells; Osteosarcoma
2.  Emergence of human-like H3N2 influenza viruses in pet dogs in Guangxi, China 
Virology Journal  2015;12:10.
Background
After the 1968 H3N2 pandemic emerged in humans, H3N2 influenza viruses continuously circulated and evolved in nature. An H3N2 variant was circulating in humans in the 1990s and subsequently introduced into the pig population in the 2000s. This virus gradually became the main subtype of swine influenza virus worldwide. However, there were no reports of infections in dogs with this virus.
Findings
In 2013, 35 nasal swabs from pet dogs were positive for Influenza A virus by RT-PCR. Two viruses were isolated and genetically characterized. In the phylogenetic trees of all gene segments, two H3N2 canine isolates clustered with Moscow/10/99 and most H3N2 swine influenza viruses. These results indicated that two H3N2 CIVs possessed high homology with human/swine influenza viruses, which at the same time exhibited some amino acid substitutions in NA, polymerase basic protein 1 (PB1), and nucleoprotein (NP), which probably were related to the interspecies transmission.
Conclusions
These two viruses share the highest homology with swine H3N2, Moscow/99-like viruses, which indicated that these viruses might originate from swine viruses.
doi:10.1186/s12985-015-0243-2
PMCID: PMC4324672  PMID: 25645259
Pet dogs; H3N2 subtype; Human-like influenza viruses
3.  Efficacy of docetaxel combined with oxaliplatin and fluorouracil against stage III/IV gastric cancer 
World Journal of Gastroenterology : WJG  2014;20(48):18413-18419.
AIM: To investigate the clinical efficacy and toxic effects of neoadjuvant chemotherapy using docetaxel combined with oxaliplatin and fluorouracil for treating stage III/IV gastric cancer.
METHODS: A total of 53 stage III/IV gastric cancer patients were enrolled into the study and treated with neoadjuvant chemotherapy. Two of the cases were excluded. The program was as follows: 75 mg/m2 docetaxel and 85 mg/m2 oxaliplatin on day 1 and 1500 mg/m2 fluorouracil on days 1 to 3 for three weeks.
RESULTS: The tumour changes, postoperative remission rate, changes in the symptoms and adverse reactions were observed. The overall clinical efficacy (complete remission + partial remission) of the neoadjuvant chemotherapy was 62.7%. R0 radical resection was performed on 60.8% of the patients, with a remission rate (pathological complete response + pathological subtotal response + pathological partial response) of 74.2%. The Karnofksy score improved in 42 cases. The toxicity reactions mostly included myelosuppression, followed by gastrointestinal mucosal lesions, nausea, vomiting and diarrhoea.
CONCLUSION: Neoadjuvant chemotherapy consisting of docetaxel combined with oxaliplatin and fluorouracil is effective for stage III/IV gastric cancer. However, the treatment is associated with a high incidence of bone marrow suppression, which should be managed clinically.
doi:10.3748/wjg.v20.i48.18413
PMCID: PMC4277980  PMID: 25561810
Gastric cancer; Neoadjuvant chemotherapy; Docetaxel; Oxaliplatin
4.  Establishment of Human Patient-Derived Endometrial Cancer Xenografts in NOD scid Gamma Mice for the Study of Invasion and Metastasis 
PLoS ONE  2014;9(12):e116064.
Objective
Most endometrial cancers are detected early and have a good prognosis, while some endometrial cancers are highly invasive, metastasize early, and respond suboptimally to therapy. Currently, appropriate model systems to study the aggressive nature of these tumors are lacking. The objective of this study was to establish a mouse xenograft model of endometrial tumors derived from patients in order to study the biological aggressive characteristics that underlie invasion and metastasis.
Methods
Endometrial tumor tissue fragments (1.5 mm×1.5 mm) from patients undergoing surgery, were transplanted under the renal capsule of NOD scid gamma mice. After 6–8 weeks, tumors were excised and serially transplanted into additional mice for propagation. Immunohistochemical analysis of the tumors was done for various tumor markers.
Results
Four cases of different subtypes of endometrial cancer were grown and propagated in mice. Three of the four tumor cases invaded into the kidneys and to adjacent organs. While all tumors exhibited minimal to no staining for estrogen receptor α, progesterone receptor staining was observed for tumor grafts. In addition, levels and localization of E-cadherin, cytokeratin and vimentin varied depending on subtype. Finally, all tumor xenografts stained positively for urokinase plasminogen activator while 3 tumor xenografts, which showed invasive characteristics, stained positively for urokinase plasminogen activator receptor.
Conclusion
Endometrial tumors transplanted under the renal capsule exhibit growth, invasion and local spread. These tumors can be propagated and used to study aggressive endometrial cancer.
doi:10.1371/journal.pone.0116064
PMCID: PMC4277433  PMID: 25542024
5.  Changes in Birth Weight between 2002 and 2012 in Guangzhou, China 
PLoS ONE  2014;9(12):e115703.
Background
Recent surveillance data suggest that mean birth weight has begun to decline in several developed countries. The aim of this study is to examine the changes in birth weight among singleton live births from 2002 to 2012 in Guangzhou, one of the most rapidly developed cities in China.
Methods
We used data from the Guangzhou Perinatal Health Care and Delivery Surveillance System for 34108 and 54575 singleton live births with 28–41 weeks of gestation, who were born to local mothers, in 2002 and 2012, respectively. The trends in birth weight, small (SGA) and large (LGA) for gestational age and gestational length were explored in the overall population and gestational age subgroups.
Results
The mean birth weight decreased from 3162 g in 2002 to 3137 g in 2012 (crude mean difference, −25 g; 95% CI, −30 to −19). The adjusted change in mean birth weight appeared to be slight (−6 g from 2002 to 2012) after controlling for maternal age, gestational age, educational level, parity, newborn's gender and delivery mode. The percentages of SGA and LGA in 2012 were 0.6% and 1.5% lower than those in 2002, respectively. The mean gestational age dropped from 39.2 weeks in 2002 to 38.9 weeks in 2012. In the stratified analysis, we observed the changes in birth weight differed among gestational age groups. The mean birth weight decreased among very preterm births (28–31 weeks), while remained relatively stable among other gestational age subcategories.
Conclusions
Among local population in Guangzhou from 2002 to 2012, birth weight appeared to slightly decrease. The percentage of SGA and LGA also simultaneously dropped, indicating that newborns might gain a healthier weight for gestational age.
doi:10.1371/journal.pone.0115703
PMCID: PMC4274089  PMID: 25531295
6.  Prediction of clinical pharmacokinetics of AMG 181, a human anti-α4β7 monoclonal antibody for treating inflammatory bowel diseases 
The purpose of this study was to predict a safe starting dose of AMG 181, a human anti-α4β7 antibody for treating inflammatory bowel diseases, based on cynomolgus monkey pharmacokinetic (PK) and pharmacodynamic (PD) data. A two-compartment model with parallel linear and target-mediated drug disposition for AMG 181 PK in cynomolgus monkey was developed. The estimated parameters were allometrically scaled to predict human PK. An Emax PD model was used to relate AMG 181 concentration and free α4β7 receptor data in cynomolgus monkey. AMG 181 clinical doses were selected based on observed exposures at the no adverse effect level of 80 mg·kg−1 in monkeys, the predicted human exposures, and AMG 181 concentration expected to produce greater than 50% α4β7 receptor occupancy in humans. The predicted human AMG 181 clearance and central volume of distribution were 144 mL·day−1 and 2900 mL, respectively. The estimated EC50 for free α4β7 receptor was 14 ng·mL−1. At the 0.7 mg starting dose in humans, the predicted exposure margins were greater than 490,000 and AMG 181 concentrations were predicted to only briefly cover the free α4β7 receptor EC10. Predictions for both Cmax and AUC matched with those observed in the first-in-human study within the 7 mg subcutaneous to 420 mg intravenous dose range. The developed model aided in selection of a safe starting dose and a pharmacological relevant dose escalation strategy for testing of AMG 181 in humans. The clinically observed human AMG 181 PK data validated the modeling approach based on cynomolgus monkey data alone.
doi:10.1002/prp2.98
PMCID: PMC4317229
AMG 181; anti-α4β7; cell trafficking; Crohn’s disease; gut homing; human antibody; inflammatory bowel diseases; PK/PD predictions; T cells; ulcerative colitis; α4β7 integrin
7.  Associations of MTHFR C677T and MTRR A66G Gene Polymorphisms with Metabolic Syndrome: A Case-Control Study in Northern China 
Prior evidence indicates that homocysteine plays a role in the development of metabolic syndrome (MetS). Methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms are common genetic determinants of homocysteine levels. To investigate the associations of the MTHFR C677T and MTRR A66G polymorphisms with MetS, 692 Chinese Han subjects with MetS and 878 controls were recruited. The component traits of MetS and the MTHFR C677T and MTRR A66G genotypes were determined. A significant association was observed between the MTHFR 677T allele and increased risk of MetS, high fasting blood glucose, high waist circumference, and increasing number of MetS components. The MTRR A66G polymorphism was associated with an increased risk of MetS when combined with the MTHFR 677TT genotype, although there was no association found between MetS and MTRR A66G alone. Furthermore, the MTRR 66GG genotype was associated with high fasting blood glucose and triglycerides. Our data suggest that the MTHFR 677T allele may contribute to an increased risk of MetS in the northern Chinese Han population. The MTRR A66G polymorphism is not associated with MetS. However, it may exacerbate the effect of the MTHFR C677T variant alone. Further large prospective population-based studies are required to confirm our findings.
doi:10.3390/ijms151221687
PMCID: PMC4284672  PMID: 25429430
MTHFR; MTRR; polymorphism; metabolic syndrome; China
8.  miR-145 inhibits tumor growth and metastasis by targeting metadherin in high-grade serous ovarian carcinoma 
Oncotarget  2014;5(21):10816-10829.
High-grade serous ovarian carcinoma (HGSOC), the most common and aggressive subtype of epithelial ovarian cancer, is characterized by TP53 mutations and genetic instability. Using miRNA profiling analysis, we found that miR-145, a p53 regulated miRNA, was frequently down-regulated in HGSOC. miR-145 down-regulation was further validated in a large cohort of HGSOCs by qPCR. Overexpression of miR-145 in ovarian cancer cells significantly suppressed proliferation, migration and invasion in vitro and inhibited tumor growth and metastasis in vivo. Metadherin (MTDH) was subsequently identified as a direct target of miR-145, and was found to be significantly up-regulated in HGSOC. Furthermore, overexpression of MTDH rescued the inhibitory effects of miR-145 in ovarian cancer cells. Finally, we found that high level of MTDH expression correlated with poor prognosis of HGSOC. Therefore, lack of suppression of MTDH by miR-145 when p53 is dysfunctional leads to increased tumor growth and metastasis of HGSOC. Our study established a new link between p53, miR-145 and MTDH in the regulation of tumor growth and metastasis in HGSOC.
PMCID: PMC4279412  PMID: 25333261
miR-145; MTDH; p53; HGSOC; metastasis
9.  Reply of the Authors: Cellular senescence in usual type uterine leiomyoma 
Fertility and sterility  2010;94(2):e44-e440.
doi:10.1016/j.fertnstert.2010.04.069
PMCID: PMC4160159  PMID: 25221340
10.  Integrated analysis of long noncoding RNAs and mRNAs reveals their potential roles in the pathogenesis of uterine leiomyomas 
Oncotarget  2014;5(18):8625-8636.
Global expression profiling studies showed that miRNAs are aberrantly expressed in uterine leiomyomas (ULMs) and are involved in ULM pathogenesis. Long noncoding RNAs (lncRNAs) are another group of regulatory RNA whose expression and roles in ULMs have not been explored. In this study, we examined the global expressions of lncRNAs and mRNAs in ULMs using microarray and interrogated their interrelationship through co-expression analysis. We found that lncRNAs and mRNAs were dysregulated in ULMs and the degree of dysregulation was positively correlated with tumor size. Further analysis showed that lncRNAs correlate to their cis mRNAs in expression levels depending on genomic locations and orientations. Moreover, we identified several dysregulated pathways that were correlated to dysregulated lncRNAs. We validated several aberrantly expressed lncRNAs in extended samples and confirmed that AK023096 was down-regulated and chromatin-associated RNA (CAR) Intergenic 10 was up-regulated in the majority of leiomyomas. Knockdown of Intergenic 10 inhibited the proliferation of leiomyoma cells in vitro, indicating its functional importance in ULM pathogenesis. The neighboring protein-coding gene ADAM12 was also downregulated in Intergenic 10 knockdown leiomyoma cells. We showed for the first time that lncRNAs were dysregulated in uterine leiomyomas. Aberrantly expressed lncRNAs may contribute to the pathogenesis of uterine leiomyomas.
PMCID: PMC4226709  PMID: 25268745
lncRNA; protein coding genes; microarray; uterine leiomyoma,CAR Intergenic 10
11.  Endometriosis and Ovarian Cancer: A Review of Clinical, Pathologic, and Molecular Aspects 
Summary
Endometriosis is a chronic disease that affects millions of reproductive-age women. Despite the destructive and invasive nature of endometrioses, most cases are perpetually benign or eventually regress; however, atypical endometriosis is a precursor lesion and can lead to certain types of ovarian cancer. Endometriosis induced inflammation and auto- and paracrine production of sex steroid hormones contribute to ovarian tumorigenesis. These changes provide microenvironment necessary to accumulate enough genetic alterations for endometriosis associated malignant transformation. It takes years for endometriosis to undergo the pathophysiological progression that begins with atypical epithelial proliferation (atypical endometriosis and metaplasia), and then is followed by the formation of well-defined borderline tumors, and finally culminates in fully malignant ovarian cancer. This study is a review of the natural history of endometriosis and the role of microenvironments that favor the accumulation of genetic alterations and endometriosis-associated ovarian cancer progression.
doi:10.1097/PGP.0b013e31821f4b85
PMCID: PMC4130217  PMID: 21979592
Endometriosis; Genetic alterations; Inflammation; Ovarian cancer; Pathogenesis
12.  RAD51 potentiates synergistic effects of chemotherapy with PCI-24781 and cis-diamminedichloroplatinum on gastric cancer 
World Journal of Gastroenterology : WJG  2014;20(29):10094-10107.
AIM: To explore the efficacy of PCI-24781, a broad-spectrum, hydroxamic acid-derived histone deacetylase inhibitor, in the treatment of gastric cancer (GC).
METHODS: With or without treatment of PCI-24781 and/or cis-diamminedichloroplatinum (CDDP), GC cell lines were subjected to functional analysis, including cell growth, apoptosis and clonogenic assays. Chromatin immunoprecipitation and luciferase reporter assays were used to determine the interacting molecules and the activity of the enzyme. An in vivo study was carried out in GC xenograft mice. Cell culture-based assays were represented as mean ± SD. ANOVA tests were used to assess differences across groups. All pairwise comparisons between tumor weights among treatment groups were made using the Tukey-Kramer method for multiple comparison adjustment to control experimental-wise type I error rates. Significance was set at P < 0.05.
RESULTS: PCI-24781 significantly reduced the growth of the GC cells, enhanced cell apoptosis and suppressed clonogenicity, and these effects synergized with the effects of CDDP. PCI-24781 modulated the cell cycle and significantly reduced the expression of RAD51, which is related to homologous recombination. Depletion of RAD51 augmented the biological functions of PCI-24781, CDDP and the combination treatment, whereas overexpressing RAD51 had the opposite effects. Increased binding of the transcription suppressor E2F4 on the RAD51 promoter appeared to play a major role in these processes. Furthermore, significant suppression of tumor growth and weight in vivo was obtained following PCI-24781 treatment, which synergized with the anticancer effect of CDDP.
CONCLUSION: These data suggest that RAD51 potentiates the synergistic effects of chemotherapy with PCI-24781 and CDDP on GC.
doi:10.3748/wjg.v20.i29.10094
PMCID: PMC4123338  PMID: 25110436
Chemotherapy; Combination; Gastric cancer; Histone deacetylase inhibitor; Homologous recombination
13.  Imaging findings of primary gastric plasmacytoma: A case report 
World Journal of Gastroenterology : WJG  2014;20(29):10202-10207.
Primary gastric plasmacytoma (GP) is a rare extramedullary plasmacytoma with clinical and imaging features that are common among other gastric tumors, such as gastric adenocarcinomas, gastric stromal tumors, and lymphomas. Here, we present a histologically confirmed case of primary GP examined with biphasic computed tomography (CT), magnetic resonance imaging (MRI), and endosonography. A well-circumscribed extraluminal mass appearing as homogeneous attenuation/intensity with gradual enhancement was identified on biphasic enhancement CT and MRI. This mass was hyperintense on diffusion-weighted imaging and hypointense on the apparent diffusion coefficient map, implying that water diffusion in the mass was restricted. In addition, endosonography indicated a low echogenic mass in the gastric wall. These imaging findings increase the available knowledge about imaging of this disease and provide valuable information for differentiating primary GP from common gastric tumors.
doi:10.3748/wjg.v20.i29.10202
PMCID: PMC4123351  PMID: 25110449
Stomach; Plasmacytoma; Computed tomography, X-ray; Magnetic resonance imaging; Diffusion; Endosonography
14.  Cellular senescence in usual type uterine leiomyoma 
Fertility and sterility  2010;94(6):e80.
doi:10.1016/j.fertnstert.2010.08.012
PMCID: PMC4108170  PMID: 25067851
15.  Expression of CCL2 and CCR2 in the hippocampus and the interventional roles of propofol in rat cerebral ischemia/reperfusion 
The aim of the present study was to determine the roles of the chemotactic factor, chemokine ligand 2 (CCL2), and its receptor, chemokine receptor type 2 (CCR2), in the hippocampus of rats with cerebral ischemia/reperfusion injury. In total, 24 Sprague-Dawley rats, weighting 250–300 g, were randomly divided into three groups (n=8): Sham-operated (C group), cerebral ischemia/reperfusion injury (I/R group) and propofol-intervention (P group) groups. The rats were sacrificed at 6 h after the ischemia/reperfusion surgery, and the brains were obtained to isolate the hippocampus. The mRNA expression levels of CCL2 and CCR2 in the hippocampus were analyzed by quantitative polymerase chain reaction, while the protein expression levels of CCL2 and CCR2 were determined by western blot analysis. The expression levels of CCL2 and CCR2 in the procerebrum were markedly elevated in the I/R and P groups at 6 h after the ischemia/reperfusion surgery when compared with the C group (P<0.05). In addition, the mRNA expression levels of CCL2 and CCR2 decreased significantly in the P group as compared with that in the I/R group (P<0.05). Therefore, CCL2 and CCR2 may be involved in the mechanisms underlying cerebral ischemia/reperfusion injury, and propofol may protect the brain through regulating the expression of CCL2 and CCR2.
doi:10.3892/etm.2014.1757
PMCID: PMC4079442  PMID: 25009636
chemokine ligand 2; chemokine receptor type 2; cerebral ischemia/reperfusion; hippocampus
16.  Genome-wide transcription analyses in Mycobacterium tuberculosis treated with lupulone 
Brazilian Journal of Microbiology  2014;45(1):333-341.
Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, still causes higher mortality than any other bacterial pathogen until now. With the emergence and spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR-TB) strains, it becomes more important to search for alternative targets to develop new antimycobacterial drugs. Lupulone is a compound extracted from Hops (Hurnulus lupulus), which exhibits a good antimicrobial activity against M. tuberculosis with minimal inhibitory concentration (MIC) value of 10 μg/mL, but the response mechanisms of lupulone against M. tuberculosis are still poorly understood. In this study, we used a commercial oligonucleotide microarray to determine the overall transcriptional response of M. tuberculosis H37Rv triggered by exposure to MIC of lupulone. A total of 540 genes were found to be differentially regulated by lupulone. Of these, 254 genes were upregulated, and 286 genes were downregulated. A number of important genes were significantly regulated which are involved in various pathways, such as surface-exposed lipids, cytochrome P450 enzymes, PE/PPE multigene families, ABC transporters, and protein synthesis. Real-time quantitative RT-PCR was performed for choosed genes to verified the microarray results. To our knowledge, this genome-wide transcriptomics approach has produced the first insights into the response of M. tuberculosis to a lupulone challenge.
doi:10.1590/S1517-83822014005000032
PMCID: PMC4059319  PMID: 24948953
antimycobacterial avticity; lupulone; DNA microarray
17.  Advances in serous tubal intraepithelial carcinoma: correlation with high grade serous carcinoma and ovarian carcinogenesis 
Early serous carcinoma in fallopian tube or serous tubal intraepithelial carcinoma (STIC), an early lesion limited to the epithelium of the fallopian tube and firstly identified from specimen obtained by prophylactic salpingo-oophorectomy, has provided insight into pelvic high grade serous carcinoma (HGSC). Increasing evidence indicates that STIC is a likely precursor for HGSC and several studies have focused on this lesion and its clinical significance. This review addresses recent advances in recognizing STIC and its correlation with HGSC and ovarian carcinogenesis. It also describes evidence regarding the fallopian tube as a source of some HGSCs, the protocol for optimizing histological evaluation of the tubes, the spectrum of tubal lesions from benign to noninvasive carcinoma, changes in diagnostic criteria from purely morphologic characteristics to a combination of morphologic features and molecular biomarkers, and new studies about potential biomarkers. However, the direct evidence regarding STIC as the precursor of HGSC is still tantalizing due to other possibilities that may also explain the origin of pelvic HGSC. Further molecular genetic studies are required to address this important question.
PMCID: PMC3971287  PMID: 24696706
Serous tubal intraepithelial carcinoma; fallopian tube; high grade serous carcinoma; ovarian cancer; carcinogenesis
18.  miR-106a Represses the Rb Tumor Suppressor p130 to Regulate Cellular Proliferation and Differentiation in High-Grade Serous Ovarian Carcinoma 
Molecular cancer research : MCR  2013;11(11):1314-1325.
The degree of differentiation in human cancers generally reflects the degree of malignancy, with the most undifferentiated cancer being also the highest grade and the most aggressive. High-grade serous ovarian carcinomas (HGSOC) are poorly differentiated and fast-growing malignancies. The molecular mechanisms underlying the poor differentiation of HGSOC has not been completely characterized. Evidence suggests that miRNA, miR are dysregulated in HGSOC. Therefore, we focused on those miRNAs that are relevant to tumor differentiation. Expression profiling of miRNAs in HGSOC, indicated miR-106a and its family members were significantly upregulated. Upregulation of miR-106a was further validated by real-time reverse transcriptase PCR (qRT-PCR) and miRNA in situ hybridization in a large cohort of HGSOC specimens. Overexpression of miR-106a in benign and malignant ovarian cells significantly increased the cellular proliferation rate and expanded the side-population fraction. In particular, SKOV3 cells with miR-106a overexpression had significantly higher tumor initial/stem cell population (CD24- and CD133-positive cells) than control SKOV3 cells. Among many miR-106a predicated target genes, p130 (RBL2), an retinoblastoma (Rb) tumor suppressor family member, was not only confirmed as a specific target of miR-106a but also related to tumor growth and differentiation. The importance of mir-106a and RBL2 was further demonstrated in vivo, in which, SKOV3 cells overexpressing miR-106a formed poorly differentiated carcinomas and had reduced RBL2 levels. To our knowledge, this is the first study of miR-106a mediating proliferation and tumor differentiation in HGSOC.
Implications
The current study suggests that the RB tumor suppressor pathway is a critical regulator of growth and differentiation in HGSOC.
doi:10.1158/1541-7786.MCR-13-0131
PMCID: PMC3911890  PMID: 24045973
19.  Protective role of retinoid X receptor in H9c2 cardiomyocytes from hypoxia/reoxygenation injury in rats 
BACKGROUND:
Retinoid X receptor (RXR) plays a central role in the regulation of intracellular receptor signaling pathways. The activation of RXR has protective effect on H2O2-induced apoptosis of H9c2 ventricular cells in rats. But the protective effect and mechanism of activating RXR in cardiomyocytes against hypoxia/reoxygenation (H/R)-induced oxidative iniury are still unclear.
METHODS:
The model of H/R injury was established through hypoxia for 2 hours and reoxygenation for 4 hours in H9c2 cardiomyocytes of rats. 9-cis-retinoic acid (9-cis RA) was obtained as an RXR agonist, and HX531 as an RXR antagonist. Cultured cardiomyocytes were randomly divided into four groups: sham group, H/R group, H/R+9-cis RA -pretreated group (100 nmol/L 9-cis RA), and H/R+9-cis RA+HX531-pretreated group (2.5 μmol/L HX531). The cell viability was measured by MTT, apoptosis rate of cardiomyocytes by flow cytometry analysis, and mitochondrial membrane potential (ΔΨm) by JC-1 fluorescent probe, and protein expressions of Bcl-2, Bax and cleaved caspase-9 with Western blotting. All measurement data were expressed as mean±standard deviation, and analyzed using one-way ANOVA and the Dunnett test. Differences were considered significant when P was <0.05.
RESULTS:
Pretreatment with RXR agonist enhanced cell viability, reduced apoptosis ratio, and stabled ΔΨm. Dot blotting experiments showed that under H/R stress conditions, Bcl-2 protein level decreased, while Bax and cleaved caspase-9 were increased. 9-cis RA administration before H/R stress prevented these effects, but the protective effects of activating RXR on cardiomyocytes against H/R induced oxidative injury were abolished when pretreated with RXR pan-antagonist HX531.
CONCLUSION:
The activation of RXR has protective effects against H/R injury in H9c2 cardiomyocytes of rats through attenuating signaling pathway of mitochondria apoptosis.
doi:10.5847/wjem.j.issn.1920-8642.2014.02.008
PMCID: PMC4129884  PMID: 25215161
Retinoid X receptor; Cardiomyocytes; Apoptosis; Mitochondria; Hypoxia reoxygenation
20.  Profiling of MicroRNAs under Wound Treatment in Aquilaria sinensis to Identify Possible MicroRNAs Involved in Agarwood Formation 
Agarwood, a kind of highly valued non-timber product across Asia, is formed only when its resource trees -- the endangered genus Aquilaria are wounded or infected by some microbes. To promote the efficiency of agarwood production and protect the wild resource of Aquilaria species, we urgently need to reveal the regulation mechanism of agarwood formation. MicroRNAs (miRNAs) are a group of gene expression regulators with overwhelming effects on a large spectrum of biological processes. However, their roles in agarwood formation remain unknown. This work aimed at identifying possible miRNAs involved in the wound induced agarwood formation. In this study, the high-throughput sequencing was adopted to identify miRNAs and monitor their expression under wound treatment in the stems of A. sinensis. The miR171, miR390, miR394, miR2111, and miR3954 families remained at the reduced level two days after the treatment. 131 homologous miRNAs in the 0.5 h library showed over three-fold variation of read number compared with the control library, of which 12 exhibiting strong expression alterations were further confirmed by real-time quantitative PCR. Target prediction and annotation of the miRNAs demonstrated that the binding, metabolic process, catalytic activity, and cellular process are the most common functions of the predicted targets of these newly identified miRNAs in A.sinensis. The cleaveage sites of three newly predicted targets were verified by 5'RACE.
doi:10.7150/ijbs.8065
PMCID: PMC4007363  PMID: 24795531
microRNA; Agarwood; Aquilaria sinensis; wound; small RNA
21.  In Vitro Screening for Antihepatic Steatosis Active Components within Coptidis Rhizoma Alkaloids Extract Using Liver Cell Extraction with HPLC Analysis and a Free Fatty Acid-Induced Hepatic Steatosis HepG2 Cell Assay 
A high-throughput method was developed and applied to screen for the active antihepatic steatosis components within Coptidis Rhizoma Alkaloids Extract (CAE). This method was a combination of two previously described assays: HepG2 cell extraction with HPLC analysis and a free fatty acid-induced (FFA) hepatic steatosis HepG2 cell assay. Two alkaloids within CAE, berberine and coptisine, were identified by HepG2 cell extraction with HPLC analysis as high affinity components for HepG2. These alkaloids were also determined to be active and potent compounds capable of lowering triglyceride (TG) accumulation in the FFA-induced hepatic steatosis HepG2 cell assay. This remarkable inhibition of TG accumulation (P < 0.01) by berberine and coptisine occurred at concentrations of 0.2 μg/mL and 5.0 μg/mL, respectively. At these concentrations, the effect seen was similar to that of a CAE at 100.0 μg/mL. Another five alkaloids within CAE, palmatine, epiberberine, jateorhizine, columbamine, and magnoline, were found to have a lower affinity for cellular components from HepG2 cells and a lower inhibition of TG accumulation. The finding of two potent and active compounds within CAE indicates that the screening method we developed is a feasible, rapid, and useful tool for studying traditional Chinese medicines (TCMs) in treating hepatic steatosis.
doi:10.1155/2013/459390
PMCID: PMC3878276  PMID: 24454495
22.  Joint Estimation of 2D-DOA and Frequency Based on Space-Time Matrix and Conformal Array 
The Scientific World Journal  2013;2013:463828.
Each element in the conformal array has a different pattern, which leads to the performance deterioration of the conventional high resolution direction-of-arrival (DOA) algorithms. In this paper, a joint frequency and two-dimension DOA (2D-DOA) estimation algorithm for conformal array are proposed. The delay correlation function is used to suppress noise. Both spatial and time sampling are utilized to construct the spatial-time matrix. The frequency and 2D-DOA estimation are accomplished based on parallel factor (PARAFAC) analysis without spectral peak searching and parameter pairing. The proposed algorithm needs only four guiding elements with precise positions to estimate frequency and 2D-DOA. Other instrumental elements can be arranged flexibly on the surface of the carrier. Simulation results demonstrate the effectiveness of the proposed algorithm.
doi:10.1155/2013/463828
PMCID: PMC3876900  PMID: 24453856
23.  XAV939, a tankyrase 1 inhibitior, promotes cell apoptosis in neuroblastoma cell lines by inhibiting Wnt/β-catenin signaling pathway 
Background
Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. The present treatment including surgery, chemotherapy and radiation, which have only 40% long-term cure rates, and usually cause tumor recurrence. Thus, looking for new effective and less toxic therapies has important significance. XAV939 is a small molecule inhibitor of tankyrase 1(TNKS1). The objective of this study is to investigate the effect of XAV939 on the proliferation and apoptosis of NB cell lines, and the related mechanism.
Methods
In the present study, we used both XAV939 treatment and RNAi method to demonstrate that TNKS1 inhibition may be a potential mechanism to cure NB. MTT method was used for determining the cell viability and the appropriate concerntration for follow-up assays. The colony formation assay, Annexin V staining and cell cycle analysis were used for detecting colony forming ability, cell apoptosis and the percentage of different cell cycle. The Western blot was used for detecting the expression of key proteins of Wnt/ beta-catenin (Wnt/β-catenin) signaling pathway.
Results
The results showed that TNKS1 inhibition decreased the viability of SH-SY5Y, SK-N-SH and IMR-32 cells, induced apoptosis in SH-SY5Y as well as SK-N-SH cells, and led to the accumulation of NB cells in the S and G2/M phase of the cell cycle. Moreover, we demonstrated TNKS1 inhibition may in part blocked Wnt/β-catenin signaling and reduced the expression of anti-apoptosis protein. Finally, we also demonstrated that TNKS1 inhibition decreased colony formation in vitro.
Conclusions
These findings suggested that TNKS1 may be a potential molecule target for the treatment of NB.
doi:10.1186/1756-9966-32-100
PMCID: PMC3866601  PMID: 24308762
Neuroblastoma; Tankyrase 1; Wnt signaling; XAV939
24.  The Influence of Long Term Hydrochlorothiazide Administration on the Relationship between Renin-Angiotensin-Aldosterone System Activity and Plasma Glucose in Patients with Hypertension 
Objective. To observe the relationship between changes in renin-angiotensin-aldosterone system (RAAS) activity and blood plasma glucose after administration of hydrochlorothiazide (HCTZ) for one year in patients with hypertension. Methods. 108 hypertensive patients were given 12.5 mg HCTZ per day for one year. RAAS activity, plasma glucose levels, and other biochemical parameters, as well as plasma oxidized low density lipoprotein (oxLDL) levels, were measured and analyzed at baseline, six weeks, and one year after treatment. Results. After one year of treatment, the reduction in plasma glucose observed between the elevated plasma renin activity (PRA) group (−0.26 ± 0.26 mmol/L) and the nonelevated PRA group (−1.36 ± 0.23 mmol/L) was statistically significant (P < 0.05). The decrease of plasma glucose in the elevated Ang II group (−0.17 ± 0.18 mmol/L) compared to the nonelevated Ang II group (−1.07 ± 0.21 mmol/L) was statistically significant (P < 0.05). The proportion of patients with elevated plasma glucose in the elevated Ang II group (40.5%) was significantly higher than those in the nonelevated Ang II group (16.3%) (P < 0.05). The relative oxLDL level was not affected by the treatment. Conclusions. Changes in RAAS activity were correlated with changes in plasma glucose levels after one year of HCTZ therapy.
doi:10.1155/2013/434618
PMCID: PMC3852583  PMID: 24349612
25.  MicroRNA-20a Constrains p300-Driven Myocardial Angiogenic Transcription by Direct Targeting of p300 
PLoS ONE  2013;8(11):e79133.
Objective
To characterize downstream effectors of p300 acetyltransferase in the myocardium.
Background
Acetyltransferase p300 is a central driver of the hypertrophic response to increased workload, but its biological targets and downstream effectors are incompletely known.
Methods and Results
Mice expressing a myocyte-restricted transgene encoding acetyltransferase p300, previously shown to develop spontaneous hypertrophy, were observed to undergo robust compensatory blood vessel growth together with increased angiogenic gene expression. Chromatin immunoprecipitation demonstrated binding of p300 to the enhancers of the angiogenic regulators Angpt1 and Egln3. Interestingly, p300 overexpression in vivo was also associated with relative upregulation of several members of the anti-angiogenic miR-17∼92 cluster in vivo. Confirming this finding, both miR-17-3p and miR-20a were upregulated in neonatal rat ventricular myocytes following adenoviral transduction of p300. Relative expression of most members of the 17∼92 cluster was similar in all 4 cardiac chambers and in other organs, however, significant downregulation of miR-17-3p and miR-20a occurred between 1 and 8 months of age in both wt and tg mice. The decline in expression of these microRNAs was associated with increased expression of VEGFA, a validated miR-20a target. In addition, miR-20a was demonstrated to directly repress p300 expression through a consensus binding site in the p300 3′UTR. In vivo transduction of p300 resulted in repression both of p300 and of p300-induced angiogenic transcripts.
Conclusion
p300 drives an angiogenic transcription program during hypertrophy that is fine-tuned in part through direct repression of p300 by miR-20a.
doi:10.1371/journal.pone.0079133
PMCID: PMC3827282  PMID: 24236097

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