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Articles by J Yu
Total Records ( 12 ) for J Yu
  J Yang , X Liu , J Yu , L Sheng , Y Shi , Z Li , Y Hu , J Xue , L Wu , Y Liang , J Xia and D. Liang
 

Gene therapy has emerged as a promising approach for the lethal disorder of Duchenne muscular dystrophy (DMD). Using a novel non-viral delivery system, the human ribosomal DNA (hrDNA) targeting vector, we targeted a minidystrophin-GFP fusion gene into the hrDNA locus of HT1080 cells with a high site-specific integrated efficiency of 10–5, in which the transgene could express efficiently and continuously. The minidystrophin-GFP fusion protein was easily found to localize on the plasma membrane of HT1080 cells, indicating its possible physiologic performance. Our findings showed that the hrDNA-targeting vector might be highly useful for DMD gene therapy study.

  L He , H Zeng , F Li , J Feng , S Liu , J Liu , J Yu , J Mao , T Hong , A. F Chen , X Wang and G. Wang
 

Hyperhomocysteinemia (HHcy) has been associated with impaired vascular endothelial function. Our previous study demonstrated significantly higher secretion of the chemokine monocyte chemoattractant protein-1 from monocytes in response to lipopolysaccharide in patients with HHcy. In the present study, we investigated whether coronary endothelial function was damaged in patients with chronic HHcy (plasma level of homocysteine >15 µmol/l) and, if so, whether this impaired endothelial function is induced by the uncoupling of endothelial nitric oxide synthase (eNOS). When tetrahydrobiopterin levels are inadequate, eNOS is no longer coupled to l-arginine oxidation, which results in reactive oxygen species rather than nitric oxide production, thereby inducing vascular endothelial dysfunction. The 71 participants were divided into two groups, control (n = 50) and HHcy (n = 21). Quantification of coronary flow velocity reserve (CFVR) was after rest and after adenosine administration done by noninvasive Doppler echocardiography. Plasma levels of nitric oxide and tetrahydrobiopterin were significantly lower in patients with HHcy than in controls (99.54 ± 32.23 vs. 119.50 ± 37.68 µmol/l and 1.43 ± 0.46 vs. 1.73 ± 0.56 pmol/ml, all P < 0.05). Furthermore, CFVR was significantly lower in the HHcy than the control group (2.76 ± 0.49 vs. 3.09 ± 0.52, P < 0.05). In addition, plasma level of homocysteine was negatively correlated with CFVR. Chronic HHcy may contribute to coronary artery disease by inducing dysfunction of the coronary artery endothelium. The uncoupling of eNOS induced by HHcy in patients with chronic HHcy may explain this adverse effect in part.

  R Garzon , S Liu , M Fabbri , Z Liu , C. E.A Heaphy , E Callegari , S Schwind , J Pang , J Yu , N Muthusamy , V Havelange , S Volinia , W Blum , L. J Rush , D Perrotti , M Andreeff , C. D Bloomfield , J. C Byrd , K Chan , L. C Wu , C. M Croce and G. Marcucci
 

Aberrant DNA hypermethylation contributes to myeloid leukemogenesis by silencing structurally normal genes involved in hematopoiesis. MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression by targeting protein-coding mRNAs. Recently, miRNAs have been shown to play a role as both targets and effectors in gene hypermethylation and silencing in malignant cells. In the current study, we showed that enforced expression of miR-29b in acute myeloid leukemia cells resulted in marked reduction of the expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3B at both RNA and protein levels. This in turn led to decrease in global DNA methylation and reexpression of p15INK4b and ESR1 via promoter DNA hypomethylation. Although down-regulation of DNMT3A and DNMT3B was the result of a direct interaction of miR-29b with the 3' untranslated regions of these genes, no predicted miR-29b interaction sites were found in the DNMT1 3' untranslated regions. Further experiments revealed that miR-29b down-regulates DNMT1 indirectly by targeting Sp1, a transactivator of the DNMT1 gene. Altogether, these data provide novel functional links between miRNAs and aberrant DNA hypermethylation in acute myeloid leukemia and suggest a potentially therapeutic use of synthetic miR-29b oligonucleotides as effective hypomethylating compounds.

  T Holopainen , H Huang , C Chen , K. E Kim , L Zhang , F Zhou , W Han , C Li , J Yu , J Wu , G. Y Koh , K Alitalo and Y. He
 

The angiopoietin-1 (Ang1)/Tie2 signaling pathway is known to play an important role in the regulation of vascular maturation and maintenance of vessel integrity. In this study, we have investigated the effect of systemic Tie2 activation or inhibition on tumor growth and metastasis. We found that treatment with Ang1 delivered via an adenoviral vector promoted s.c. implanted tumor metastasis to the lungs. Ang1 treatment did not significantly increase vascular density in the tumors but induced enlargement of blood vessels in both the tumor and normal tissues, which increased tumor cell dissemination into the blood circulation. Ang1 also enhanced the formation of metastatic foci in the lungs when tumor cells were injected into the circulation via the tail vein. The effect of Ang1 on metastasis was validated by a simultaneous treatment with a soluble form of Tie2 (sTie2), which led to the suppression of Ang1-induced increase of tumor metastasis. Furthermore, using a highly metastatic tumor model, we confirmed that systemic treatment with sTie2 suppressed tumor metastasis to the lungs and lymph nodes, whereas tumor-associated angiogenesis and lymphangiogenesis were not significantly affected. This suggests that the Ang1/Tie2 signals contribute to tumor progression by increasing vascular entry and exit of tumor cells to facilitate tumor dissemination and establishment of metastases. [Cancer Res 2009;69(11):4656–64]

  Y Wang , J Li , Y Cui , T Li , K. M Ng , H Geng , H Li , X. s Shu , W Liu , B Luo , Q Zhang , T. S. K Mok , W Zheng , X Qiu , G Srivastava , J Yu , J. J.Y Sung , A. T.C Chan , D Ma , Q Tao and W. Han
 

Closely located at the tumor suppressor locus 16q22.1, CKLF-like MARVEL transmembrane domain-containing member 3 and 4 (CMTM3 and CMTM4) encode two CMTM family proteins, which link chemokines and the transmembrane-4 superfamily. In contrast to the broad expression of both CMTM3 and CMTM4 in normal human adult tissues, only CMTM3 is silenced or down-regulated in common carcinoma (gastric, breast, nasopharyngeal, esophageal, and colon) cell lines and primary tumors. CMTM3 methylation was not detected in normal epithelial cell lines and tissues, with weak methylation present in only 5 of 35 (14%) gastric cancer adjacent normal tissues. Furthermore, immunohistochemistry showed that CMTM3 protein was absent in 12 of 35 (34%) gastric and 1 of 2 colorectal tumors, which was well correlated with its methylation status. The silencing of CMTM3 is due to aberrant promoter CpG methylation that could be reversed by pharmacologic demethylation. Ectopic expression of CMTM3 strongly suppressed the colony formation of carcinoma cell lines. In addition, CMTM3 inhibited tumor cell growth and induced apoptosis with caspase-3 activation. Thus, CMTM3 exerts tumor-suppressive functions in tumor cells, with frequent epigenetic inactivation by promoter CpG methylation in common carcinomas. [Cancer Res 2009;69(12):5194–201]

  W. P Tsang , E. K.O Ng , S. S.M Ng , H Jin , J Yu , J. J.Y Sung and T. T. Kwok
 

H19 is an imprinted oncofetal non-coding RNA recently shown to be the precursor of miR-675. The pathophysiological roles of H19 and its mature product miR-675 to carcinogenesis have, however, not been defined. By quantitative reverse transcription–polymerase chain reaction, both H19 and miR-675 were found to be upregulated in human colon cancer cell lines and primary human colorectal cancer (CRC) tissues compared with adjacent non-cancerous tissues. Subsequently, the tumor suppressor retinoblastoma (RB) was confirmed to be a direct target of miR-675 as the microRNA suppressed the activity of the luciferase reporter carrying the 3'-untranslated region of RB messenger RNA that contains the miR-675-binding site. Suppression of miR-675 by transfection with anti-miR-675 increased RB expression and at the same time, decreased cell growth and soft agar colony formation in human colon cancer cells. Reciprocally, enhanced miR-675 expression by transfection with miR-675 precursor decreased RB expression, increased tumor cell growth and soft agar colony formation. Moreover, the inverse relationship between the expressions of RB and H19/miR-675 was also revealed in human CRC tissues and colon cancer cell lines. Our findings demonstrate that H19-derived miR-675, through downregulation of its target RB, regulates the CRC development and thus may serve as a potential target for CRC therapy.

  H. v Korn , J Yu , M. A Ohlow , B Huegl , W Schulte , A Wagner , G Wassmer , S Gruene , O Petek and B. Lauer
 

Background— Treatment of bifurcations is a complex problem. The clinical value of treating side branches is an unsolved problem in the field of interventional cardiology.

Methods and Results— We initiated a prospective randomized controlled trial. One hundred and ten patients with bifurcations were randomly assigned to 2 arms: Stenting of the main branch (MB, Taxus-stent, paclitaxel-eluting stents) and mandatory side branch (SB) percutaneous coronary intervention (PCI; kissing balloons) with provisional SB stenting (therapy A), or stenting of the MB (paclitaxel-eluting stents) with provisional SB-PCI only when the SB had a thrombolysis in myocardial infarction flow <2 (therapy B). The primary end point was target lesion revascularization. The mean ages were 66.8 years (A) versus 65.1 years (B, P=0.4), 71.4% (A) versus 77.8% were men (P=0.4), patients with diabetes were present in 25.0% versus 25.9% (P=0.9). The MB was left anterior descending artery in 80.4% versus 81.5% (A versus B, P=0.9). The SB-PCI and kissing balloon-PCI were performed according to the study protocol in 82.1%/73.2% versus 16.7%/13.0% (P<0.05 for both), while changing of the intended therapy was necessary in 17.9% versus 16.7% (A versus B, P=0.9). A final thrombolysis in myocardial infarction flow 3 (MB) was reached in all patients (groups A and B), final thrombolysis in myocardial infarction flow 3 (SB) was observed in 96.4% versus 88.9% (A versus B, P=0.3). Radiation time (min) and contrast medium (mL) were 14.2/210 (group A) versus 7.8/151.6 (group B; P for both <0.05). Six month – follow up: major adverse cardiac events was 23.2% (A) versus 24.1% (B, P=0.9), target lesion revascularization was 17.9% (A) versus 14.8% (B, P=0.7), and late lumen loss (MB) was 0.2 mm (A) versus 0.3 mm (B, P=0.5). In group B, no PCI of the SB was done during follow up.

Conclusion— A simple strategy using paclitaxel-eluting stents with only provisional SB-PCI may be of equal value to a more complex strategy with mandatory SB-PCI.

Clinical Trial Registration— URL: http://www.controlled.trials.com. Unique identifier: ISRCTN22637771.

  B Assmus , A Rolf , S Erbs , A Elsasser , W Haberbosch , R Hambrecht , H Tillmanns , J Yu , R Corti , D. G Mathey , C. W Hamm , T Suselbeck , T Tonn , S Dimmeler , T Dill , A. M Zeiher , V Schachinger and for the REPAIR AMI Investigators
 

Background— The aim of this study was to investigate the clinical outcome 2 years after intracoronary administration of autologous progenitor cells in patients with acute myocardial infarction (AMI).

Methods and Results— Using a double-blind, placebo-controlled, multicenter trial design, we randomized 204 patients with successfully reperfused AMI to receive intracoronary infusion of bone marrow–derived progenitor cells (BMC) or placebo medium into the infarct artery 3 to 7 days after successful infarct reperfusion therapy. At 2 years, the cumulative end point of death, myocardial infarction, or necessity for revascularization was significantly reduced in the BMC group compared with placebo (hazard ratio, 0.58; 95% CI, 0.36 to 0.94; P=0.025). Likewise, the combined end point death and recurrence of myocardial infarction and rehospitalization for heart failure, reflecting progression toward heart failure, was significantly reduced in the BMC group (hazard ratio, 0.26; 95% CI, 0.085 to 0.77; P=0.015). Intracoronary administration of BMC remained a significant predictor of a favorable clinical outcome by Cox regression analysis when adjusted for classical predictors of poor outcome after AMI. There was no evidence of increased restenosis or atherosclerotic disease progression after BMC therapy nor any evidence of increased ventricular arrhythmias or neoplasms. In addition, regional left ventricular contractility of infarcted segments, as assessed by MRI in a subgroup of patients at 2-year follow-up, was significantly higher in the BMC group compared with the placebo group (P<0.001).

Conclusions— Intracoronary administration of BMC is associated with a significant reduction of the occurrence of major adverse cardiovascular events maintained for 2 years after AMI. Moreover, functional improvements after BMC therapy may persist for at least 2 years. Larger studies focusing on clinical event rates are warranted to confirm the effects of BMC administration on mortality and progression of heart failure in patients with AMIs.

Clinical Trial Registration— clinicaltrials.gov. Identifier: NCT00279175.

  S Eleswarapu , X Ge , Y Wang , J Yu and H. Jiang
 

IGF-I is abundantly expressed in the liver under the stimulation of GH. We showed previously that expression of hepatocyte nuclear factor (HNF)-3, a liver-enriched transcription factor, was strongly stimulated by GH in bovine liver. In this study, we determined whether GH-increased HNF-3 might contribute to GH stimulation of IGF-I gene expression in bovine liver and the underlying mechanism. A sequence analysis of the bovine IGF-I promoter revealed three putative HNF-3 binding sites, which all appear to be conserved in mammals. Chromatin immunoprecipitation assays showed that GH injection increased binding of HNF-3 to the IGF-I promoter in bovine liver. Gel-shift assays indicated that one of the three putative HNF-3 binding sites, HNF-3 binding site 1, bound to the HNF-3 protein from bovine liver with high affinity. Cotransfection analyses demonstrated that this HNF-3 binding site was essential for the transcriptional response of the IGF-I promoter to HNF-3 in CHO cells and to GH in primary mouse hepatocytes. Using similar approaches, we found that GH increased binding of the signal transducer and activator of transcription 5 (STAT5) to the HNF-3 promoter in bovine liver, that this binding occurred at a conserved STAT5 binding site, and that this STAT5 binding site was necessary for the HNF-3 promoter to respond to GH. Taken together, these results suggest that in addition to direct action, GH-activated STAT5 may also indirectly stimulate IGF-I gene transcription in the liver by directly enhancing the expression of the HNF-3 gene.

  N Sidell , Y Feng , L Hao , J Wu , J Yu , M. A Kane , J. L Napoli and R. N. Taylor
 

Vascular endothelial growth factor (VEGF) and endometrial angiogenesis play a critical role in successful embryonic implantation. Despite many studies of the effects of estrogen and progesterone on VEGF expression, its focal regulation at the site of implantation is unknown. Retinoic acid (RA) has been reported to regulate VEGF in a variety of cell types. Because localized RA synthesis occurs within the periimplantation endometrium, we tested the possibility that RA regulates VEGF production in endometrial stromal cells. Using primary and telomerase-immortalized human endometrial stromal cells, we determined that RA alone did not alter constitutive levels of VEGF production, but markedly amplified secretion when the cells were cotreated with activators of VEGF gene transcription (12-O-tetradecanoyl phorbol-13-acetate, TPA; TGF-β; and IL-1β). Whereas TPA or TGF-β alone stimulated VEGF promoter activity and up-regulated mRNA levels, significant protein secretion was detected only after RA was added to the culture systems. Analysis of retinoids in secretory phase endometrial biopsies indicated that endogenous RA accumulated at concentrations sufficient to induce VEGF secretion. Polyribosome profile analysis showed that the addition of RA to transcriptional activators of VEGF shifted the translational suppressed VEGF mRNA transcripts into larger polyribosome complexes engaged in active translation. Although the precise mechanism(s) of the RA effect remains to be defined, it appears to be mediated by reactive oxygen species; the antioxidant N-acetylcysteine inhibited RA+TPA-stimulated secretion of VEGF by more than 80%. Together, our results demonstrate that in human endometrial stromal cells, RA can combine with transcriptional activators of VEGF to augment VEGF secretion through a translational mechanism of action mediated by reactive oxygen species. These findings suggest a link between the spatiotemporal changes of retinoid synthesis in the periimplantation stroma and the capacity to quickly up-regulate focal VEGF secretion needed to induce early angiogenic events of pregnancy.

  H Li , G Liu , J Yu , W Cao , V. G Lobo and J. Xie
 

Alternative pre-mRNA splicing is often controlled by cell signals, for example, those activating the cAMP-dependent protein kinase (PKA) or the Ca2+/calmodulin-dependent protein kinase IV (CaMKIV). We have shown that CaMKIV regulates alternative splicing through short CA repeats and hnRNP L. Here we use a splicing reporter that shows PKA/CaMKIV promotion of exon inclusion to select from exons containing random 13-nt sequences for RNA elements responsive to the kinases in cultured cells. This selection not only identified both PKA- and CaMKIV-responsive elements that are similar to the CaMKIV-responsive RNA element 1 (CaRRE1) or CA repeats, but also A-rich elements not previously known to respond to these kinases. Consistently, hnRNP L is identified as a factor binding the CA-rich elements. Analyses of the motifs in the highly responsive elements indicate that they are indeed critical for the kinase effect and are enriched in alternative exons. Interestingly, a CAAAAAA motif is sufficient for the PKA/CaMKIV-regulated splicing of the exon 16 of the CaMK kinase β1 (CaMKK2) transcripts, implying a role of this motif in signaling cross-talk or feedback regulation between these kinases through alternative splicing. Therefore, these experiments identified a group of RNA elements responsive to PKA and CaMKIV from in vivo selection. This also provides an approach for selecting RNA elements similarly responsive to other cell signals controlling alternative splicing.

  P. L Wright , J Yu , Y. P. P Di , R. J Homer , G Chupp , J. A Elias , L Cohn and W. C. Sessa
 

Nogo-B is a member of the reticulon family of proteins (RTN-4B) that is highly expressed in lung tissue; however, its function remains unknown. We show that mice with Th2-driven lung inflammation results in a loss of Nogo expression in airway epithelium and smooth muscle compared with nonallergic mice, a finding which is replicated in severe human asthma. Mice lacking Nogo-A/B (Nogo-KO) display an exaggerated asthma-like phenotype, and epithelial reconstitution of Nogo-B in transgenic mice blunts Th2-mediated lung inflammation. Microarray analysis of lungs from Nogo-KO mice reveals a marked reduction in palate lung and nasal clone (PLUNC) gene expression, and the levels of PLUNC are enhanced in epithelial Nogo-B transgenic mice. Finally, transgenic expression of PLUNC into Nogo-KO mice rescues the enhanced asthmatic-like responsiveness in these KO mice. These data identify Nogo-B as a novel protective gene expressed in lung epithelia, and its expression regulates the levels of the antibacterial antiinflammatory protein PLUNC.

 
 
 
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