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Articles by J Sun
Total Records ( 8 ) for J Sun
  W Yuan , J Guo , X Li , Z Zou , G Chen , J Sun , T Wang and D. Lu
 

It has been reported that phospholipase C-1 (PLC-1) plays an important protective role in hydrogen peroxide (H2O2)-induced pheochromocytoma (PC) 12 cells death. However, most studies have used high doses of H2O2 and the downstream targets of PLC-1 activation remain to be identified. The present study was designed to examine the roles of PLC-1 signaling pathway in the apoptosis of PC12 cells induced by low dose of H2O2, as well as the downstream factors involved in this pathway. Low-dose treatment of H2O2 resulted in PLC-1 tyrosine phosphorylation in a time-dependent manner and H2O2 killed the PC12 cells by inducing necrosis. In contrast, pretreatment of PC12 cells with U73122, a specific inhibitor of PLC, markedly increased the percentage of dead cells. The mode of cell death was converted to apoptosis as determined by Hoechst/PI nuclear staining and fluorescence microscopy. Western blot analysis demonstrated that the expression of Bcl-2 protein and the activation of pro-caspase-3 were not significantly affected by low dose of H2O2 alone. However, after pretreatment with U73122, Bcl-2 protein expression was dramatically decreased and the activation of pro-caspase-3 was significantly increased. We concluded that PLC-1 plays an important protective role in H2O2-induced PC12 cells death. Bcl-2 and caspase-3 probably participate in the signaling pathway as downstream factors.

  J Sun and D. Kong
 

Chromosomal DNA replication in eukaryotic cells is highly complicated and sophisticatedly regulated. Owing to its large size, a typical eukaryotic genome contains hundreds to tens of thousands of initiation sites called DNA replication origins where DNA synthesis takes place. Multiple initiation sites remove the constraint of a genome size because only a certain amount of DNA can be replicated from a single origin in a limited time. The activation of these multiple origins must be coordinated so that each segment of chromosomal DNA is precisely duplicated only once per cell cycle. Although DNA replication is a vital process for cell growth and its mechanism is highly conserved, recent studies also reveal significant diversity in origin structure, assembly of pre-replication complex (pre-RC) and regulation of replication initiation along evolutionary lines. The DNA replication origins in the fission yeast Schizosaccharomyces pombe are found to contain a second essential element that is bound by Sap1 protein besides the essential origin recognition complex-binding site. Sap1 is recently demonstrated to be a novel replication initiation protein that plays an essential role in loading the initiation protein Cdc18 to origins and thus directly participates in pre-RC formation. In this review, we summarize the recent advance in understanding how DNA replication origins are organized, how pre-RC is assembled and how DNA replication is initiated and regulated in yeast and metazoans.

  H Hayashi , H Nakagami , Y Takami , H Koriyama , M Mori , K Tamai , J Sun , K Nagao , R Morishita and Y. Kaneda
 

Objective— In the functional screening of a human heart cDNA library to identify a novel antiangiogenic factor, the prime candidate gene was "four-and-a-half LIM only protein-2" (FHL-2). The goal of this study is to clear the mechanism of antiangiogenic signaling of FHL-2 in endothelial cells (ECs).

Methods and Results— Overexpressed FHL-2 strongly inhibited vascular endothelial growth factor (VEGF)-induced EC migration. In the angiogenic signaling, we focused on sphingosine kinase-1 (SK1), which produces sphingosine-1-phosphate (S1P), a bioactive sphingolipid, as a potent angiogenic mediator in ECs. Immunoprecipitation and immunostaining analysis showed that FHL-2 might bind to SK1. Importantly, overexpression of FHL-2 in ECs inhibited VEGF-induced SK1 activity, phosphatidylinositol 3-kinase activity, and phosphorylation of Akt and eNOS. In contrast, overexpression of FHL-2 had no effect on S1P-induced Akt phosphorylation. Interestingly, VEGF stimulation decreased the binding of FHL-2 and SK1. Depletion of FHL-2 by siRNA increased EC migration accompanied with SK1 and Akt activation, and increased the expression of VEGF receptor-2 which further enhanced VEGF signaling. Furthermore, injection of FHL-2 mRNA into Xenopus embryos resulted in inhibition of vascular network development, assessed by in situ hybridization with endothelial markers.

Conclusions— FHL-2 may regulate phosphatidylinositol 3-kinase/Akt via direct suppression of the SK1-S1P pathway in ECs.

  S. L Zheng , V. L Stevens , F Wiklund , S. D Isaacs , J Sun , S Smith , K Pruett , K. E Wiley , S. T Kim , Y Zhu , Z Zhang , F. C Hsu , A. R Turner , J. E Johansson , W Liu , J. W Kim , B. L Chang , D Duggan , J Carpten , C Rodriguez , W Isaacs , H Gronberg and J. Xu
 

Single nucleotide polymorphisms (SNP) at 11q13 were recently implicated in prostate cancer risk by two genome-wide association studies and were consistently replicated in multiple study populations. To explore prostate cancer association in the regions flanking these SNPs, we genotyped 31 tagging SNPs in a ~110 kb region at 11q13 in a Swedish case-control study (Cancer of the Prostate in Sweden), including 2,899 cases and 1,722 controls. We found evidence of prostate cancer association for the previously implicated SNPs including rs10896449, which we termed locus 1. In addition, multiple SNPs on the centromeric side of the region, including rs12418451, were also significantly associated with prostate cancer risk (termed locus 2). The two groups of SNPs were separated by a recombination hotspot. We then evaluated these two representative SNPs in an additional ~4,000 cases and ~3,000 controls from three study populations and confirmed both loci at 11q13. In the combined allelic test of all four populations, P = 4.0 x 10–11 for rs10896449 at locus 1 and P = 1.2 x 10–6 for rs12418451 at locus 2, and both remained significant after adjusting for the other locus and study population. The prostate cancer association at these two 11q13 loci was unlikely confounded by prostate-specific antigen (PSA) detection bias because neither SNP was associated with PSA levels in controls. Unlike locus 1, in which no known gene is located, several putative mRNAs are in close proximity to locus 2. Additional confirmation studies at locus 2 and functional studies for both loci are needed to advance our knowledge on the etiology of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1815–20)

  B Hibbert , X Ma , A Pourdjabbar , E Holm , K Rayner , Y. X Chen , J Sun , L Filion and E. R. O'Brien
  Aims

Endothelial progenitor cells (EPCs) are circulating pluripotent vascular cells capable of enhancing re-endothelialization and diminishing neointima formation following arterial injury. Glycogen synthase kinase (GSK)-3β is a protein kinase that has been implicated in the regulation of progenitor cell biology. We hypothesized that EPC abundance and function could be enhanced with the use of an inhibitor of GSK-3β (GSKi), thereby resulting in improved arterial repair.

Methods and results

Human EPCs were expanded ex vivo, treated with a specific GSKi, and then assessed for both yield and functional characteristics by in vitro assays for adherence, apoptosis, and survival. In vivo functionality of treated human EPCs was assessed in immune-tolerant mice subjected to femoral artery wire injury. Re-endothelialization was assessed at 72 h and neointima formation at 7 and 14 days following injury. GSKi treatment resulted in an improvement in the yield of EPCs and a reduction in apoptosis in cells derived from both healthy controls and patients with coronary artery disease. Treatment also increased vascular endothelial growth factor secretion, up-regulated expression of mRNA for the -4 integrin subunit, and improved adhesion, an effect which could be abrogated with an -4 integrin blocking antibody. EPCs without or with ex vivo GSKi treatment enhanced re-endothelialization 72 h following injury as well as reduced neointima formation at 7 days (e.g. endothelial coverage: 7.2 ± 1.7% vs. 70.7 ± 5.8% vs. 87.2 ± 4.1%; intima to media ratios: 1.05 ± 0.19 vs. 0.39 ± 0.08 vs. 0.14 ± 0.02; P < 0.05 for all comparisons), an effect that was persistent at 14 days.

Conclusion

GSKi improves the functional profile of EPCs and is associated with improved re-endothelialization and reduced neointima formation following injury.

  J Sun , K Hartvigsen , M. Y Chou , Y Zhang , G. K Sukhova , J Zhang , M Lopez Ilasaca , C. J Diehl , N Yakov , D Harats , J George , J. L Witztum , P Libby , H Ploegh and G. P. Shi
 

Background— Adaptive immunity and innate immunity play important roles in atherogenesis. Invariant chain (CD74) mediates antigen-presenting cell antigen presentation and T-cell activation. This study tested the hypothesis that CD74-deficient mice have reduced numbers of active T cells and resist atherogenesis.

Methods and Results— In low-density lipoprotein receptor–deficient (Ldlr–/–) mice, CD74 deficiency (Ldlr–/–Cd74–/–) significantly reduced atherosclerosis and CD25+-activated T cells in the atheromata. Although Ldlr–/–Cd74–/– mice had decreased levels of plasma immunoglobulin (Ig) G1, IgG2b, and IgG2c against malondialdehyde-modified LDL (MDA-LDL), presumably as a result of impaired antigen-presenting cell function, Ldlr–/–Cd74–/– mice showed higher levels of anti–MDA-LDL IgM and IgG3. After immunization with MDA-LDL, Ldlr–/–Cd74–/– mice had lower levels of all anti–MDA-LDL Ig isotypes compared with Ldlr–/– mice. As anticipated, only Ldlr–/– splenocytes responded to in vitro stimulation with MDA-LDL, producing Th1/Th2 cytokines. Heat shock protein-65 immunization enhanced atherogenesis in Ldlr–/– mice, but Ldlr–/– Cd74–/– mice remained protected. Compared with Ldlr–/– mice, Ldlr–/–Cd74–/– mice had higher anti–MDA-LDL autoantibody titers, fewer lesion CD25+-activated T cells, impaired release of Th1/Th2 cytokines from antigen-presenting cells after heat shock protein-65 stimulation, and reduced levels of all plasma anti–heat shock protein-65 Ig isotypes. Cytofluorimetry of splenocytes and peritoneal cavity cells of MDA-LDL– or heat shock protein-65–immunized mice showed increased percentages of autoantibody-producing marginal zone B and B-1 cells in Ldlr–/–Cd74–/– mice compared with Ldlr–/– mice.

Conclusions— Invariant chain deficiency in Ldlr–/– mice reduced atherosclerosis. This finding was associated with an impaired adaptive immune response to disease-specific antigens. Concomitantly, an unexpected increase in the number of innate-like peripheral B-1 cell populations occurred, resulting in increased IgM/IgG3 titers to the oxidation-specific epitopes.

  Z. Q Chen , Y Zhao , Z. H Lu , X. Y Li , H. J Shi , J Sun and R. Patrick
  Background

A large number of sudden cardiac arrests occur annually, but the worldwide survival rate is less than 1%. Early initiation of bystander Cardiopulmonary resuscitation (CPR) would improve the survival rate of out-of-hospital sudden cardiac arrests. Students play an important role as bystanders on and off campus both now and in the future. So we wanted to investigate the awareness and attitudes towards CPR of Chinese students, in order to improve the dissemination of bystander CPR in China.

Methods

The survey was conducted by questionnaire in November 2007. We had chosen 3500 students from the city of Wuhan in China randomly according to the stratified cluster sampling technique.

Results

There were 3248 questionnaires answered, and 2763 questionnaires were considered valid. Few respondents reported that they had heard (28%) and studied (27%) of CPR, and only 3% of the respondents had attended a CPR course. The two major sources of information about CPR for Chinese students were television and books. Most respondents expressed a desire to learn CPR (77%), and were willing to disseminate CPR (73%).

Conclusion

Dissemination of CPR among Chinese students has not been executed satisfactorily. The finding highlights the importance of CPR dissemination and efforts should be made to provide more convenient, effective and attractive ways for the Chinese public, especially students, to learn CPR.

  J Sun , E. Y Yu , Y Yang , L. A Confer , S. H Sun , K Wan , N. F Lue and M. Lei
 

In budding yeast, Cdc13, Stn1, and Ten1 form a heterotrimeric complex (CST) that is essential for telomere protection and maintenance. Previous bioinformatics analysis revealed a putative oligonucleotide/oligosaccharide-binding (OB) fold at the N terminus of Stn1 (Stn1N) that shows limited sequence similarity to the OB fold of Rpa2, a subunit of the eukaryotic ssDNA-binding protein complex replication protein A (RPA). Here we present functional and structural analyses of Stn1 and Ten1 from multiple budding and fission yeast. The crystal structure of the Candida tropicalis Stn1N complexed with Ten1 demonstrates an Rpa2N–Rpa3-like complex. In both structures, the OB folds of the two components pack against each other through interactions between two C-terminal helices. The structure of the C-terminal domain of Saccharomyces cerevisiae Stn1 (Stn1C) was found to comprise two related winged helix–turn–helix (WH) motifs, one of which is most similar to the WH motif at the C terminus of Rpa2, again supporting the notion that Stn1 resembles Rpa2. The crystal structure of the fission yeast Schizosaccharomyces pombe Stn1N–Ten1 complex exhibits a virtually identical architecture as the C. tropicalis Stn1N–Ten1. Functional analyses of the Candida albicans Stn1 and Ten1 proteins revealed critical roles for these proteins in suppressing aberrant telomerase and recombination activities at telomeres. Mutations that disrupt the Stn1–Ten1 interaction induce telomere uncapping and abolish the telomere localization of Ten1. Collectively, our structural and functional studies illustrate that, instead of being confined to budding yeast telomeres, the CST complex may represent an evolutionarily conserved RPA-like telomeric complex at the 3' overhangs that works in parallel with or instead of the well-characterized POT1–TPP1/TEBP–β complex.

 
 
 
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