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Articles by G Wang
Total Records ( 13 ) for G Wang
  X Li , C Dong , S Shi , G Wang , Y Li , X Wang , Q Shi , C Tian , R Zhou , C Gao and X. Dong
 

Prion protein (PrP) is considered to associate with microtubule and its major component, tubulin. In the present study, octarepeat region of PrP (PrP51–91) was expressed in prokaryotic-expressing system. Using GST pull-down assay and co-immunoprecipitation, the molecular interaction between PrP51–91 and tubulin was observed. Our data also demonstrated that PrP51–91 could efficiently stimulate microtubule assembly in vitro, indicating a potential effect of PrP on microtubule dynamics. Moreover, PrP51–91 was confirmed to be able to antagonize Cu2+-induced microtubule-disrupting activity in vivo, partially protecting against Cu2+ intoxication to culture cells and stabilize cellular microtubule structure. The association of the octarepeat region of PrP with tubulin may further provide insight into the biological function of PrP in the neurons.

  D Han , Y Ding , S. L Liu , G Wang , I. C Si , X Wang , L Cui and D. Huang
 

Fas ligand (FasL) may play an important role in maintaining the immune privilege of intervertebral disc (IVD). Besides, it is closely related to the apoptosis of degenerative disc cells. Nowadays, lots of reports have described about the paradoxical effects of FasL, although the effect of FasL on IVD cells is still under debate. In this study, we tried to investigate the effects of FasL on Fas expression and on the apoptosis of nucleus pulposus (NP) cells in Sprague–Dawley rats. The results showed that the expression of Fas in NP cells was significantly increased by the recombinant FasL. Meanwhile, the apoptosis of NP cells increased markedly in a FasL dose-dependent manner. Interestingly, RNA interference results indicated that the increase of Fas expression and the NP cell apoptosis described previously were inhibited by Fas siRNA, suggesting that RNA interference might be one of novel strategies to prevent IVD cells from apoptosis.

  Y Chang , H Zheng , Y Shang , Y Jin , G Wang , X Shen and X. Liu
 

The prototypic foot-and-mouth disease virus (FMDV) was shown more than a century ago to be the first filterable agent capable of causing FMD, and it has served as an important model for studying basic principles of Aphthovirus molecular biology. However, the complex structure and antigenic diversity of FMDV have posed a major obstacle to the attempts at manipulating the infectious virus by reverse genetic techniques. Here, we report the recovery of infectious FMDV from cDNAs based on an efficient in vivo RNA polymerase I (polI) transcription system. Intracellular transcription of the full-length viral genome from polI-based vectors resulted in efficient formation of infectious virus displaying a genetic marker. Compared with wild-type virus, an abundance of genomic mRNA and elevated expression levels of viral antigens were indicative of the hyperfunction throughout the life-cycle of this cDNA-derived virus at transcription, replication, and translation levels. The technology described here could be an extremely valuable molecular biology tool for studying FMDV complex infectious characteristics. It is an operating platform for studying FMDV functional genomics, molecular mechanism of pathogenicity and variation, and lays a solid foundation for the development of viral chimeras toward the prospect of a genetically engineered vaccine.

  G Wang , X Zhou , Y Bai , Z Zhang and D. Zhao
 

Prion diseases are infectious and fatal neurodegenerative disorders. The cellular prion protein (PrPC) converting into misfolded isoform of prion protein (PrPSc) is responsible for prion disease infection. Immune system plays an important role in facilitating the spread of prion infections from the periphery to the central nervous system. Macrophages were considered associated with the transportation and replication of PrPSc. So, understanding the PrPC trafficking in macrophages is important to explore the transport mechanism for PrPSc. Here, we isolated exosomes from the culture medium of Ana-1 macrophage cell line and investigated the PrPC trafficked by exosomes and the interaction of PrPC with Hsp70 in secreted exosomes by western blotting, immunoelectron microscopy, and co-immunoprecipitation. The results showed that the isolated vesicles from the culture medium of macrophages were characterized by exosomes and bore PrPC. And PrPC bound to Hsp70 both in intracellular environment and secreted exosomes. In contrast, PrPC had no interaction with marker proteins of exosomes, Tag101 and Flotillin-1. These results suggested that PrPC present in extracellular space might be externalized through secreted exosomes from macrophages, and Hsp70 may play roles in the process of PrPC released via secreted exosomes.

  L Fan , F Zhang , G Wang and Z. Liu
 

Motivation: EMAN is one of the most popular software packages for single particle reconstruction. But the particle clusters produced during its model refining stage are of low qualities. We attempt to refine the particle clusters by more accurately determining orientations of particles, and thereby achieving higher resolutions of consequent 3D structures.

Results: A particle reclustering framework (PRF) is introduced, which consists of three components. Each of them is responsible for one of the basic tasks of PRF: normalization, threshold determination and reclustering. Our implementation is also described and proved to meet the constraints proposed by PRF. Experiments revealed that our implementation improved resolutions of consequent structures for most cases, but only a little extra execution time was incurred. Therefore, it is practical to incorporate PRF in EMAN to improve qualities of generated 3D structures.

Availability and Implementation: Implementation of our algorithm is available upon request from the authors.

Contact: fanliya@ict.ac.cn; zf@ncic.ac.cn

  T Zhou , S Wang , H Ren , X. R Qi , S Luchetti , W Kamphuis , J. N Zhou , G Wang and D. F. Swaab
 

The recently discovered dendritic cell nuclear protein-1 is the product of a novel candidate gene for major depression. The A allele encodes full-length dendritic cell nuclear protein-1, while the T allele encodes a premature termination of translation at codon number 117 on chromosome 5. In the present study we investigate whether the two forms of dendritic cell nuclear protein-1 might act on corticotropin-releasing hormone, which plays a crucial role in the stress response and in the pathogenesis of depression. The messenger RNA expression of dendritic cell nuclear protein-1 appeared to be increased in the laser micro-dissected paraventricular nucleus of patients with depression compared with control subjects. Dendritic cell nuclear protein-1 was also found to be co-localized with corticotropin-releasing hormone in paraventricular nucleus neurons. Moreover, full-length dendritic cell nucleus protein-1 bound to and transactivated the promoter of corticotropin-releasing hormone in human embryonic kidney 293 cells. We propose that full-length dendritic cell nucleus protein-1 may play a role in the pathogenesis of depressive disorders by enhancing corticotropin-releasing hormone expression in the hypothalamic paraventricular nucleus.

  A Zampetaki , L Zeng , A Margariti , Q Xiao , H Li , Z Zhang , A. E Pepe , G Wang , O Habi , E deFalco , G Cockerill , J. C Mason , Y Hu and Q. Xu
 

Background— Histone deacetylase 3 (HDAC3) is known to play a crucial role in the differentiation of endothelial progenitors. The role of HDAC3 in mature endothelial cells, however, is not well understood. Here, we investigated the function of HDAC3 in preserving endothelial integrity in areas of disturbed blood flow, ie, bifurcation areas prone to atherosclerosis development.

Methods and Results— En face staining of aortas from apolipoprotein E-knockout mice revealed increased expression of HDAC3, specifically in these branching areas in vivo, whereas rapid upregulation of HDAC3 protein was observed in endothelial cells exposed to disturbed flow in vitro. Interestingly, phosphorylation of HDAC3 at serine/threonine was observed in these cells, suggesting that disturbed flow leads to posttranscriptional modification and stabilization of the HDAC3 protein. Coimmunoprecipitation experiments showed that HDAC3 and Akt form a complex. Using a series of constructs harboring deletions, we found residues 136 to 206 of HDAC3 to be crucial in this interaction. Enforced expression of HDAC3 resulted in increased phosphorylation of Akt and upregulation of its kinase activity. In line with these findings, knockdown of HDAC3 with lentiviral vectors (shHDAC3) led to a dramatic decrease in cell survival accompanied by apoptosis in endothelial cells. In aortic isografts of apolipoprotein E-knockout mice treated with shHDAC3, a robust atherosclerotic lesion was formed. Surprisingly, 3 of the 8 mice that received shHDAC3-infected grafts died within 2 days after the operation. Miller staining of the isografts revealed disruption of the basement membrane and rupture of the vessel.

Conclusions— Our findings demonstrated that HDAC3 serves as an essential prosurvival molecule with a critical role in maintaining the endothelial integrity via Akt activation and that severe atherosclerosis and vessel rupture in isografted vessels of apolipoprotein E-knockout mice occur when HDAC3 is knocked down.

  J. D Turner , L. D Gaspers , G Wang and A. P. Thomas
 

Rationale: Uncoupling protein (UCP)2 is a mitochondrial inner membrane protein that is expressed in mammalian myocardium under normal conditions and upregulated in pathological states such as heart failure. UCP2 is thought to protect cardiomyocytes against oxidative stress by dissipating the mitochondrial proton gradient and mitochondrial membrane potential (m), thereby reducing mitochondrial reactive oxygen species generation. However, in apparent conflict with its uncoupling role, UCP2 has also been proposed to be essential for mitochondrial Ca2+ uptake, which could have a protective action by stimulating mitochondrial ATP production.

Objective: The goal of this study was to better understand the role of myocardial UCP2 by examining the effects of UCP2 on bioenergetics, Ca2+ homeostasis, and excitation-contraction coupling in neonatal cardiomyocytes.

Methods and Results: Adenoviral-mediated expression of UCP2 caused a mild depression of m and increased the basal rate of oxygen consumption but did not affect total cellular ATP levels. Mitochondrial Ca2+ uptake was examined in permeabilized cells loaded with the mitochondria-selective Ca2+ probe, rhod-2. UCP2 overexpression markedly inhibited mitochondrial Ca2+ uptake. Pretreatment with the UCP2-specific inhibitor genipin largely reversed the effects UCP2 expression on mitochondrial Ca2+ handling, bioenergetics, and oxygen utilization. Electrically evoked cytosolic Ca2+ transients and spontaneous cytosolic Ca2+ sparks were examined using fluo-based probes and confocal microscopy in line scan mode. UCP2 overexpression significantly prolonged the decay phase of [Ca2+]c transients in electrically paced cells, increased [Ca2+]c spark activity and increased the probability that Ca2+ sparks propagated into Ca2+ waves. This dysregulation results from a loss of the ability of mitochondria to suppress local Ca2+-induced Ca2+ release activity of the sarcoplasmic reticulum.

Conclusion: Increases in UCP2 expression that lower m and contribute to protection against oxidative stress, also have deleterious effects on beat-to-beat [Ca2+]c handling and excitation-contraction coupling, which may contribute to the progression of heart disease.

  C. C Szeto , B. C. H Kwan , K. B Lai , F. M. M Lai , K. M Chow , G Wang , C. C. W Luk and P. K. T. Li
 

Background and objectives: The outcome of renal transplantation after an episode of acute rejection is difficult to predict, even with an allograft biopsy. We examined whether urinary expression of specific biomarker mRNA could be used as a noninvasive prognostic marker in kidney transplant recipients.

Design, setting, participants, & measurements: We studied 63 kidney transplant recipients who require graft biopsy because of progressive worsening of kidney function. The mRNA of neutrophil gelatinase-associated lipocalin, kidney injury molecule-1 (KIM-1), IL-18, surfactant protein-C, and S100 calcium-binding proteins A8 and A9 in urinary sediment were quantified.

Results: Urinary expressions of neutrophil gelatinase-associated lipocalin, KIM-1, and IL-18, but not other target genes, were significantly different between histologic groups (P < 0.0001 for all). After followed for an average of 39.7 ± 21.1 months, the rate of renal function decline significantly correlated with urinary KIM-1 expression (r = –0.434, P = 0.0004) but not other target genes. At 48 months, the graft survival rate for the high and low KIM-1 groups were 46.2 and 78.6%, respectively. After adjusting for confounding variables, each log of higher urinary KIM-1 expression conferred an ~2.9-fold higher risk of developing graft failure (95% confidence interval, 1.3- to 6.2-fold; P = 0.006). The result remained similar when only patients with no acute cellular rejection were analyzed.

Conclusions: In kidney allograft recipients, urinary KIM-1 expression provides prognostic information in relation to the rate of renal function decline, irrespective of the kidney pathology.

  J Zheng , G Wang , G. Y Yang , D Wang , X Luo , C Chen , Z Zhang , Q Li , W Xu , Z Li and D. Wang
  Objective

This Phase II study was conducted to evaluate the activity and feasibility of a regimen of nedaplatin and 5-fluorouracil as induction chemotherapy, followed by intensity-modulated radiotherapy concurrent with chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma.

Methods

Patients received neoadjuvant chemotherapy comprised two cycles of 5-fluorouracil at 700 mg/m2/day administered on days 1–4 as continuous intravenous infusion and nedaplatin (100 mg/m2 administered i.v. over 2 h) given after the administration of 5-fluorouracil on day 1, repeated every 3 weeks, followed by intensity-modulated radiotherapy concurrent with nedaplatin. During intensity-modulated radiotherapy, nedaplatin was administered at a dose of 100 mg/m2 intravenous infusion on days 1, 22 and 43, given ~60 min before radiation.

Results

Fifty-nine (95.8%) of the 60 patients were assessable for response. Thirty-eight cases of complete response and 14 cases of partial response were confirmed after completion of chemoradiation, with the objective response rate of 86.7% (95% CI, 78.1–95.3%). The median follow-up period was 48 months (range, 30–62 months). The 3-year progression-free survival and overall survival were 75.0% (95% CI, 63.0–87.0%) and 85.5% (95% CI, 75.9–95.1%). No patient showed Grade 3 or higher renal dysfunction. The most commonly observed late effect was xerostomia, but the severity diminished over time, and the detectable xerostomia at 24 months was 10.2%. There were no treatment-related deaths during this study.

Conclusions

Neoadjuvant chemotherapy with nedaplatin and 5-fluorouracil followed by concomitant nedaplatin and intensity-modulated radiotherapy is an effective and safe treatment for Southern China patients affected by locoregionally advanced nasopharyngeal carcinoma.

  G Wang , F. M. M Lai , L. S Tam , E. K. M Li , B. C. H Kwan , K. M Chow , P. K. T Li and C. C. Szeto
 

Objective. Regulatory T lymphocytes (Tregs) probably play an important role in the pathogenesis of SLE.

Methods. We quantified messenger RNA (mRNA) expression of FOXP3, a critical regulator for the development and function of Tregs, in the urinary sediment of 25 subjects with active lupus nephritis (LN), 17 with inactive lupus and 7 healthy subjects.

Results. We found that the expression level of FOXP3 was significantly higher in urine from patients with active LN than from subjects with inactive lupus and healthy controls (24.5 ± 45.8 vs 0.8 ± 1.0 vs 0.6 ± 0.8 copy; P < 0.001). In the active group, urinary FOXP3 mRNA expression level was higher in patients with proliferative LN than non-proliferative nephritis (34.6 ± 56.3 vs 2.7 ± 2.1 copy; P = 0.019). Urinary FOXP3 mRNA level significantly correlated with SLEDAI (r = 0.668; P < 0.001) and proteinuria (r = 0.414; P = 0.006). In the active group, urinary FOXP3 mRNA level also significantly correlated with histological activity index (r = 0.541; P = 0.009) and marginally with intra-renal FOXP3 mRNA level (r = 0.360; P = 0.08). Urinary FOXP3 mRNA in patients with no response to therapy was higher than those with partial response or complete response (57.6 ± 69.8 vs 2.4 ± 1.9 copies; P = 0.02).

Conclusion. We concluded that urinary FOXP3 mRNA is markedly up-regulated in patients with active LN, and the level of expression is closely correlated with the clinical and histological disease activity. A high urinary FOXP3 mRNA in LN predicts a poor therapeutic response. Measurement of FOXP3 mRNA in urine sediment may be a non-invasive biomarker for assessing the severity and risk stratification in LN.

  S Laing , G Wang , T Briazova , C Zhang , A Wang , Z Zheng , A Gow , A. F Chen , S Rajagopalan , L. C Chen , Q Sun and K. Zhang
 

Recent studies have suggested a link between inhaled particulate matter (PM) exposure and increased mortality and morbidity associated with pulmonary and cardiovascular diseases. However, a precise understanding of the biological mechanism underlying PM-associated toxicity and pathogenesis remains elusive. Here, we investigated the impact of PM exposure in intracellular stress signaling pathways with animal models and cultured cells. Inhalation exposure of the mice to environmentally relevant fine particulate matter (aerodynamic diameter < 2.5 µm, PM2.5) induces endoplasmic reticulum (ER) stress and activation of unfolded protein response (UPR) in the lung and liver tissues as well as in the mouse macrophage cell line RAW264.7. Ambient PM2.5 exposure activates double-strand RNA-activated protein kinase-like ER kinase (PERK), leading to phosphorylation of translation initiation factor eIF2 and induction of C/EBP homologous transcription factor CHOP/GADD153. Activation of PERK-mediated UPR pathway relies on the production of reactive oxygen species (ROS) and is critical for PM2.5-induced apoptosis. Furthermore, PM2.5 exposure can activate ER stress sensor IRE1, but it decreases the activity of IRE1 in splicing the mRNA encoding the UPR trans-activator X-box binding protein 1 (XBP1). Together, our study suggests that PM2.5 exposure differentially activates the UPR branches, leading to ER stress-induced apoptosis through the PERK-eIF2-CHOP UPR branch. This work provides novel insights into the cellular and molecular basis by which ambient PM2.5 exposure elicits its cytotoxic effects that may be related to air pollution-associated pathogenesis.

 
 
 
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