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Articles by G Chen
Total Records ( 10 ) for G Chen
  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.

  B Chen , Y Ma , R Meng , Z Xiong , C Zhang , G Chen , A Zhang and Y. Dong
 

Proteasome inhibitors are involved in cell cycle control, growth and inflammatory signaling, and transcriptional regulation of mitotic cells. A recent study has suggested that specific proteasome inhibitor MG132 may suppress cardiomyocyte hypertrophy in vitro. However, the underlying molecular mechanisms are not clear. In this study, we investigated the effects of long-term MG132 treatment on cardiac hypertrophy and the related molecular mechanisms in vivo. MG132 (0.1 mg/kg/day) was intraperitoneally injected to rats with abdominal aortic banding (AAB) for 8 weeks. Results showed that treatment with MG132 significantly attenuated left ventricular (LV) myocyte area, LV weight/body weight, and lung weight/body weight ratios, decreased LV diastolic diameter and wall thickness, and increased fractional shortening in AAB rats. AAB induced the phosphorylation of ERK1/2, JNK1, and p38 in cardiac myocytes. The elevated phosphorylation levels of ERK1/2 and JNK1 in AAB rats were significantly reversed by MG132 treatment. In conclusion, our results suggested that long-term treatment with MG132 attenuates pressure-overload-induced cardiac hypertrophy and improves cardiac function in AAB rats through regulation of ERK1/2 and JNK1 signaling pathways.

  X Zhang , Z Zhang , G Chen , M Zhao , D Wang , Z Du , Y Xu and X. Yu
 

Previous studies have shown that histone deacetylase inhibitors (HDACis) can kill cancer cells. In addition, HDACis can induce mitotic catastrophe in cancer cells due to insufficient localization of chromosomal passenger complex (CPC) to the centromere. However, the mechanisms behind these phenomena remain unclear. In this study, we found that a HDACi, FK228, affected multiple epigenetic modification characteristics of the centromere, including enhanced acetylation of histone H3 lysine 9 (H3K9), decreased trimethylation of H3K9, and decreased phosphorylation of histone H3 serine 10 (H3S10) and centromere protein A (CENP-A). These epigenetic changes implied that H3K9 hyperacetylation inhibits the CPC recruitment, induces impaired centromere assembly and function, and eventually leads to aberrant mitosis. These data suggested that hypoacetylation of histone in the pericentromere is the most important landmark for recruiting CPC and leading to the mitotic catastrophe in HDACi-induced killing of cancer cells.

  Q ZhuGe , M Zhong , W Zheng , G. Y Yang , X Mao , L Xie , G Chen , Y Chen , M. T Lawton , W. L Young , D. A Greenberg and K. Jin
 

A role for the Notch signalling pathway in the formation of arteriovenous malformations during development has been suggested. However, whether Notch signalling is involved in brain arteriovenous malformations in humans remains unclear. Here, we performed immunohistochemistry on surgically resected brain arteriovenous malformations and found that, compared with control brain vascular tissue, Notch-1 signalling was activated in smooth muscle and endothelial cells of the lesional tissue. Western blotting showed an activated form of Notch-1 in brain arteriovenous malformations, irrespective of clinical presentation and with or without preoperative embolization, but not in normal cerebral vessels from controls. In addition, the Notch-1 ligands Jagged-1 and Delta-like-4 and the downstream Notch-1 target Hes-1 were increased in abundance and activated in human brain arteriovenous malformations. Finally, increased angiogenesis was found in adult rats treated with a Notch-1 activator. Our findings suggest that activation of Notch-1 signalling is a phenotypic feature of brain arteriovenous malformations, and that activation of Notch-1 in normal vasculature induces a pro-angiogenic state, which may contribute to the development of vascular malformations.

  O Malkesman , D. R Austin , G Chen and H. K. Manji
  Oz Malkesman, Daniel R. Austin, Guang Chen, and Husseini K. Manji

Bipolar disorder (BD) affects a significant portion of the population of the world, yet there has been limited success in developing novel treatments for the disorder. One of the major reasons for this dearth is the absence of suitable animal models for BD. Traditionally, animal models of human phenomena have been evaluated based on similarity to the human syndrome, response to appropriately corresponding medications, and the degree to which a model supports a common mechanistic theory between the human disorder and the model itself. The following review emphasizes the use of ‘reverse translation’, drawing on patient-based findings to develop suitable animal models for BD. We highlight some examples of this strategy, emphasizing their construct validity as a starting point. These studies have produced informative models that have altered the expression of genes/pathways implicated in BD, including the point mutation D181A of mouse mitochondrial DNA polymerase (POLG), glutamate receptor 6 (GluR6),...

  M. M. W Chong , N Simpson , M Ciofani , G Chen , A Collins and D. R. Littman
 

The stability of a lineage program (cellular memory) is dependent on mechanisms that epigenetically maintain active or repressed states of gene expression (transcriptional memory). Although epigenetic silencing of genes has been clearly demonstrated from yeast to mammals, heritable maintenance of active transcription has been less clearly defined. To investigate the potential role of active transcriptional memory during lineage diversification, we employed targeted mutation of a positive-acting cis element in the Cd4 locus to determine the impact on CD4 expression and the differentiation of CD4+ helper T cells in mice. We show that the proximal enhancer (E4P) of Cd4 is essential for CD4 expression in immature CD4+8+ thymocytes. Futhermore, its loss resulted in reduced and unstable expression of CD4 in mature T cells. However, if the enhancer was deleted after cells had already committed to the helper T-cell lineage, CD4 expression remained high and was stable upon cell division. "Active" histone modifications, once initiated by E4P, were also propagated independently of the enhancer. Thus, E4P is responsible for establishing an epigenetically inherited active Cd4 locus in the helper T-cell lineage. To our knowledge, this is the first genetic demonstration of active transcriptional memory in mammalian cells.

  P. E Chen , M. L Errington , M Kneussel , G Chen , A. J Annala , Y. H Rudhard , G. F Rast , C. G Specht , C. M Tigaret , M. A Nassar , R. G.M Morris , T. V.P Bliss and R. Schoepfer
 

The NMDA receptor (NMDAR) subunit GluN1 is an obligatory component of NMDARs without a known functional homolog and is expressed in almost every neuronal cell type. The NMDAR system is a coincidence detector with critical roles in spatial learning and synaptic plasticity. Its coincidence detection property is crucial for the induction of hippocampal long-term potentiation (LTP). We have generated a mutant mouse model expressing a hypomorph of the Grin1N598R allele, which leads to a minority (about 10%) of coincidence detection-impaired NMDARs. Surprisingly, these animals revealed specific functional changes in the dentate gyrus (DG) of the hippocampal formation. Early LTP was expressed normally in area CA1 in vivo, but was completely suppressed at perforant path-granule cell synapses in the DG. In addition, there was a pronounced reduction in the amplitude of the evoked population spike in the DG. These specific changes were accompanied by behavioral impairments in spatial recognition, spatial learning, reversal learning, and retention. Our data show that minor changes in GluN1-dependent NMDAR physiology can cause dramatic consequences in synaptic signaling in a subregion-specific fashion despite the nonredundant nature of the GluN1 gene and its global expression.

  G Chen , Y Yang , O Frohlich , J. D Klein and J. M. Sands
 

Protein restriction and hypercalcemia result in a urinary concentrating defect in rats and humans. Previous tubular perfusion studies show that there is an increased active urea transport activity in the initial inner medullary (IM) collecting duct in low-protein diet (LPD) and vitamin D (Vit D) animal models. To investigate the possible mechanisms that cause the urinary concentrating defect and to clone the new active urea transporter, we employed a modified two-tester suppression subtractive hybridization (ttSSH) approach and examined gene expression induced by LPD and Vit D in kidney IM base. Approximately 600 clones from the subtracted library were randomly selected; 150 clones were further confirmed to be the true positive genes by slot blot hybridization with subtracted probes from LPD and Vit D and sent for DNA sequencing. We identified 10 channel/transporter genes that were upregulated in IM base in LPD and Vit D animal models; 8 were confirmed by real-time PCR. These genes include aquaporin 2 (AQP2), two-pore calcium channel protein 2, brain-specific organic cation transporter, Na+- and H+-coupled glutamine transporter, and solute carrier family 25. Nine genes are totally new, and twelve are uncharacterized hypothetical proteins. Among them, four genes were shown to be new transmembrane proteins as judged by Kyte-Doolittle hydrophobic plot analysis. ttSSH provides a useful method to identify new genes from two conditioned populations.

  J Xu , A. T De Jong , G Chen , H. K Chow , C. O Damaso , A Schwartz Mittelman and J. A. Shin
 

To explore the role of the HLH subdomain in bHLHZ proteins, we designed sets of minimalist proteins based on bHLHZ protein Max, bHLH/PAS protein Arnt and bZIP protein C/EBP. In the first, the Max bHLH and C/EBP leucine zipper were fused such that the leucine heptad repeats were not in register; therefore, the protein dimerization interface was disrupted. Max1bHLH-C/EBP showed little ability to activate transcription from the E-box (5'-CACGTG) in the yeast one-hybrid assay, and no E-box binding by quantitative fluorescence anisotropy. Max1bHLH-C/EBP's activity was significantly improved after library selection (three amino acids randomized between HLH and leucine zipper), despite the Max bHLH and C/EBP zipper still being out of register: a representative mutant gave a high nanomolar Kd value for E-box binding. Thus, selection proved to be a powerful tool for salvaging the flawed Max1bHLH-C/EBP, although the out-of-register mutants still did not achieve the strong DNA-binding affinities displayed by their in-register counterparts. ArntbHLH-C/EBP hybrids further demonstrated the importance of maintaining register, as out-of-register mutants showed no E-box-responsive activity, whereas the in-register hybrid showed moderate activity. In another design, we eliminated the HLH altogether and fused the Max basic region to the C/EBP zipper to generate bZIP-like hybrids. Despite numerous designs and selections, these hybrids possessed no E-box-responsive activity. Finally, we tested the importance of the loop sequence in MaxbHLHZ by fluorescence and circular dichroism. In one mutant, the loop was shortened by two residues; in the other, the Lys57:DNA-backbone interaction was abolished by mutation to Gly57. Both showed markedly decreased E-box-binding relative to MaxbHLHZ. Our results suggest that, in contrast to the more rigid bZIP, the HLH is capable of significant conformational adaptation to enable gene-regulatory function and is required for protein dimerization and positioning the basic region for DNA recognition.

  G Chen , Z Wang , X. y Liu and F. y. Liu
  Background

Even if complete resection was performed, some patients with esophageal carcinoma still develop tumor recurrence. This study was undertaken to evaluate the effectiveness of adjuvant radiotherapy after modified Ivor-Lewis esophagectomy on preventing lymph node recurrence of the mid-thoracic esophageal carcinoma.

Methods

Three hundred sixty-six patients with mid-thoracic esophageal squamous cell carcinoma who underwent modified Ivor-Lewis esophagectomy between June 1999 and June 2004 were retrospectively reviewed. All patients were followed up within 3 years after surgery to detect lymph node recurrence. The Kaplan-Meier method was used to calculate the recurrence rate, and Cox regression analysis was performed to identify risk factors of lymph node recurrence.

Results

The overall 3-year and 5-year survival rates in all patients were 57.9% and 43.7%, respectively. Lymph node recurrence occurred in 105 patients (28.7%) within 3 years after surgery. The lymph node recurrence rate of patients with postoperative adjuvant radiotherapy was significantly lower than that of those with adjuvant chemotherapy (p = 0.03) and those without adjuvant therapy (p < 0.01). Cox regression analysis showed that T stage, N status, and postoperative adjuvant radiotherapy were independent relevant factors for lymph node recurrence.

Conclusions

Postoperative adjuvant radiotherapy after modified Ivor-Lewis esophagectomy might prevent lymph node recurrence of mid-thoracic esophageal carcinoma.

 
 
 
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