Yong Chen

Fourth Military Medical University, Xi’an, Liaoning, China

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Publications (30)95.17 Total impact

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    ABSTRACT: Several risk factors exist for hepatocellular carcinoma in patients with post-hepatitis cirrhosis (PHC), including hypersplenism. Splenectomy is a common but controversial procedure in the management of hypersplenism, but its impact on hepatocellular carcinoma (HCC) remains uncertain. We conducted a hospital-based study of PHC patients to identify potential risk factors, including a history of splenectomy, which has been associated with progression from PHC to HCC. From 2002 to 2012, 2678 patients developed hypersplenism secondary to PHC. Of these patients, 828 developed HCC and 1850 did not. Potential risk factors of HCC were determined by univariate and multivariate analyses to exclude confounding variables. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were determined for each factor. Many factors, such as liver function, platelet (PLT) counts, Child-Pugh class, and history of hepatitis, were associated with progression to HCC. PHC patients with hypersplenism who displayed elevated levels of alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyltransferase (GGT), ALK, phosphatase, and prolonged prothrombin time (PT) had a significantly increased risk of HCC. However, the patients who had splenectomy showed better liver function test results and less progression to HCC. In patients with PHC and hypersplenism, abnormal levels of ALT, AST, ALP, and GGT and prolonged PT are risk factors of HCC. Splenectomy, as the intervention method of hypersplenism, is performed less frequently in patients who developed HCC than in patients who did not develop HCC. Therefore, splenectomy may act as an independent factor that is significantly associated with HCC development.
    No preview · Article · Jan 2016 · Tumor Biology
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    ABSTRACT: Endoplasmic reticulum (ER) stress is involved in ischemic preconditioning that protects various organs from ischemia/reperfusion (I/R) injury. We established an in vivo ER stress preconditioning model in which tunicamycin was injected into rats before hepatic I/R. The hepatic I/R injury, demonstrated by serum aminotransferase level and the ultra-structure of the liver, was alleviated by administration of tunicamycin, which induced ER stress in rat liver by activating inositol-requiring enzyme 1 (IRE1) and upregulating 78 kDa glucose-regulated protein (GRP78). The proteomic identification for IRE1 binders revealed interaction and cooperation among receptor for activated C kinase 1 (RACK1), phosphorylated AMPK, and IRE1 under ER stress conditions in a spatiotemporal manner. Furthermore, in vitro ER stress preconditioning was induced by thapsigargin and tunicamycin in L02 and HepG2 cells. Surprisingly, BCL2 was found to be phosphorylated by IRE1 under ER stress conditions to prevent apoptotic process by activation of autophagy. In conclusion, ER stress preconditioning protects against hepatic I/R injury, which is orchestrated by IRE1–RACK1 axis through the activation of BCL2. Our findings provide novel insights into the molecular pathways underlying ER stress preconditioning-elicited cytoprotective effect against hepatic I/R injury.
    No preview · Article · Dec 2015 · Journal of Molecular Cell Biology
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    ABSTRACT: Sorafenib is one of the preferred drugs for the treatment of advanced primary hepatocellular carcinoma (HCC). However, its side-effects and acquired resistance limit its use. The unfolded protein response (UPR) induced by chemotherapeutics has been demonstrated to be required for tumor cells to maintain malignancy and therapy resistance. Activation of the IRE1/XBP1 pathway during the UPR is important for tumor survival under pathophysiological conditions. In the present study, we found that the UPR was activated and RACK1 was overexpressed in three human HCC cell lines and in HCC samples. Activation of the IRE1/XBP1 signaling pathway plays a protective role when HCC cells encounter endoplasmic reticulum (ER) stress due to in vitro sorafenib treatment. We then found that the interaction between IRE1 and RACK1 was essential for the activation of IRE1 signaling in sorafenib-treated cells. Exogenous overexpression of RACK1 enhanced the phosphorylation level of IRE1 and increased XBP1 mRNA splicing activity, which protected the HCC cells from sorafenib-induced apoptosis. However, the re-expression of RACK1 led HCC cells to regain susceptibility to sorafenib-induced apoptosis. Taken together, the present study suggests that the RACK1/IRE1 complex may contribute to activation of the UPR in HCC cells. Targeting RACK1 in combination with sorafenib administration is a potential strategy for clinical trials of advanced HCC treatment.
    No preview · Article · Apr 2015 · Oncology Reports
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    ABSTRACT: Baiyin city, which is located upstream of the Yellow River and in the central part of Gansu province, China, is severely contaminated by heavy metals such as chromium. A Gram-positive bacterium BYCr-1 capable of reducing hexavalent chromium (Cr(VI)) to trivalent (Cr(III)) aerobically was isolated from a rare-earth ore in Baiyin, Gansu, China. 16S rRNA analysis revealed that it was closely related to Bacillus subtilis. It can reduce 0.2 mM Cr(VI) to Cr(III) in M9 medium after 48 h incubation. Transmission electron microscopy (TEM) image showed that Cr(III) precipitates were located both inside and outside the cells. An nfrA gene was upregulated by 5.3 folds upon Cr(VI) treatment. Furthermore, E. coli-NfrA demonstrated elevated chromate-reducing ability. Our results indicate that BYCr-1 is able to resist and reduce high concentrations of Cr(VI), which makes it a potentially suitable candidate for bioremediation of Cr(VI) contamination. This study also reveals that nfrA confers Cr(VI)-reducing ability in Bacillus subtilis.
    No preview · Article · Nov 2014 · International Biodeterioration & Biodegradation
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    ABSTRACT: Hexavalent chromium [Cr(VI)] is one of the major environmental contaminants in the Lanzhou reaches of the Yellow River, and actinomycetes' Cr(VI) bioremediation within this area is still scarce. In the present study, twenty actinomycete strains were isolated from the Lanzhou reaches which could resist 1.2 mM Cr(VI) on Starch-Casein (SC) agar plates. Based on the 16S rRNA sequence data, sixteen strains belong to Streptomyces and four other strains belong to Gordonia, Nocardiopsis, Nocardia and Cellulosimicrobium. One strain named LZ-26-1 which is closely related to Streptomyces violaceoruber demonstrated a notable ability of Cr(VI) reduction. It could reduce 92.86% of the 0.6 mM Cr(VI) to trivalent chromium [Cr(III)] in SC liquid medium in 144 h. The optimum temperature and pH were 28 °C and 7.0 for Cr(VI) reduction. Transmission electron microscopy images showed that chromium was precipitated inside the cells. In resting cells and crude chromate reductase assays, strain LZ-26-1's Cr(VI) reduction was stimulated when NADPH was used as an electron donor and Cd2+ treatment inhibited Cr(VI) reduction. Furthermore, thioredoxin operon, which consists of three genes encoding a thioredoxin, thioredoxin reductase (NADPH) and a possible membrane protein, was upregulated by Cr(VI) treatment. These results suggested that LZ-26-1 might utilize a thioredoxin pathway to reduce Cr(VI).
    Full-text · Article · Oct 2014 · International Biodeterioration & Biodegradation
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    ABSTRACT: Entosis, a cell-in-cell process, has been implicated in the formation of aneuploidy associated with an aberrant cell division control. Microtubule plus-end-tracking protein TIP150 facilitates the loading of MCAK onto the microtubule plus ends and orchestrates microtubule plus-end dynamics during cell division. Here we show that TIP150 cooperates with MCAK to govern entosis via a regulatory circuitry that involves Aurora A-mediated phosphorylation of MCAK. Our biochemical analyses show that MCAK forms an intra-molecular association, which is essential for TIP150 binding. Interestingly, Aurora A-mediated phosphorylation of MCAK modulates its intra-molecular association, which perturbs the MCAK–TIP150 interaction in vitro and inhibits entosis in vivo. To probe if MCAK–TIP150 interaction regulates microtubule plasticity to affect the mechanical properties of cells during entosis, we used an optical trap to measure the mechanical rigidity of live MCF7 cells. We find that the MCAK cooperates with TIP150 to promote microtubule dynamics and modulate the mechanical rigidity of the cells during entosis. Our results show that a dynamic interaction of MCAK–TIP150 orchestrated by Aurora A-mediated phosphorylation governs entosis via regulating microtubule plus-end dynamics and cell rigidity. These data reveal a previously unknown mechanism of Aurora A regulation in the control of microtubule plasticity during cell-in-cell processes.
    Full-text · Article · May 2014 · Journal of Molecular Cell Biology
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    ABSTRACT: Lanzhou reach of the Yellow River is contaminated by cadmium (Cd(II)).The aim of this study was to screen bacterial strains that is able to resist and absorb cadmium from soil sediment and elucidate the molecular mechanism. A strain named LZ-11 which can resist 1 mmol l(-1) and absorb 0.3 mmol l(-1) cadmium was isolated from a petrochemical wastewater discharge site. 16S rRNA gene sequencing data and Vitek phenotype results revealed that it was closely related to Enterococcus faecalis. Transmission Electron Microscopy images and Energy Dispersive X-Ray Analysis results showed that Cd(II) was absorbed both intracellularly and extracellularly. Blast results showed that Enterococcus faecalis genome owns cadA, ppx and dsbA which are proven to be involved in Cd(II) resistance and absorption. Quantitative real-time PCR data demonstrated that thesethree genes were upregulated 2-3 folds in LZ-11 under Cd(II) treatment. We've isolated a strain named LZ-11 from Lanzhou reach of the Yellow River which can resist and absorb Cd(II). LZ-11 was closely related to Enterococcus faecalis. Genes encoding CadA, Ppx and DsbA were up-regulated under Cd(II) treatment. These genes might confer Cd(II) resistance and absorption in Enterococcus faecalis strain LZ-11. Lanzhou reach of the Yellow River is contaminated by heavy metals. Microbial research and remediation is still scarce. LZ-11 is the first strain that is able to resist and absorb Cd(II) isolated from this area and might be a good candidate for future cadmium bioremediation. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2014 · Journal of Applied Microbiology
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    ABSTRACT: ArfGAP With Coiled-Coil, Ankyrin Repeat And PH Domains 4 (ACAP4) is an ADP-ribosylation factor 6 (ARF6) GTPase-activating protein essential for EGF-elicited cell migration. However, how ACAP4 regulates membrane dynamics and curvature in response to EGF stimulation is unknown. Here, we show that phosphorylation of the N-terminal region of ACAP4, named the Bin, Amphiphysin, and RSV161/167 (BAR) domain, at Tyr34 is necessary for EGF-elicited membrane remodeling. Domain structure analysis demonstrates that the BAR domain regulates membrane curvature. EGF stimulation of cells causes phosphorylation of ACAP4 at Tyr34, which subsequently promotes ACAP4 homodimer curvature. The phospho-mimicking mutant of ACAP4 demonstrates lipid-binding activity and tubulation in vitro, and ARF6 enrichment at the membrane is associated with ruffles of EGF-stimulated cells. Expression of the phospho-mimicking ACAP4 mutant promotes ARF6-dependent cell migration. Thus, the results present a previously undefined mechanism by which EGF-elicited phosphorylation of the BAR domain controls ACAP4 molecular plasticity and plasma membrane dynamics during cell migration.
    Full-text · Article · Jun 2013 · Proceedings of the National Academy of Sciences
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    ABSTRACT: Desulfovibrio vulgaris can use lactate as an electron donor and accumulate hydrogen. Hydrogen can also be consumed as an electron donor when lactate is depleted or absent. The aim of this study was to determine whether D. vulgaris has an electron donor preference system between lactate and hydrogen and how this system is regulated. In order to be sure that D. vulgaris was grown under the same conditions except for electron donors, continuous growth mode was conducted and the optical density (600 nm) was kept constant. When 20 mmol/l lactate was the sole electron donor, it was depleted after 9 h of incubation while hydrogen was accumulated to 1,500 ppm. After that, the hydrogen level was decreased to and maintained at 400 ppm. When 1,200 ppm hydrogen was provided as the electron donor, the culture reached an OD of 0.2 after 24 h incubation and hydrogen was consumed to 600 ppm. When 1,200 ppm hydrogen and 20 mmol/l lactate were both present, the lactate was consumed during the first 9 h incubation and hydrogen was accumulated to 1,800 ppm. D. vulgaris used hydrogen as an electron donor after the lactate was depleted and the hydrogen level was decreased to 600 ppm. D. vulgaris has both pathways to utilize lactate and hydrogen as electron donors. It prefers lactate over hydrogen and the system is regulated by lactate starvation.
    No preview · Article · Jun 2013 · Annals of Microbiology
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    ABSTRACT: To evaluate the one year effect of modified Roux-en-Y gastric bypass (RYGP) in the treatment of non-obese type 2 diabetes and to investigate the reasonable indications for surgery. Totally 72 patients diagnosed as type 2 diabetes underwent RYGP from May 2009 to June 2010. There were 45 male and 27 female patients, with an average age of (47 ± 10) years. Preoperative body mass index (BMI) of the patients was 18.69 to 31.22 kg/m(2), average (26 ± 4) kg/m(2). The follow-up data included fasting plasma glucose (FPG), 2 h plasma glucose after oral glucose challenge (2hPG), weight, BMI and medication usage in 1, 3, 6 and 12 months postoperative; hemoglobin A1c (HbA1c), fasting C-peptide (C-P), fasting serum insulin (Fins) and homeostasis model assessment of insulin resistance index (HOMA-IR) in 6 and 12 months postoperative, respectively. Compared with the preoperative, FPG, 2hPG, weight and BMI in 1, 3, 6 and 12 months after surgery were improved (t = 7.014 to 10.254, P = 0.000), while HbA1c, C-P and HOMA-IR in 6 and 12 months after surgery were improved (t = 1.782 to 7.789, P = 0.000 to 0.103) and there was no significant difference in Fins (P > 0.05). The rates of complete remission in 1, 3, 6 and 12 months after surgery were gradually improved to 22.2%, 27.8%, 36.1% and 60.6%, respectively, and the rate of remission in 1 year was 94.3%. The complete remission of 1 year after surgery was associated with normal C-P, insulin antibody and oral antidiabetic drugs (χ(2) = 11.730, P = 0.003; χ(2) = 7.131, P = 0.028;χ(2) = 6.149, P = 0.046). Modified RYGP is safely and effectively in the treatment of no-obese type 2 diabetes patients. The function of islet cells is significantly improved after operation. Especially for the patients of whom C-P is normal, insulin antibody is negative before surgery, the rate of complete remission after 1 year is better.
    No preview · Article · Oct 2012 · Zhonghua wai ke za zhi [Chinese journal of surgery]
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    ABSTRACT: ARF6 GTPase is an important regulator of membrane trafficking and actin-based cytoskeleton dynamics active at the leading edge of migrating cells. The integrin family heterodimeric transmembrane proteins serve as major receptors for extracellular matrix proteins, which play essential roles in cell adhesion and migration. Our recent proteomic analyses of ARF6 effectors have identified a novel ARF6 GTPase-activating protein, ACAP4, essential for EGF-induced cell migration. However, molecular mechanisms underlying ACAP4-mediated cell migration have remained elusive. Here, we show that ACAP4 regulates integrin β1 dynamics during EGF-stimulated cell migration by interaction with Grb2. Our biochemical study shows that EGF stimulation induces phosphorylation of tyrosine 733, which enables ACAP4 to bind Grb2. This interaction of ACAP4 with Grb2 regulates integrin β1 recycling to the plasma membrane. Importantly, knockdown of ACAP4 by siRNA or overexpression of ACAP4 decreased recycling of integrin β1 to the plasma membrane and reduced integrin-mediated cell migration. Taken together, these results suggest a novel function for ACAP4 in the regulation of cell migration through controlling integrin β1 dynamics.
    Preview · Article · Dec 2011 · Journal of Biological Chemistry
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    ABSTRACT: ARF6 GTPase is an important regulator of membrane trafficking and actin-based cytoskeleton dynamics active at the leading edge of migrating cells. The integrin family heterodimeric transmembrane proteins serve as major receptors for extracellular matrix proteins, which play essential roles in cell adhesion and migration. Our recent proteomic analyses of ARF6 effectors have identified a novel ARF6 GTPase-activating protein, ACAP4, essential for EGF-induced cell migration. However, molecular mechanisms underlying ACAP4-mediated cell migration has remained elusive. Here we show that ACAP4 regulates integrin β1 dynamics during EGF-stimulated cell migration by interaction with Grb2. Our biochemical study shows that EGF stimulation induces phosphorylation of tyrosine 733 which enables ACAP4 to bind Grb2. This interaction of ACAP4 with Grb2 regulates integrin β1 recycling to the plasma membrane. Importantly, knockdown of ACAP4 by siRNA or overexpression of ACAP4 decreased recycling of integrin β1 to the plasma membrane and reduced integrin-mediated cell migration. Taken together, these results suggest a novel function for ACAP4 in the regulation of cell migration through controlling integrin β1 dynamics.
    Preview · Article · Oct 2011 · Journal of Biological Chemistry
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    ABSTRACT: During progression of hepatocellular carcinoma, multiple genetic and epigenetic alterations act to posttranslationally modulate the function of proteins that promote cancer invasion and metastasis. To define such abnormalities that contribute to liver cancer metastasis, we carried out a proteomic comparison of primary hepatocellular carcinoma and samples of intravascular thrombi from the same patient. Mass spectrometric analyses of the liver cancer samples revealed a series of acidic phospho-isotypes associated with the intravascular thrombi samples. In particular, we found that Thr567 hyperphosphorylation of the cytoskeletal protein ezrin was tightly correlated to an invasive phenotype of clinical hepatocellular carcinomas and to poor outcomes in tumor xenograft assays. Using phospho-mimicking mutants, we showed that ezrin phosphorylation at Thr567 promoted in vitro invasion by hepatocarcinoma cells. Phospho-mimicking mutant ezrinT567D, but not the nonphosphorylatable mutant ezrinT567A, stimulated formation of membrane ruffles, suggesting that Thr567 phosphorylation promotes cytoskeletal-membrane remodeling. Importantly, inhibition of Rho kinase, either by Y27632 or RNA interference, resulted in inhibition of Thr567 phosphorylation and a blockade to cell invasion, implicating Rho kinase-ezrin signaling in hepatocellular carcinoma cell invasion. Our findings suggest a strategy to reduce liver tumor metastasis by blocking Rho kinase-mediated phosphorylation of ezrin.
    Full-text · Article · Mar 2011 · Cancer Research
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    ABSTRACT: This study was designed to evaluate the protective effect of cyclosporin A (CsA) on brain injury in rats with acute necrotic pancreatitis (ANP) in order to provide a scientific basis for the use of the drug in treating brain injury caused by pancreatitis. The rats were divided into a sham group, an ANP group and an ANP+CsA group. The ANP model was induced by administering 5% sodium taurocholate through the biliopancreatic duct. Five minutes before the preparation of the ANP model, 1 ml of CsA (10mg/kg) was injected in a clinically used pharmaceutical formulation (Sandimmun) via the dorsal vein of the penis. Twelve hours after the model was established, samples were taken from the rats in all groups for measurement of appropriate indexes. The serum levels of pro-inflammatory tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), and anti-inflammatory interleukin 10 (IL-10) were determined by ELISA. The pancreatic mRNA expressions of these cytokines were evaluated by RT-PCR. Brain water content was tested by the dry-wet method, and brain malondialdehyde (MDA) content was detected by the chemical colorimetry method. Both the serum levels and the pancreatic tissue mRNA expression of TNF-alpha and IL-1beta, as well as the brain water content and brain MDA content, were significantly increased in the ANP group. CsA treatment noticeably reduced both the serum levels and the pancreatic mRNA expression of TNF-alpha and IL-1beta and decreased brain water and MDA contents. In contrast to the pro-inflammatory cytokines, the serum levels and the pancreatic tissue mRNA expression of IL-10 were markedly increased by the injection of CsA. CsA could alleviate acute pancreatitis-associated brain injury.
    No preview · Article · Jul 2010 · Life sciences
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    ABSTRACT: ARF6 GTPase is a conserved regulator of membrane trafficking and actin-based cytoskeleton dynamics at the leading edge of migrating cells. A key determinant of ARF6 function is the lifetime of the GTP-bound active state, which is orchestrated by GTPase-activating protein (GAP) and GTP-GDP exchanging factor. However, very little is known about the molecular mechanisms underlying ARF6-mediated cell migration. To systematically analyze proteins that regulate ARF6 activity during cell migration, we performed a proteomic analysis of proteins selectively bound to active ARF6 using mass spectrometry and identified a novel ARF6-specific GAP, ACAP4. ACAP4 encodes 903 amino acids and contains two coiled coils, one pleckstrin homology domain, one GAP motif, and two ankyrin repeats. Our biochemical characterization demonstrated that ACAP4 has a phosphatidylinositol 4,5-bisphosphate-dependent GAP activity specific for ARF6. The co-localization of ACAP4 with ARF6 occurred in ruffling membranes formed upon AIF(4) and epidermal growth factor stimulation. ACAP4 overexpression limited the recruitment of ARF6 to the membrane ruffles in the absence of epidermal growth factor stimulation. Expression of GTP hydrolysis-resistant ARF6(Q67L) resulted in accumulations of ACAP4 and ARF6 in the cytoplasmic membrane, suggesting that GTP hydrolysis is required for the ARF6-dependent membrane remodeling. Significantly the depletion of ACAP4 by small interfering RNA or inhibition of ARF6 GTP hydrolysis by overexpressing GAP-deficient ACAP4 suppressed ARF6-dependent cell migration in wound healing, demonstrating the importance of ACAP4 in cell migration. Thus, our study sheds new light on the biological function of ARF6-mediated cell migration.
    No preview · Article · Sep 2006 · Molecular & Cellular Proteomics
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    ABSTRACT: High levels of adenosine accumulate in hypoxic tissues during the rapid growth of tumors, suggesting activation of adenosine receptors may facilitate tumor progress. The relevance of adenosine receptors to hepatocellular carcinoma (HCC), in particular the adenosine A(2b) receptor (A(2b)), is not yet fully understood. The aim of this study was to assess whether A(2b) was differentially expressed in normal and cancerous tissues and evaluate the clinicopathological correlation of A(2b) level in HCC. Expression of A(2b) in tumor cells was investigated by immunohistochemical staining. Protein analysis was done by Western blotting and evaluation of A(2b) mRNA expression levels utilized quantitative real-time PCR analysis of tissue samples of 64 hepatocellular carcinomas and in their paired adjacent normal tissues. Western blot data suggested that A(2b) was expressed predominantly in the cell membrane and cytoplasm of tumor cells and that the intensity of A(2b) protein expression was consistently higher in HCC than in adjacent normal tissues. Levels of A(2b) mRNA in HCC were significantly higher than in adjacent tissues, as measured by real-time PCR (P<0.001). With regard to venous invasion, satellite lesions and advanced pathologic Tumor-Node-Metastasis (pTNM) stage, the A(2b) level tended to be higher than that seen in negative cases (P<0.05). Our findings demonstrate that A(2b) expression is up-regulated in HCC, the expression level of A(2b) is correlated to tumor progression in HCC, and suggest that A(2b) may be a novel target for HCC therapeutic strategy.
    No preview · Article · Sep 2006 · Hepatology Research
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    ABSTRACT: The ezrin-radixin-moesin proteins provide a regulated linkage between membrane proteins and the cortical cytoskeleton, and also participate in signal-transduction pathways. Ezrin is localized to the apical membrane of parietal cells and couples the cAMP-dependent protein kinase activation cascade to the regulated HCl secretion in gastric parietal cells. Our recent studies have mapped the PKA-mediated phosphorylation site to Ser(66) and established its functional role in parietal cell activation [R. Zhou et al., Characterization of protein kinase A-mediated phosphorylation of ezrin in gastric parietal cell activation, J. Biol. Chem. 278 (2003) 35651-35659], but the underlying basis for this regulation is not known. Here, we provide the first evidence that PKA-mediated phosphorylation of Ser(66)regulates the interaction of ezrin with WWOX, a WW domain-containing protein. Our biochemical study reveals that ezrin directly binds to the first WW domain of WWOX via its C-terminal tyrosine-containing polyproline sequence (470)PPPPPPVY(477). Mutational analyses further demonstrate that tyrosine(477) is essential for the ezrin-WWOX interaction. In addition, our study shows that PKA-mediated phosphorylation of ezrin is essential and sufficient for the apical localization of WWOX protein as disruption of ezrin-WWOX interaction eliminated the apical localization of WWOX. Finally, our study demonstrates the essential role of ezrin-WWOX interaction in the apical membrane remodeling associated with H,K-ATPase recruitment. Taken together, these results define a novel molecular mechanism underlying phospho-regulation of ezrin function by PKA in parietal cell activation.
    No preview · Article · Apr 2006 · Biochemical and Biophysical Research Communications
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    ABSTRACT: The goal of this study was to examine the efficacy of liver-targeted gene delivery by chitosan-DNA nanoparticles through retrograde intrabiliary infusion (RII). The transfection efficiency of chitosan-DNA nanoparticles, as compared with PEI-DNA nanoparticles or naked DNA, was evaluated in Wistar rats by infusion into the common bile duct, portal vein, or tail vein. Chitosan-DNA nanoparticles administrated through the portal vein or tail vein did not produce detectable luciferase expression. In contrast, rats that received chitosan-DNA nanoparticles showed more than 500 times higher luciferase expression in the liver 3 days after RII; and transgene expression levels decreased gradually over 14 days. Luciferase expression in the kidney, lung, spleen, and heart was negligible compared with that in the liver. RII of chitosan-DNA nanoparticles did not yield significant toxicity and damage to the liver and biliary tree as evidenced by liver function analysis and histopathological examination. Luciferase expression by RII of PEI-DNA nanoparticles was 17-fold lower than that of chitosan-DNA nanoparticles on day 3, but it increased slightly over time. These results suggest that RII is a promising routine to achieve liver-targeted gene delivery by non-viral nanoparticles; and both gene carrier characteristics and mode of administration significantly influence gene delivery efficiency.
    Full-text · Article · Feb 2006 · International Journal of Nanomedicine
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    ABSTRACT: Different strategies have been proposed to increase and prolong liver-targeted transgene expression using non-viral vectors. Hepatic Kupffer cells (KCs) are known to eliminate a large proportion of i.v.-injected vector particles and contribute to innate immune responses following viral and non-viral vector administration. Recently, we have shown that KCs play an important role in limiting gene transfer in hepatocytes by DNA nanoparticles or naked DNA1. Transient depletion of KCs by clodronate liposomes, for example, enhances transgene expression in the liver by 14,510-, 100- and 2,020-fold in rats received intrabiliary infusion of PEI/DNA nanoparticles, chitosan/DNA nanoparticles and naked DNA, respectively. To better understand the mechanism of this phenomenon, in this study we selectively blocked the activity of transcriptional factor NK-κB in KCs using NF-κB/decoy/ODN liposomes 24 hours prior to intrabiliary infusion of plasmid DNA. Sequences of the double-stranded phosphorothioate ODNs used as NF-κB decoy were 5′-CCTTGAAGGGATTTCCCTCC-3′ and 3′-GGAACTTCCCTAAAGGGAGG-5′ (consensus sequences are underlined)2. This pretreatment yielded more than 200-fold higher gene expression than non-treatment group. We also inhibited TNF-α, one of the major proinflammatory cytokines secreted by KCs upon activation, by pentoxifylline 30 min before intrabiliary infusion of DNA nanoparticles or naked DNA. This pretreatment increased luciferase expression by more than 60-fold for the naked DNA group, and about 12-fold for the chitosan/DNA nanoparticle and PEI/DNA nanoparticle groups. While this suggests the inhibitory role of TNF-α in vivo, its role in transfection of primary rat hepatocytes in vitro was not as obvious. Instead, the in vitro transfection was clearly inhibited by a conditioned medium containing cytokines released by KCs upon activation by LPS. Taken together, this study showed that, following intrabiliary infusion of DNA nanoparticles or naked DNA, proinflammatory cytokines secreted by activated KCs may act collectively to reduce or inhibit the transgene expression in hepatocytes. This reduction in transgene expression might be related to the inactivation of CMV promoter involving KC-released cytokines such as TNF-α and IFN-γ. In summary, this study suggests that, in addition to sequestration, proinflammatory cytokines secreted by activated KCs play an important role in modulating transgene expression in the liver. (See Figure)
    Full-text · Article · Aug 2005 · Molecular Therapy
  • Yihua Cao · Yong Chen · Yong Zhou
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    ABSTRACT: The analytical capacity models of an airport with two runways system are developed in this paper and the theoretical capacity curves yielded by this model are analysed. The statistic airport capacity estimation methodology based on historical data is introduced as well. Both analytical models and statistic strategy are applied to estimate the capacity of the two runways system of a typical airport. Two sets of airport capacity curves obtained in different ways are compared and analysed. The result of the analysis indicates that the mathematical model works effectively in a fairly accurate way in the estimation of airport capacity.
    No preview · Article · Aug 2005 · Aeronautical Journal -New Series-

Publication Stats

236 Citations
95.17 Total Impact Points

Institutions

  • 2003-2015
    • Fourth Military Medical University
      • • Department of Hepatobiliary Surgery
      • • Department of Hematology
      Xi’an, Liaoning, China
  • 2014
    • Lanzhou University
      • School of Life Science
      Kao-lan-hsien, Gansu Sheng, China
  • 2004
    • Beijing University of Aeronautics and Astronautics (Beihang University)
      Peping, Beijing, China