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Articles by C Xu
Total Records ( 14 ) for C Xu
  L Sun , J Li , C Xu , F Yu , H Zhou , L Tang and J. He
 

A device has been invented for protein crystallization by sandwiching the liquid droplet between two surfaces, in which both hydrophilic and hydrophobic surfaces can be used as crystallization substrates. Comparing with the traditional hanging drop method, it can also reduce the evaporation rate of the liquid droplet and provide a stable environment for the crystal growth. In this work, crystal growth experiments for several proteins, especially on the hydrophilic substrate of mica, have shown the positive effect on crystal growth for improving crystallization conditions and the quality of crystals. The features of this new sandwich method and its mechanism have also been discussed.

  C Xu , B. E Shmukler , K Nishimura , E Kaczmarek , S Rossetti , P. C Harris , A Wandinger Ness , R. L Bacallao and S. L. Alper
 

Flow-induced cytosolic Ca2+ Cai2+ signaling in renal tubular epithelial cells is mediated in part through P2 receptor (P2R) activation by locally released ATP. The ability of P2R to regulate salt and water reabsorption has suggested a possible contribution of ATP release and paracrine P2R activation to cystogenesis and/or enlargement in autosomal dominant polycystic kidney disease (ADPKD). We and others have demonstrated in human ADPKD cyst cells the absence of flow-induced Cai2+ signaling exhibited by normal renal epithelial cells. We now extend these findings to primary and telomerase-immortalized normal and ADPKD epithelial cells of different genotype and of both proximal and distal origins. Flow-induced elevation of Cai2+ concentration ([Ca2+]i) was absent from ADPKD cyst cells, but in normal cells was mediated by flow-sensitive ATP release and paracrine P2R activation, modulated by ecto-nucleotidase activity, and abrogated by P2R inhibition or extracellular ATP hydrolysis. In contrast to the elevated ATP release from ADPKD cells in static isotonic conditions or in hypotonic conditions, flow-induced ATP release from cyst cells was lower than from normal cells. Extracellular ATP rapidly reduced thapsigargin-elevated [Ca2+]i in both ADPKD cyst and normal cells, but cyst cells lacked the subsequent, slow, oxidized ATP-sensitive [Ca2+]i recovery present in normal cells. Telomerase-immortalized cyst cells also exhibited altered CD39 and P2X7 mRNA levels. Thus the loss of flow-induced, P2R-mediated Cai2+ signaling in human ADPKD cyst epithelial cells was accompanied by reduced flow-sensitive ATP release, altered purinergic regulation of store-operated Ca2+ entry, and altered expression of gene products controlling extracellular nucleotide signaling.

  Y Lu , Y Zhang , N Wang , Z Pan , X Gao , F Zhang , H Shan , X Luo , Y Bai , L Sun , W Song , C Xu , Z Wang and B. Yang
  Background—

A characteristic of both clinical and experimental atrial fibrillation (AF) is atrial electric remodeling associated with profound reduction of L-type Ca2+ current and shortening of the action potential duration. The possibility that microRNAs (miRNAs) may be involved in this process has not been tested. Accordingly, we assessed the potential role of miRNAs in regulating experimental AF.

Methods and Results—

The miRNA transcriptome was analyzed by microarray and verified by real-time reverse-transcription polymerase chain reaction with left atrial samples from dogs with AF established by right atrial tachypacing for 8 weeks and from human atrial samples from AF patients with rheumatic heart disease. miR-223, miR-328, and miR-664 were found to be upregulated by >2 fold, whereas miR-101, miR-320, and miR-499 were downregulated by at least 50%. In particular, miR-328 level was elevated by 3.9-fold in AF dogs and 3.5-fold in AF patients relative to non-AF subjects. Computational prediction identified CACNA1C and CACNB1, which encode cardiac L-type Ca2+ channel 1c- and β1 subunits, respectively, as potential targets for miR-328. Forced expression of miR-328 through adenovirus infection in canine atrium and transgenic approach in mice recapitulated the phenotypes of AF, exemplified by enhanced AF vulnerability, diminished L-type Ca2+ current, and shortened atrial action potential duration. Normalization of miR-328 level with antagomiR reversed the conditions, and genetic knockdown of endogenous miR-328 dampened AF vulnerability. CACNA1C and CACNB1 as the cognate target genes for miR-328 were confirmed by Western blot and luciferase activity assay showing the reciprocal relationship between the levels of miR-328 and L-type Ca2+ channel protein subunits.

Conclusions—

miR-328 contributes to the adverse atrial electric remodeling in AF through targeting L-type Ca2+ channel genes. The study therefore uncovered a novel molecular mechanism for AF and indicated miR-328 as a potential therapeutic target for AF.

  J Luan , J Yuan , X Li , S Jin , L Yu , M Liao , H Zhang , C Xu , Q He , B Wen , X Zhong , X Chen , H. L.Y Chan , J. J.Y Sung , B Zhou and C. Ding
 

Background: Variations in the hepatitis B virus (HBV) genome may develop spontaneously or under selective pressure from antiviral therapy. Such variations may confer drug resistance or affect virus replication capacity, resulting in failure of antiviral therapy.

Methods: A duplex PCR was used to amplify the region of the reverse transcriptase gene, the precore promoter, and the basal core promoter of the HBV genome. Four multiplex primer-extension reactions were used to interrogate 60 frequently observed HBV variants during antiviral therapy. Automated MALDI-TOF mass spectrometry (MS) was used for mutation detection. Capillary sequencing was used to confirm the MS results.

Results: The limit of quantification was 1000 HBV copies/mL for multiplex detection of HBV variants. Fifty-three variants (88.3%) were analyzed successfully in at least 90% of the sera from 88 treatment-naive patients and 80 patients with virologic breakthrough. MS was able to detect twice as many minor variants as direct sequencing while achieving close to full automation. MS and direct sequencing showed only 0.1% discordance in variant calls.

Conclusions: This platform based on multiplex primer extension and MALDI-TOF MS was able to detect 60 HBV variants in 4 multiplex reactions with accuracy and low detection limits.

  C Xu , X Wang and J. L. Staudinger
 

The liver- and intestine-enriched carboxylesterase 2 (CES2) enzyme catalyzes the hydrolysis of several clinically important anticancer agents administered as prodrugs. For example, irinotecan, a carbamate prodrug used in the treatment of colorectal cancer, is biotransformed in vivo by CES2 in intestine and liver, thereby producing a potent topoisomerase I inhibitor. Pregnane X receptor (PXR) and constitutive androstane receptor (CAR), two members of the nuclear receptor superfamily of ligand-activated transcription factors, mediate gene activation in response to xenobiotic stress. Together, these receptors comprise a protective response in mammals that coordinately regulate hepatic transport, metabolism, and elimination of numerous xenobiotic compounds. In the present study, microarray analysis was used to identify PXR target genes in duodenum in mice. Here, we show that a gene encoding a member of the CES2 subtype of liver- and intestine-enriched CES enzymes, called Ces6, is induced after treatment with pregnenolone 16-carbonitrile in a PXR-dependent manner in duodenum and liver in mice. Treatment of mice with the CAR activator 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene also induced expression of Ces6 in duodenum and liver in a CAR-dependent manner, whereas treatment with phenobarbital produced induction of Ces6 exclusively in liver. These data identify a key role for PXR and CAR in regulating the drug-inducible expression and activity of an important CES enzyme in vivo. Future studies should focus on determining whether these signaling pathways governing drug-inducible CES expression in intestine and liver are conserved in humans.

  C Xu , X Wang and J. L. Staudinger
 

The liver- and intestine-enriched carboxylesterase 2 (CES2) enzyme catalyzes the hydrolysis of several clinically important anticancer agents administered as prodrugs. For example, irinotecan, a carbamate prodrug used in the treatment of colorectal cancer, is biotransformed in vivo by CES2 in intestine and liver, thereby producing a potent topoisomerase I inhibitor. Pregnane X receptor (PXR) and constitutive androstane receptor (CAR), two members of the nuclear receptor superfamily of ligand-activated transcription factors, mediate gene activation in response to xenobiotic stress. Together, these receptors comprise a protective response in mammals that coordinately regulate hepatic transport, metabolism, and elimination of numerous xenobiotic compounds. In the present study, microarray analysis was used to identify PXR target genes in duodenum in mice. Here, we show that a gene encoding a member of the CES2 subtype of liver- and intestine-enriched CES enzymes, called Ces6, is induced after treatment with pregnenolone 16-carbonitrile in a PXR-dependent manner in duodenum and liver in mice. Treatment of mice with the CAR activator 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene also induced expression of Ces6 in duodenum and liver in a CAR-dependent manner, whereas treatment with phenobarbital produced induction of Ces6 exclusively in liver. These data identify a key role for PXR and CAR in regulating the drug-inducible expression and activity of an important CES enzyme in vivo. Future studies should focus on determining whether these signaling pathways governing drug-inducible CES expression in intestine and liver are conserved in humans.

  W Cao , C Xu , G Lou , J Jiang , S Zhao , M Geng , W Xi , H Li and Y. Jin
  Objective

The aim of this study was to assess the efficacy and toxicity of the combination of paclitaxel and nedaplatin as a first-line chemotherapy for patients with advanced esophageal cancer.

Methods

Patients with advanced esophageal cancer received 175 mg/m2 of paclitaxel over a 3 h infusion, followed by nedaplatin 80 mg/m2 in a 1 h infusion on day 1 every 3 weeks until the documented disease progression, unacceptable toxicity or patient's refusal.

Results

Between March 2005 and December 2007, 48 patients entered in the study. Forty-six (95.8%) of the 48 patients were assessable for response. The overall response rate was 41.7% (95% CI, 27.8–55.7%) with 2 complete responses and 18 partial responses. The median follow-up period was 20.5 months (range, 12.5–27.2 months). The median overall time to progression and overall survival (OS) were 6.1 months (95% CI, 4.8–7.4 months) and 11.5 months (95% CI, 9.1–13.9 months), respectively. The estimate of OS at 12 and 24 months was 43.8% (95% CI, 29.7–77.8%) and 10.4% (95% CI, 1.8–19.1%), respectively. Most patients experienced anemia, during their course of therapy with 6 (13.0%) patients for grade 3/4 anemia, and grade 1 or 2 anemia was detected in 23 (50%) patients. Grade 3 leucopenia, neutropenia and thrombocytopenia were documented in 8 (17.4%), 9 (17.4%) and 2 (4.3%) patients, respectively. Grade 3 nausea and vomiting were detected in 3 (6.5%) and 2 (4.3%) patients, respectively. Two patients (4.3%) were hospitalized because of treatment-related complications. The treatment was well tolerated and no toxic death occurred.

Conclusions

Combination of paclitaxel and nedaplatin is a tolerated treatment modality with promising activity in previously untreated advanced esophageal cancer.

  H Wang , D Zhang , W Wu , J Zhang , D Guo , Q Wang , T Jing , C Xu , X Bian and K. Yang
 

Steroid receptor coactivator-3 (SRC-3) has been reported to be overexpressed in the development and progression of many tumor types. SRC-3 has been detected in several lung cancer cell lines, but its expression and clinical significance in non–small cell lung cancer (NSCLC) remain unclear. In this study, 48 NSCLC tissues were collected and tissue microarrays were performed. The expression of SRC-3 was examined using nickel-intensified IHC. The results showed that of these 48 cases, 18 (37.5%) exhibited high levels of SRC-3 immunoreactivity, 23 (47.9%) exhibited moderate levels of SRC-3 immunoreactivity, and 7 (14.6%) were negative; thus, the total frequency of SRC-3 overexpression was 85.4% (41/48). This SRC-3 overexpression frequency was similar to the overexpression frequency observed for squamous cell carcinoma and adenocarcinoma (82.1% vs 90%) and for metastasis and non-metastasis patients (84.6% vs 85.7%). Data analysis demonstrated a significantly higher overexpression frequency in male patients compared with that in female patients (88.6% vs 76.9%). However, female patients tended to have higher expression levels of SRC-3, as measured by immunoreactivity, than male patients. These results demonstrate a high frequency of SRC-3 overexpression in NSCLC with a gender difference, suggesting that there is a specific role for SRC-3 in the pathogenesis of NSCLC. (J Histochem Cytochem 58:1121–1127, 2010)

  C Xu , J He , H Jiang , L Zu , W Zhai , S Pu and G. Xu
 

Hypercortisolemia and glucocorticoid treatment cause elevated level of circulating free fatty acids (FFAs). The basis of this phenomenon has long been linked to the effect of glucocorticoids permitting and enhancing the adipose lipolysis response to various hormones. In this study, we demonstrate that glucocorticoids directly stimulate lipolysis in rat primary adipocytes in a dose- and time-responsive manner; this lipolytic action was attenuated by treatment with the glucocorticoid antagonist RU486. Dexamethasone down-regulates mRNA and protein levels of cyclic-nucleotide phosphodiesterase 3B, thereby elevating cellular cAMP production and activating protein kinase A (PKA). On inhibition of PKA but not other kinases, the lipolysis response ceases. Furthermore, dexamethasone induces phosphorylation and down-regulation of perilipin, a lipid droplet-associating protein that modulates lipolysis; this effect is restored by RU486 or PKA inhibitor H89. Dexamethasone up-regulates mRNA and protein levels of hormone-sensitive lipase (HSL) and adipose triglyceride lipase; these effects, parallel to increased lipolysis, are attenuated by RU486 or actinomycin D. Phosphorylation at Ser-563 and Ser-660 residues of HSL and activity of cellular lipases are elevated on dexamethasone stimulation but abrogated by the coaddition of H89. However, dexamethasone does not induce HSL translocation to the lipid droplet surface in differentiated adipocytes. We show that elevated FFA concentration in plasma is associated with increased lipase activity and lipolysis in vivo in adipose tissues of dexamethasone-treated rats. Therefore, the lipolytic action of glucocorticoids liberates FFA efflux from adipocytes to the bloodstream, which could be a cellular basis of systemic FFA elevation in response to glucocorticoid challenge.

  M Yuan , Z Chu , X Li , C Xu and S. Wang
 

The fully recessive disease resistance (R) gene xa13, which mediates race-specific resistance to Xanthomonas oryzae pv. oryzae (Xoo), encodes a plasma membrane protein that differs by one amino acid from that encoded by its dominant (susceptible) allele Xa13. The molecular mechanism of xa13-mediated resistance is largely unknown. Here we show that, compared with its dominant allele, expressional non-reaction of xa13 to Xoo infection, not its protein composition, is the key factor for xa13-mediated resistance. We used the promoter (PXa13) of the dominant Xa13, which was induced by only the incompatible Xoo strain for xa13, to regulate xa13 and xa13Leu49 (a natural recessive allele of xa13) in the rice line IRBB13 carrying xa13. The transgenic plants showed the same level of susceptibility and bacterial growth rate as those of the rice line carrying dominant Xa13, accompanied by the induced accumulation of xa13 or xa13Leu49 proteins. Constitutive expression of dominant XA13 or different xa13 proteins (xa13, xa13Leu49, xa13Ala85 or xa13Val184) in IRBB13 had no effect on Xoo infection in the transgenic plants. These results suggest that race-specific pathogen-induced Xa13 expression is critical for infection. Thus, xa13 stands out from other R genes in that its functions in disease resistance are due to only the loss of pathogen-induced transcriptional motivation caused by natural selection.

 
 
 
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