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Articles by Y Guo
Total Records ( 9 ) for Y Guo
  Q Li , Y Guo , Q Ou , C Cui , W. J Wu , W Tan , X Zhu , L. B Lanceta , S. K Sanganalmath , B Dawn , K Shinmura , G. D Rokosh , S Wang and R. Bolli
 

Background— Although inducible nitric oxide synthase (iNOS) is known to impart powerful protection against myocardial infarction, the mechanism for this salubrious action remains unclear.

Methods and Results— Adenovirus-mediated iNOS gene transfer in mice resulted 48 to 72 hours later in increased expression not only of iNOS protein but also of heme oxygenase (HO)-1 mRNA and protein; HO-2 protein expression did not change. iNOS gene transfer markedly reduced infarct size in wild-type mice, but this effect was completely abrogated in HO-1–/– mice. At 48 hours after iNOS gene transfer, nuclear factor-B was markedly activated. In transgenic mice with cardiomyocyte-restricted expression of a dominant negative mutant of IB (IBS32A,S36A), both basal HO-1 levels and upregulation of HO-1 by iNOS gene transfer were suppressed. Chromatin immunoprecipitation analysis of mouse hearts provided direct evidence that nuclear factor-B subunits p50 and p65 were recruited to the HO-1 gene promoter (–468 to –459 bp) 48 hours after iNOS gene transfer.

Conclusions— This study demonstrates for the first time the existence of a close functional coupling between cardiac iNOS and cardiac HO-1: iNOS upregulates HO-1 by augmenting nuclear factor-B binding to the region of the HO-1 gene promoter from –468 to –459 bp, and HO-1 then mediates the cardioprotective effects of iNOS. These results also reveal an important role of nuclear factor-B in both basal and iNOS-induced expression of cardiac HO-1. Collectively, the present findings significantly expand our understanding of the regulation of cardiac HO-1 and of the mechanism whereby iNOS exerts its cardioprotective actions.

  G Agnetti , N Kaludercic , L. A Kane , S. T Elliott , Y Guo , K Chakir , D Samantapudi , N Paolocci , G. F Tomaselli , D. A Kass and J. E. Van Eyk
 

Background— Cardiac resynchronization therapy (CRT) improves chamber mechanoenergetics and morbidity and mortality of patients manifesting heart failure with ventricular dyssynchrony; however, little is known about the molecular changes underlying CRT benefits. We hypothesized that mitochondria may play an important role because of their involvement in energy production.

Methods and Results— Mitochondria isolated from the left ventricle in a canine model of dyssynchronous or resynchronized (CRT) heart failure were analyzed by a classical, gel-based, proteomic approach. Two-dimensional gel electrophoresis revealed that 31 mitochondrial proteins where changed when controlling the false discovery rate at 30%. Key enzymes in anaplerotic pathways, such as pyruvate carboxylation and branched-chain amino acid oxidation, were increased. These concerted changes, along with others, suggested that CRT may increase the pool of Krebs cycle intermediates and fuel oxidative phosphorylation. Nearly 50% of observed changes pertained to subunits of the respiratory chain. ATP synthase-β subunit of complex V was less degraded, and its phosphorylation modulated by CRT was associated with increased formation (2-fold, P=0.004) and specific activity (+20%, P=0.05) of the mature complex. The importance of these modifications was supported by coordinated changes in mitochondrial chaperones and proteases. CRT increased the mitochondrial respiratory control index with tightened coupling when isolated mitochondria were reexposed to substrates for both complex I (glutamate and malate) and complex II (succinate), an effect likely related to ATP synthase subunit modifications and complex quantity and activity.

Conclusions— CRT potently affects both the mitochondrial proteome and the performance associated with improved cardiac function.

  B. G Nordestgaard , A. S Adourian , J. J Freiberg , Y Guo , P Muntendam and E. Falk
 

Background: Limited information is available regarding risk factors for the near-term (4 years) onset of myocardial infarction (MI). We evaluated established cardiovascular risk factors and putative circulating biomarkers as predictors for MI within 4 years of measurement.

Methods: We conducted a matched, nested case-control study (252 cases and 499 controls) drawing on 45 735 men and women participating in the Copenhagen City Heart Study and the Copenhagen General Population Study. Established risk factors and 17 putative biomarkers, including inflammation-sensitive plasma proteins (C-reactive protein, fibrinogen, l-antitrypsin, complement 3), apolipoproteins (A1, B, E, B/A1 ratio), markers of iron overload (iron, transferrin, transferrin saturation), creatinine, alkaline phosphatase, -glutamyl transpeptidase, and leukocytes (lymphocyte count, neutrophil count, neutrophil/lymphocyte ratio) were assessed.

Results: Among women and men, only 13% and 50%, respectively, of those with near-term MI were classified as high risk by Framingham risk score at baseline. After adjustment for established risk factors, odds ratios for near-term MI, which compared highest to lowest quintiles, were 2.87(95% CI 1.51–5.48; P = 0.001) for l-antitrypsin, 2.84(1.42–5.67; P = 0.003) for C-reactive protein, 1.97(1.09–3.57; P = 0.03) for creatinine, 1.99(1.09–3.65; P = 0.03) for fibrinogen, and 0.37(0.19–0.73; P = 0.004) for iron. The corresponding odds ratio for all biomarkers combined was 7.24 (3.28–16.0; P < 0.001).

Conclusions: We identified 5 biomarkers associated with increased near-term risk of MI independently of established risk factors. All putative biomarkers combined explained a 7-fold increase in the odds of near-term MI.

  Y Zhang , Y Jia , R Zheng , Y Guo , Y Wang , H Guo , M Fei and S. Sun
  BACKGROUND:

The liver is frequently subject to insult because of viral infection, alcohol abuse, or toxic chemical exposure. Extensive research has been conducted to identify blood markers that can better discern liver damage, but little progress has been achieved in clinical practice. Recently, circulating microRNAs (miRNAs) have been reported as potential biomarkers for the noninvasive diagnosis of cancer. In this study, we investigated whether plasma miRNAs have diagnostic utility in identifying liver disease.

METHODS:

The study was divided into 2 phases: marker selection by real-time quantitative PCR analysis of a small set of plasma samples, and marker validation with a large set of plasma samples from 83 patients with chronic hepatitis B viral infections, 15 patients with skeletal muscle disease, and 40 healthy controls. Two mouse model systems, d-galactosamine- and alcohol-induced liver injury, were also developed to evaluate whether differences in miRNA concentration were associated with various liver diseases.

RESULTS:

Among the miRNA candidates identified, miR-122 presented a disease severity–dependent change in plasma concentration in the patients and animal models. Compared with an increase in aminotransferase activity in the blood, the change in miR-122 concentration appeared earlier. Furthermore, this change was more specific for liver injury than for other organ damage and was more reliable, because the change was correlated with liver histologic stage.

CONCLUSIONS:

Our findings suggest that circulating miR-122 has potential as a novel, predictive, and reliable blood marker for viral-, alcohol-, and chemical-induced liver injury.

  H. H Liu , P Lu , Y Guo , E Farrell , X Zhang , M Zheng , B Bosano , Z Zhang , J Allard , G Liao , S Fu , J Chen , K Dolim , A Kuroda , J Usuka , J Cheng , W Tao , K Welch , Y Liu , J Pease , S. A de Keczer , M Masjedizadeh , J. S Hu , P Weller , T Garrow and G. Peltz
 

Acetaminophen-induced liver toxicity is the most frequent precipitating cause of acute liver failure and liver transplant, but contemporary medical practice has mainly focused on patient management after a liver injury has been induced. An integrative genetic, transcriptional, and two-dimensional NMR-based metabolomic analysis performed using multiple inbred mouse strains, along with knowledge-based filtering of these data, identified betaine-homocysteine methyltransferase 2 (Bhmt2) as a diet-dependent genetic factor that affected susceptibility to acetaminophen-induced liver toxicity in mice. Through an effect on methionine and glutathione biosynthesis, Bhmt2 could utilize its substrate (S-methylmethionine [SMM]) to confer protection against acetaminophen-induced injury in vivo. Since SMM is only synthesized in plants, Bhmt2 exerts its beneficial effect in a diet-dependent manner. Identification of Bhmt2 and the affected biosynthetic pathway demonstrates how a novel method of integrative genomic analysis in mice can provide a unique and clinically applicable approach to a major public health problem.

  M Li , Y Seki , P. H. L Freitas , M Nagata , T Kojima , S Sultana , S Ubaidus , T Maeda , J Shimomura , J. E Henderson , M Tamura , K Oda , Z Liu , Y Guo , R Suzuki , T Yamamoto , R Takagi and N. Amizuka
 

The signaling axis comprising the parathyroid hormone (PTH)-related peptide (PTHrP), the PTH/PTHrP receptor and the fibroblast growth factor receptor 3 (FGFR3) plays a central role in chondrocyte proliferation. The Indian hedgehog (IHH) gene is normally expressed in early hypertrophic chondrocytes, and its negative feedback loop was shown to regulate PTH/PTHrP receptor signaling. In this study, we examined the regulation of PTH/PTHrP receptor gene expression in a FGFR3-transfected chondrocytic cell line, CFK2. Expression of IHH could not be verified on these cells, with consequent absence of hypertrophic differentiation. Also, expression of the PTH/PTHrP receptor (75% reduction of total mRNA) and the PTHrP (50% reduction) genes was reduced in CFK2 cells transfected with FGFR3 cDNA. Interestingly, we verified significant reduction in cell growth and increased apoptosis in the transfected cells. STAT1 was detected in the nuclei of the CFK2 cells transfected with FGFR3 cDNA, indicating predominance of the JAK/STAT signaling pathway. The reduction in PTH/PTHrP receptor gene in CFK2 cells overexpressing FGFR3 was partially blocked by treatment with an inhibitor of JAK3 (WHI-P131), but not with an inhibitor of MAPK (SB203580) or JAK2 (AG490). Altogether, these findings suggest that FGFR3 down-regulates PTH/PTHrP receptor gene expression via the JAK/STAT signaling in chondrocytic cells.

  Y Guo , M Su , M. A McNutt and J. Gu
 

The importance of the molecule cystic fibrosis transmembrane conductance regulator (CFTR) is reflected in the many physiological functions it regulates. It is known to be present in epithelial cells of the lungs, pancreas, sweat glands, gut, and other tissues, and gene mutations of CFTR cause cystic fibrosis (CF). We studied the expression and distribution of CFTR in the human brain with reverse transcriptase polymerase chain reaction, in situ hybridization, and immunohistochemistry. This study demonstrates widespread and abundant expression of CFTR in neurons of the human brain. Techniques of double labeling and evaluation of consecutive tissue sections localized CFTR protein and mRNA signals to the cytoplasm of neurons in all regions of the brain studied, but not to glial cells. The presence of CFTR in central neurons not only provides a possible explanation for the neural symptoms observed in CF patients, but also may lead to a better understanding of the functions of CFTR in the human brain. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials. (J Histochem Cytochem 57:1113–1120, 2009)

  M Bhaskaran , Y Wang , H Zhang , T Weng , P Baviskar , Y Guo , D Gou and L. Liu
 

MicroRNAs (miRNAs) are small endogenous RNAs and are widely regarded as one of the most important regulators of gene expression in both plants and animals. To define the roles of miRNAs in fetal lung development, we profiled the miRNA expression pattern during lung development with a miRNA microarray. We identified 21 miRNAs that showed significant changes in expression during lung development. These miRNAs were grouped into four distinct clusters based on their expression pattern. Cluster 1 contained miRNAs whose expression increased as development progressed, while clusters 2 and 3 showed the opposite trend of expression. miRNAs in cluster 4 including miRNA-127 (miR-127) had the highest expression at the late stage of fetal lung development. Quantitative real-time PCR validated the microarray results of six selected miRNAs. In situ hybridization demonstrated that miR-127 expression gradually shifted from mesenchymal cells to epithelial cells as development progressed. Overexpression of miR-127 in fetal lung organ culture significantly decreased the terminal bud count, increased terminal and internal bud sizes, and caused unevenness in bud sizes, indicating improper development. These findings suggest that miR-127 may have an important role in fetal lung development.

  T Ma , Z Wang , Y Guo and D. Pei
 

Overexpression of Nanog in mouse embryonic stem (ES) cells has been shown to abrogate the requirement of leukemia inhibitory factor for self-renewal in culture. Little is known about the molecular mechanism of Nanog function. Here we describe the role of the tryptophan repeat (WR) domain, one of the two transactivators at its C terminus, in regulating stem cell proliferation as well as pluripotency. We first created a supertransactivator, W2W3x10, by duplicating repeats W2W3 10 times and discovered that it can functionally substitute for wild type WR at sustaining pluripotency, albeit with a significantly slower cell cycle, phenocopying Nanog(9W) with the C-terminal pentapeptide (WNAAP) of WR deleted. ES cells carrying both W2W3x10 and Nanog(9W) have a longer G1 phase, a shorter S phase in cell cycle distribution and progression analysis, and a lower level of pAkt(Ser473) compared with wild type Nanog, suggesting that both mutants impact the cell cycle machinery via the phosphatidylinositol 3-kinase/Akt pathway. Both mutants remain competent in dimerizing with Nanog but cannot form a complex with Nac1 efficiently, suggesting that WNAAP may be involved in Nac1 binding. By tagging Gal4DBD with WNAAP, we demonstrated that this pentapeptide is sufficient to confer Nac1 binding. Furthermore, we can rescue W2W3x10 by placing WNAAP at the corresponding locations. Finally, we found that Nanog and Nac1 synergistically up-regulate ERas expression and promote the proliferation of ES cells. These results suggest that Nanog interacts with Nac1 through WNAAP to regulate the cell cycle of ES cells via the ERas/phosphatidylinositol 3-kinase/Akt pathway, but not pluripotency, thus decoupling cell cycle control from pluripotency.

 
 
 
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