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Articles by W Zhu
Total Records ( 9 ) for W Zhu
  W Zhu , D Czyzyk , S. A Paranjape , L Zhou , A Horblitt , G Szabo , M. R Seashore , R. S Sherwin and O. Chan
 

Local delivery of glucose into a critical glucose-sensing region within the brain, the ventromedial hypothalamus (VMH), can suppress glucose counterregulatory responses to systemic hypoglycemia. Here, we investigated whether this suppression was accomplished through changes in GABA output in the VMH. Sprague-Dawley rats had catheters and guide cannulas implanted. Eight to ten days later, microdialysis-microinjection probes were inserted into the VMH, and they were dialyzed with varying concentrations of glucose from 0 to 100 mM. Two groups of rats were microdialyzed with 100 mM glucose and microinjected with either the KATP channel opener diazoxide or a GABAA receptor antagonist. These animals were then subjected to a hyperinsulinemic-hypoglycemic glucose clamp. As expected, perfusion of glucose into the VMH suppressed the counterregulatory responses. Extracellular VMH GABA levels positively correlated with the concentration of glucose in the perfusate. In turn, extracellular GABA concentrations in the VMH were inversely related to the degree of counterregulatory hormone release. Of note, microinjection of either diazoxide or the GABAA receptor antagonist reversed the suppressive effects of VMH glucose delivery on counterregulatory responses. Some GABAergic neurons in the VMH respond to changes in local glucose concentration. Glucose in the VMH dose-dependently stimulates GABA release, and this in turn dose-dependently suppresses the glucagon and epinephrine responses to hypoglycemia. These data suggest that during hypoglycemia a decrease in glucose concentration within the VMH may provide an important signal that rapidly inactivates VMH GABAergic neurons, reducing inhibitory GABAergic tone, which in turn enhances the counterregulatory responses to hypoglycemia.

  T Tanvetyanon , D Qin , T Padhya , J McCaffrey , W Zhu , D Boulware , R DeConti and A. Trotti
 

Objective  To investigate the potential value of postoperative concurrent chemoradiation among patients with high-risk salivary gland carcinomas.

Design  Case control study based on retrospective medical record review.

Setting  A tertiary care comprehensive cancer center.

Patients  A total of 24 patients, 12 with major salivary gland carcinoma who were treated with postoperative concurrent chemoradiotherapy from 1998 to 2007 (chemoradiation group), and a control group of 12 patients treated with postoperative radiation alone.

Main Outcome Measures  Overall survival, progression-free survival, toxic effects.

Results  All but 1 patient had stage III or IV disease; close or positive surgical margins were identified in 20 patients (83%). The median radiation dose was 63 Gy. In the chemoradiation group, platinum-based regimens were used in all. Treatment was well tolerated, but toxic effects, predominantly hematologic, were increased in the chemoradiation group. To date, 8 patients have died; the median overall survival was 53 months. The overall survival in the chemoradiation group was significantly better than in the radiation-alone group: 3-year survival rates were 83% and 44%, respectively (P = .05).

Conclusions  Locally advanced or high-grade salivary gland carcinomas follow an aggressive clinical course. Based on our limited experience, postoperative chemoradiation with a platinum-based regimen seems to be effective in selected patients and warrants further investigation.

  H. C Cheung , T Hai , W Zhu , K. A Baggerly , S Tsavachidis , R Krahe and G. J. Cote
 

Polypyrimidine tract-binding protein 1 (PTBP1) is a multi-functional RNA-binding protein that is aberrantly overexpressed in glioma. PTBP1 and its brain-specific homologue polypyrimidine tract-binding protein 2 (PTBP2) regulate neural precursor cell differentiation. However, the overlapping and non-overlapping target transcripts involved in this process are still unclear. To determine why PTBP1 and not PTBP2 would promote glial cell-derived tumours, both PTBP1 and PTBP2 were knocked down in the human glioma cell lines U251 and LN229 to determine the role of these proteins in cell proliferation, migration, and adhesion. Surprisingly, removal of both PTBP1 and PTBP2 slowed cell proliferation, with the double knockdown having no additive effects. Decreased expression of both proteins individually and in combination inhibited cell migration and increased adhesion of cells to fibronectin and vitronectin. A global survey of differential exon expression was performed following PTBP1 knockdown in U251 cells using the Affymetrix Exon Array to identify PTBP1-specific splicing targets that enhance gliomagenesis. In the PTBP1 knockdown, previously determined targets were unaltered in their splicing patterns. A single gene, RTN4 (Nogo) had significantly enhanced inclusion of exon 3 when PTBP1 was removed. Overexpression of the splice isoform containing exon 3 decreased cell proliferation to a similar degree as the removal of PTBP1. These results provide the first evidence that RNA-binding proteins affect the invasive and rapid growth characteristics of glioma cell lines. Its actions on proliferation appear to be mediated, in part, through alternative splicing of RTN4.

  W Zhu and M. L. DePamphilis
 

Eukaryotic cells normally restrict genome duplication to once per cell division. In metazoa, re-replication of DNA during a single S phase seems to be prevented solely by suppressing CDT1 activity, a protein required for loading the replicative MCM DNA helicase. However, siRNA suppression of geminin (a specific inhibitor of CDT1) arrested proliferation only of cells derived from cancers by inducing DNA re-replication and DNA damage that spontaneously triggered apoptosis. None of these effects were detected either in cells derived from normal human tissues or in cells immortalized by a viral oncogene. To induce these effects in noncancer cells required suppression of both geminin and cyclin A, another cell cycle regulator. Therefore, initiating DNA replication in some cancer cells is limited solely by regulating the level of CDT1 activity with geminin, whereas noncancer cells contain additional safeguards that prevent DNA re-replication. These results show that inhibition of geminin activity could be used to selectively kill cancer cells without harming other cells. [Cancer Res 2009;69(11):4870–7]

  W Zhu , C. M Trivedi , D Zhou , L Yuan , M. M Lu and J. A. Epstein
 

Rationale: Cardiac hypertrophy occurs in response to a variety of extrinsic and intrinsic stimuli that impose increased biomechanical stress. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway has previously been strongly associated with hypertrophic signaling in the heart, and with the control of cell size in multiple contexts. This pathway is tightly regulated by many factors, including a host of kinases and phosphatases that function at multiple steps in the signaling cascade. For example, the PTEN (phosphatase and tensin homolog) tumor suppressor protein is a phosphoinositide 3-phosphatase that, by metabolizing phosphatidylinositol 3,4,5-trisphosphate (PtdIns[3,4,5]P3, PIP3), acts in direct antagonism to growth factor–stimulated PI3K. Inhibition of PTEN leads to cardiomyocyte hypertrophy. Another polyphoinositide phosphatase, inositol polyphosphate-5-phosphatase F (Inpp5f) has recently been implicated in regulation of cardiac hypertrophy. Like PTEN, this phosphatase can degrade PtdIns(3,4,5)P3 and thus modulates the PI3K/Akt pathway.

Objective: To characterize the role of Inpp5f in regulating cardiac hypertrophy.

Methods and Results: We generated homozygous Inpp5f knockout mice and cardiac specific Inpp5f overexpression transgenic mice. We evaluated their hearts for biochemical, structural and functional changes. Inpp5f knockout mice have augmented hypertrophy and reactivation of the fetal gene program in response to stress when compared to wild-type littermates. Furthermore, cardiac overexpression of Inpp5f in transgenic mice reduces hypertrophic responsiveness.

Conclusions: Our results suggest that Inpp5f is a functionally important endogenous modulator of cardiac myocyte size and of the cardiac response to stress.

  W Peng , Y Zhang , M Zheng , H Cheng , W Zhu , C. M Cao and R. P. Xiao
 

Rationale: Ca2+/calmodulin-dependent protein kinase (CaMK)II is a multifunctional kinase involved in vital cellular processes such as Ca2+ handling and cell fate regulation. In mammalian heart, 2 primary CaMKII isoforms, B and C, localize in nuclear and cytosolic compartments, respectively. Although previous studies have established an essential role of CaMKII-C in cardiomyocyte apoptosis, the functional role of the more abundant isoform, CaMKII-B, remains elusive.

Objective: Here, we determined the potential role of CaMKII-B in regulating cardiomyocyte viability and explored the underlying mechanism.

Methods and Results: In cultured neonatal rat cardiomyocytes, the expression of CaMKII-B and CaMKII-C was inversely regulated in response to H2O2-induced oxidative stress with a profound reduction of the former and an increase of the later. Similarly, in vivo ischemia/reperfusion (IR) led to an opposite regulation of these CaMKII isoforms in a rat myocardial IR model. Notably, overexpression of CaMKII-B protected cardiomyocytes against oxidative stress-, hypoxia-, and angiotensin II-induced apoptosis, whereas overexpression of its cytosolic counterpart promoted apoptosis. Using cDNA microarray, real-time PCR and Western blotting, we demonstrated that overexpression of CaMKII-B but not CaMKII-C elevated expression of heat shock protein (HSP)70 family members, including inducible (i)HSP70 and its homolog (Hst70). Moreover, overexpression of CaMKII-B led to phosphorylation and activation of heat shock factor (HSF)1, the primary transcription factor responsible for HSP70 gene regulation. Importantly, gene silencing of iHSP70, but not Hst70, abolished CaMKII-B-mediated protective effect, indicating that only iHSP70 was required for CaMKII-B elicited antiapoptotic signaling.

Conclusions: We conclude that cardiac CaMKII-B and CaMKII-C were inversely regulated in response to oxidative stress and IR injury, and that in contrast to CaMKII-C, CaMKII-B serves as a potent suppressor of cardiomyocyte apoptosis triggered by multiple death-inducing stimuli via phosphorylation of HSF1 and subsequent induction of iHSP70, marking both CaMKII- isoforms as promising therapeutic targets for the treatment of ischemic heart disease.

  W Wang , R Lau , D Yu , W Zhu , A Korman and J. Weber
 

Regulatory CD4+CD25Hi T cells (Treg) and programmed death-1 (PD-1) molecule have emerged as pivotal players in immune regulation. However, the underlying mechanisms by which they impact antigen-specific CD8+ immune responses in cancer patients and how they interact with each other under physiologic conditions remain unclear. Herein, we examined the relationship of PD-1 and its abrogation to the function of Treg in patients with melanoma using short-term in vitro assays to generate melanoma-specific T cells. We identified Treg in the circulation of vaccinated melanoma patients and detected PD-1 expression on vaccine-induced melanoma antigen-specific CTLs, as well as on and within Treg from patients’ peripheral blood. Programmed death ligand (PD-L) 1 expression was also detected on patients’ Treg. PD-1 blockade promoted the generation of melanoma antigen-specific CTLs and masked their inhibition by Treg. The mechanisms by which PD-1 blockade mediated immune enhancement included direct augmentation of melanoma antigen-specific CTL proliferation, heightening their resistance to inhibition by Treg and direct limitation of the inhibitory ability of Treg. PD-1 blockade reversed the increased expression of PD-1 and PD-L1 on melanoma antigen-specific CTL by Treg, rescued INF- and IL-2 or INF- and tumor necrosis factor- co-expression and expression of IL-7 receptor by melanoma antigen-specific CTL which were diminished by Treg. PD-1 blockade also resulted in down-regulation of intracellular FoxP3 expression by Treg. These data suggest that PD-1 is importantly implicated in the regulation of Treg function in melanoma patients.

  S Hunter , K Love Jackson , R Abdulla , W Zhu , J. H Lee , K. J Wells and R. Roetzheim
  Background

Elementary schools represent both a source of childhood sun exposure and a setting for educational interventions.

Methods

Sun Protection of Florida's Children was a cluster randomized trial promoting hat use at (primary outcome) and outside of schools among fourth-grade students during August 8, 2006, through May 22, 2007. Twenty-two schools were randomly assigned to the intervention (1115 students) or control group (1376 students). Intervention schools received classroom sessions targeting sun protection attitudes and social norms. Each student attending an intervention school received two free wide-brimmed hats. Hat use at school was measured by direct observation and hat use outside of school was measured by self-report. A subgroup of 378 students (178 in the intervention group and 200 in the control group) underwent serial measurements of skin pigmentation to explore potential physiological effects of the intervention. Generalized linear mixed models were used to evaluate the intervention effect by accounting for the cluster randomized trial design. All P values were two-sided and were claimed as statistically significant at a level of .05.

Results

The percentage of students observed wearing hats at control schools remained essentially unchanged during the school year (baseline = 2%, fall = 0%, and spring = 1%) but increased statistically significantly at intervention schools (baseline = 2%, fall = 30%, and spring = 41%) (P < .001 for intervention effect comparing the change in rate of hat use over time at intervention vs control schools). Self-reported use of hats outside of school did not change statistically significantly during the study (control: baseline = 14%, fall = 14%, and spring = 11%; intervention: baseline = 24%, fall = 24%, and spring = 23%) nor did measures of skin pigmentation.

Conclusions

The intervention increased use of hats among fourth-grade students at school but had no effect on self-reported wide-brimmed hat use outside of school or on measures of skin pigmentation.

  W Zhu , U. M Chandrasekharan , S Bandyopadhyay , S. M Morris , P. E DiCorleto and V. S. Kashyap
 

Arterial thrombosis is a common disease leading to severe ischemia beyond the obstructing thrombus. Additionally, endothelial dysfunction at the site of thrombosis can be rescued by l-arginine supplementation or arginase blockade in several animal models. Exposure of rat aortic endothelial cells (RAECs) to thrombin upregulates arginase I mRNA and protein levels. In this study, we further investigated the molecular mechanism of thrombin-induced arginase changes in endothelial cells. Thrombin strikingly increased arginase I promoter and enzyme activity in primary cultured RAECs. Using different deletion and point mutations of the promoter, we demonstrated that the activating protein-1 (AP-1) consensus site located at –3,157 bp in the arginase I promoter was a thrombin-responsive element. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay further confirmed that upon thrombin stimulation, c-Jun and activating transcription factor-2 (ATF-2) bound to the AP-1 site, which initiated the transactivation. Moreover, loss-of-function studies using small interfering RNA confirmed that recruitment of these two transcription factors to the AP-1 site was required for thrombin-induced arginase upregulation. In the course of defining the signaling pathway leading to the activation of AP-1 by thrombin, we found thrombin-induced phosphorylation of stress-activated protein kinase/c-Jun-NH2-terminal kinase (SAPK/JNK or JNK1/2/3) and p38 mitogen-activated protein kinase, which were followed by the phosphorylation of both c-Jun and ATF-2. These findings reveal the basis for thrombin induction of endothelial arginase I and indicate that arginase inhibition may be an attractive therapeutic alternative in the setting of arterial thrombosis and its associated endothelial dysfunction.

 
 
 
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