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Articles by R Zhang
Total Records ( 26 ) for R Zhang
  J Tsai , R Zhang , W Qiu , Q Su , M Naples and K. Adeli
 

Insulin-resistant states are commonly associated with chronic inflammation and hepatic overproduction of apolipoprotein B100 (apoB100), leading to hypertriglyceridemia and a metabolic dyslipidemic profile. Molecular mechanisms linking hepatic inflammatory cascades and the pathways of apoB100-lipoprotein production are, however, unknown. In the present study, we employed a diet-induced, insulin-resistant hamster model, as well as cell culture studies, to investigate the potential link between activation of hepatic inflammatory nuclear factor-B (NF-B) signaling cascade and the synthesis and secretion of apoB100-containing lipoproteins. Using an established insulin-resistant animal model, the fructose-fed hamster, we found that feeding fructose (previously shown to induce hepatic inflammation) for as little as 4 days reduced hepatic IB (inhibitor of NF-B) level, indicating activation of the inflammatory NF-B cascade. Importantly, IKK (IB kinase) inhibition was found to suppress apoB100 overproduction in fructose-fed hamster hepatocytes. As IKK, the upstream activator of NF-B has been shown to inhibit insulin signaling, and insulin is a major regulator of apoB100, we modulated IKK activity in primary hamster hepatocytes and HepG2 cells and assessed the effects on hepatic apoB100 biosynthesis. Inhibition of the IKK-NF-B pathway by BMS345541 and activation of the pathway by adenoviral-mediated IKK overexpression decreased and increased newly synthesized apoB100 levels, respectively. Pulse-chase and metabolic labeling experiments revealed that IKK activation regulates apoB100 levels at the levels of apoB100 biosynthesis and protein stability. Inhibition of the IKK-NF-B pathway significantly enhanced proteasomal degradation of hepatic apoB100, while direct IKK activation led to reduced degradation and increased apoB100 mRNA translation. Together, our results reveal important links between modulation of the inflammatory IKK-NF-B signaling cascade and hepatic synthesis and secretion of apoB100-containing lipoproteins. Hepatic inflammation may be an important underlying factor in hepatic apoB100 overproduction observed in insulin resistance.

  K Shannon , T Kerr , B Marshall , K Li , R Zhang , S. A Strathdee , M. W Tyndall , J. G. S Montaner and E. Wood
 

Objective  To examine whether there were differential rates of hepatitis C virus (HCV) incidence in injecting drug–using youths who did and did not report involvement in survival sex work.

Design  Data were derived from 2 prospective cohort studies of injecting drug users (May 1, 1996, to July 31, 2007). Analyses were restricted to HCV antibody–negative youths who completed baseline and at least 1 follow-up assessment.

Setting  Vancouver, British Columbia, Canada.

Participants  Of 3074 injecting drug users, 364 (11.8%) were youths (aged 14-24 years) with a median age of 21.3 years and a duration of injecting drug use of 3 years.

Main Exposure  Survival sex work involvement.

Main Outcome Measure  The Kaplan-Meier method and Cox proportional hazards regression were used to compare HCV incidence among youths who did and did not report survival sex work.

Results  Baseline HCV prevalence was 51%, with youths involved in survival sex work significantly more likely to be HCV antibody positive (60% vs 44%; P = .002). In baseline HCV antibody–negative youths, the cumulative HCV incidence at 36 months was significantly higher in those involved in survival sex work (68.4% vs 38.8%; P < .001). The HCV incidence density was 36.8 (95% confidence interval [CI], 24.2-53.5) per 100 person-years in youths reporting survival sex work involvement at baseline compared with 14.1 (9.4-20.3) per 100 person-years in youths not reporting survival sex work. In multivariate Cox proportional hazards analyses, survival sex work was the strongest predictor of elevated HCV incidence (adjusted relative hazard, 2.30; 95% CI, 1.27-4.15).

Conclusion  This study calls attention to the critical need for evidence-based social and structural HCV prevention efforts that target youths engaged in survival sex work.

  R. P Sahu , R Zhang , S Batra , Y Shi and S. K. Srivastava
 

In our previous studies, we have shown that benzyl isothiocyanate (BITC) inhibits the growth of human pancreatic cancer cells by inducing apoptosis. In the present study, we demonstrate the activation of all the three (MAPK) family members [extracellular signal-regulated protein kinase (ERK), c-jun N-terminal kinase (JNK) and P38] in response to BITC treatment. Exposure of Capan-2 cells with varying concentrations of BITC for 24 h resulted in the phosphorylation (activation) of ERK at Thr202/Tyr204, JNK at Thr183/Tyr185 and P38 at Thr180/Tyr182, leading to the induction of apoptosis. Similar MAPK activation was also observed in MiaPaCa-2 cells in response to BITC treatment. However, normal human pancreatic ductal epithelial cells did not show the activation of MAPK's and remained unaffected by BITC treatment. To confirm the role of ERK, JNK and P38 in BITC-induced G2/M arrest and apoptosis, Capan-2 cells were pre-treated with MAPK-specific inhibitors or MAPK8-short hairpin RNA (shRNA) prior to BITC treatment. Significant protection from BITC-induced G2/M arrest was observed in the cells pre-treated with MAPK kinase (MEK-1) but not JNK or P38 inhibitors. On the other hand, BITC-induced apoptosis was almost completely abrogated in the cells pre-treated with MEK-1, JNK or P38 inhibitors. Similarly, MAPK8-shRNA also offered almost complete protection against BITC-induced G2/M arrest and apoptosis. Furthermore, we observed that BITC treatment leads to the generation of reactive oxygen species (ROS) in Capan-2 and MiaPaCa-2 cells, which in part was orchestrated by depletion of reduced glutathione (GSH) level. Blocking ROS generation with N-acetyl-L-cysteine (NAC) significantly prevented GSH depletion and activation of ERK and JNK but not P38. Further, NAC or tiron prevented G2/M arrest by blocking G2/M regulatory proteins and completely protected the cells from BITC-induced apoptosis. Taken together, our results suggest that BITC-mediated G2/M arrest is mediated through ERK activation, whereas apoptosis is via ERK, JNK and P38.

  S Shi , D. Y Yoon , K. C Hodge Bell , I. G Bebenek , M. J Whitekus , R Zhang , A. J Cochran , S Huerta Yepez , S. H Yim , F. J Gonzalez , A. K Jaiswal and O. Hankinson
 

Benzo[a]pyrene (B[a]P) is a ligand for the aryl hydrocarbon receptor (Ahr). After binding ligand, Ahr dimerizes with the aryl hydrocarbon receptor nuclear translocator (Arnt) protein, and the dimer upregulates the transcription of Cyp1a1, Cyp1b1 and other enzymes involved in the metabolic activation of B[a]P. Arnt null mice die in utero. Mice in which Arnt deletion occurs constitutively in the epidermis die perinatally. In the current study, mice were developed in which the Arnt gene could be deleted specifically in adult skin epidermis. This deletion had no overt pathological effect. Homozygosity for a null reduced nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase allele was introduced into the above mouse strain to render it more susceptible to tumor initiation by B[a]P. Deletion of Arnt in the epidermis of this strain completely prevented the induction of skin tumors in a tumor initiation–promotion protocol in which a single topical application of B[a]P acted as the tumor-initiating event, and tumor promotion was provided by repeated topical applications of 12-O-tetradecanoyl phorbol-13-acetate (TPA). In contrast, deletion of Arnt did not prevent the induction of skin tumors in a protocol also using TPA as the promoter but using as the initiator N-methyl-N'-nitro-N-nitrosoguanidine, whose activity is unlikely to be affected by the activity of Ahr, Arnt or their target genes. These observations demonstrate that Arnt is required for tumor initiation by B[a]P in this system.

  H Chen , T Kluz , R Zhang and M. Costa
 

Epigenetic silencing of tumor suppressor genes commonly occurs in human cancers via increasing DNA methylation and repressive histone modifications at gene promoters. However, little is known about how pathogenic environmental factors contribute to cancer development by affecting epigenetic regulatory mechanisms. Previously, we reported that both hypoxia and nickel (an environmental carcinogen) increased global histone H3 lysine 9 methylation in cells through inhibiting a novel class of iron- and -ketoglutarate-dependent histone demethylases. Here, we investigated whether inhibition of histone demethylase JMJD1A by hypoxia and nickel could lead to repression/silencing of JMJD1A-targeted gene(s). By using Affymetrix GeneChip and ChIP-on-chip technologies, we identified Spry2 gene, a key regulator of receptor tyrosine kinase/extracellular signal-regulated kinase (ERK) signaling, as one of the JMJD1A-targeted genes in human bronchial epithelial BEAS-2B cells. Both hypoxia and nickel exposure increased the level of H3K9me2 at the Spry2 promoter by inhibiting JMJD1A, which probably led to a decreased expression of Spry2 in BEAS-2B cells. Repression of Spry2 potentiated the nickel-induced ERK phosphorylation, and forced expression of Spry2 in BEAS-2B cells decreased the nickel-induced ERK phosphorylation and significantly suppressed nickel-induced anchorage-independent growth. Taken together, our results suggest that histone demethylases could be targets of environmental carcinogens and their inhibition may lead to altered gene expression and eventually carcinogenesis.

  R Zhang , A Paramesh , S Florman , C. L Yau , S Balamuthusamy , N. K Krane and D. Slakey
 

Background and objectives: The optimal donor age for transplanting a single pediatric kidney in an adult recipient remains unknown. En block kidney transplantation is usually performed when the donor age is <5 yr.

Design, setting, participants, & measurements: We compared the outcomes of adult patients who underwent transplantation with single pediatric kidneys from donors who were younger than 5 yr (group 1, n = 40) and from donors who were aged 5 to 10 yr of age (group 2, n = 39) in our center.

Results: The donor kidney sizes were significantly smaller in group 1 than in group 2 (P < 0.001), and group 1 required more ureteral stents than group 2 (73 versus 38%). The surgical complications, delayed graft function, and development of proteinuria were similar in both groups. Group 1 had slightly higher rejection episodes than group 2 (25 versus 18%; P = 0.67), and graft function was comparable in both groups. There were no statistical differences between the two groups in patient (P = 0.73) or death-censored graft (P = 0.68) survivals over 5 yr.

Conclusions: Single pediatric kidney transplants from donors who are younger than 5 yr can be used with acceptable complications and long-term outcomes as those from older donors.

  N. G Kutner , R Zhang , Y Huang and K. L. Johansen
 

Background and objectives: When patients start dialysis, their employment rate declines and disability benefits are an option. With patient sociodemographic and clinical characteristics including disability income status controlled, we investigated the significance of depressed mood and usual activity level as predictors of patients' continued employment after dialysis start.

Design, setting, participants, & measurements: Incident patients from 296 randomly selected dialysis clinics were surveyed in the Comprehensive Dialysis Study (CDS). Participants provided information about employment status, disability income status, education, depressive symptoms measured by the Patient Health Questionnaire-2 (PHQ-2), and usual activity level/energy expenditure measured by the Human Activity Profile. Age, gender, race, insurance, diabetes, inability to ambulate or transfer, chronic obstructive pulmonary disease, cardiovascular conditions, and hemoglobin and serum albumin values at treatment start were obtained from US Renal Data System files. Dialysis modality was defined at time of interview.

Results: Among 585 CDS participants who worked in the previous year, 191 (32.6%) continued working after dialysis start. On the basis of the PHQ-2 cutoff score ≥3, 12.1% of patients who remained employed had possible or probable depression, compared with 32.8% of patients who were no longer employed. In adjusted analyses, higher Human Activity Profile scores were associated with increased likelihood of continued employment, and there was a borderline association between lower PHQ-2 scores and continued employment.

Conclusions: Screening and management of depressive symptoms and support for increased activity level may facilitate patients' opportunity for continued employment after dialysis start, along with generally improving their overall quality of life.

  R Zhang , E Maratos Flier and J. S. Flier
 

The concept that obesity is an inflammatory state has changed our understanding of this condition and suggested that pharmacological interventions targeting inflammation may be useful strategies to improve metabolic complications of obesity. Phosphodiesterase 4 (PDE4) inhibitors exhibit profound antiinflammatory effects, but whether PDE4 inhibition suppresses obesity-induced inflammation is unknown. Among PDE4 isoforms, PDE4B is the major species mediating inflammatory responses. We therefore examined obesity-related phenotypes in mice deficient for PDE4B. Compared with wild-type littermates, PDE4B-null mice were leaner, with lower fat pad weights, smaller adipocytes, and decreased serum leptin levels on both chow and high-fat diets (HFDs). PDE4B deficiency suppressed TNF- mRNA levels and macrophage infiltration in white adipose tissue in mice on HFD, but insulin sensitivity was unaltered. PDE4B-null mice on HFDs had increased locomotor activity. These results suggest a previously unappreciated role for PDE4B in the regulation of energy balance and that PDE4B inhibitors could have utility in treatment of obesity and for suppression of obesity-induced inflammation in white adipose tissue.

  M. A Grobei , E Qeli , E Brunner , H Rehrauer , R Zhang , B Roschitzki , K Basler , C. H Ahrens and U. Grossniklaus
 

Pollen, the male gametophyte of flowering plants, represents an ideal biological system to study developmental processes, such as cell polarity, tip growth, and morphogenesis. Upon hydration, the metabolically quiescent pollen rapidly switches to an active state, exhibiting extremely fast growth. This rapid switch requires relevant proteins to be stored in the mature pollen, where they have to retain functionality in a desiccated environment. Using a shotgun proteomics approach, we unambiguously identified ~3500 proteins in Arabidopsis pollen, including 537 proteins that were not identified in genetic or transcriptomic studies. To generate this comprehensive reference data set, which extends the previously reported pollen proteome by a factor of 13, we developed a novel deterministic peptide classification scheme for protein inference. This generally applicable approach considers the gene model–protein sequence–protein accession relationships. It allowed us to classify and eliminate ambiguities inherently associated with any shotgun proteomics data set, to report a conservative list of protein identifications, and to seamlessly integrate data from previous transcriptomics studies. Manual validation of proteins unambiguously identified by a single, information-rich peptide enabled us to significantly reduce the false discovery rate, while keeping valuable identifications of shorter and lower abundant proteins. Bioinformatic analyses revealed a higher stability of pollen proteins compared to those of other tissues and implied a protein family of previously unknown function in vesicle trafficking. Interestingly, the pollen proteome is most similar to that of seeds, indicating physiological similarities between these developmentally distinct tissues.

  J Chettiar , K Shannon , E Wood , R Zhang and T. Kerr
  Background

Drug users engaged in survival sex work are at heightened risk for drug- and sexual-related harms. We examined factors associated with survival sex work among street-involved youth in Vancouver, Canada.

Methods

From September 2005 to November 2007, baseline data were collected for the At-Risk Youth Study (ARYS), a prospective cohort of street-recruited youth aged 14–26 who use illicit drugs. Using multiple logistic regression, we compared youth who reported exchanging sex for money, drugs etc. with those who did not.

Results

The sample included 560 youth: median age 22; 179 (32%) female; 63 (11%) reporting recent survival sex work. Factors associated with survival sex work in multivariate analyses included non-injection crack use [adjusted odds ratio (AOR) = 3.45, 95% confidence interval (CI): 1.75–6.78], female gender (AOR = 3.02, 95% CI: 1.66–5.46), Aboriginal ethnicity (AOR = 2.35, 95% CI: 1.28–4.29) and crystal methamphetamine use (AOR = 2.02, 95% CI: 1.13–3.62). In subanalyses, the co-use of crack cocaine and methamphetamine was shown to be driving the association between methamphetamine and survival sex work.

Conclusions

This study demonstrates a positive interactive effect of dual stimulant use in elevating the odds of survival sex work among street youth who use drugs. Novel approaches to reduce the harms associated with survival sex work among street youth who use stimulants are needed.

  M. J. S Milloy , T Kerr , R Zhang , M Tyndall , J Montaner and E. Wood
  Background

Treatment for drug addiction is effective in reducing the harms of injection drug use, including infection with HIV and/or hepatitis C. We sought to examine the prevalence and correlates of being unable to access addiction treatment in a representative sample of injection drug users randomly recruited from a supervised injection facility.

Methods

Using generalized estimating equations, we determined the prevalence and factors associated with being unable to access addiction treatment.

Results

Between 1 July 2004 and 30 June 2006, 889 individuals completed at least one interview and were included in this analysis. At each interview, ~20% of respondents reported trying but being unable to access any type of drug or alcohol treatment in the previous 6 months. Being unable to access treatment was independently associated with recent incarceration, daily use of heroin and borrowing used syringes. In a secondary question, the majority of individuals reported waiting lists were the reason for being unable to access treatment.

Conclusion

Given the independent association between inability to access addiction treatment and elevated HIV risk behavior, these results suggest expanding addiction treatment may contribute significantly to HIV prevention efforts in this population.

  Y Wang , D Liang , S Wang , Z Qiu , X Chu , S Chen , L Li , X Nie , R Zhang , Z Wang and D. Zhu
 

It has been previously reported by us that hypoxia activates lung 15-lipoxygenase (15-LO), which catalyzes arachidonic acid to 15-hydroxyeicosatetraenoic acid (15-HETE), leading to the constriction of pulmonary artery (PA). Rho-associated serine/threonine kinase (ROK), a downstream effector of small GTPase RhoA that may be modulated by G-protein and tyrosine kinase, plays an important role in smooth muscle contraction. However, whether the 15-HETE induced PA vasoconstriction involves the Rho/ROK pathway remains to be demonstrated. Therefore, we studied the contribution of ROK as well as G-protein and tyrosine kinase to the 15-HETE induced pulmonary vasoconstriction using PA ring technique, RNA interference technology, RP-HPLC, western blot and RT-PCR combined with the blockers. The hypoxia-induced expression of ROK is regulated by 15-HETE in rat PA smooth muscle cells (PASMCs), leading to vasoconstriction. The up-regulation of ROK expression caused by 15-HETE appears to be mediated by the G-protein and tyrosine kinase pathways. The translocation of ROK2 from the nucleus to the cytoplasm during hypoxia exposure relies on the mechanism for 15-HETE production. These results suggest that 15-HETE may mediate the up-regulation of ROK expression through G-protein and tyrosine kinase pathways under hypoxic condition, leading to PA vasoconstriction.

  M. A Moody , H. X Liao , S. M Alam , R. M Scearce , M. K Plonk , D. M Kozink , M. S Drinker , R Zhang , S. M Xia , L. L Sutherland , G. D Tomaras , I. P Giles , J. C Kappes , C Ochsenbauer Jambor , T. G Edmonds , M Soares , G Barbero , D. N Forthal , G Landucci , C Chang , S. W King , A Kavlie , T. N Denny , K. K Hwang , P. P Chen , P. E Thorpe , D. C Montefiori and B. F. Haynes
 

Traditional antibody-mediated neutralization of HIV-1 infection is thought to result from the binding of antibodies to virions, thus preventing virus entry. However, antibodies that broadly neutralize HIV-1 are rare and are not induced by current vaccines. We report that four human anti-phospholipid monoclonal antibodies (mAbs) (PGN632, P1, IS4, and CL1) inhibit HIV-1 CCR5-tropic (R5) primary isolate infection of peripheral blood mononuclear cells (PBMCs) with 80% inhibitory concentrations of <0.02 to ~10 µg/ml. Anti-phospholipid mAbs inhibited PBMC HIV-1 infection in vitro by mechanisms involving binding to monocytes and triggering the release of MIP-1 and MIP-1β. The release of these β-chemokines explains both the specificity for R5 HIV-1 and the activity of these mAbs in PBMC cultures containing both primary lymphocytes and monocytes.

 
 
 
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