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Articles by S Zhang
Total Records ( 15 ) for S Zhang
  D Sun , S Zhang , Y Wei and L. Yin
 

Mangostin (MAG), a kind of xanthone widely used in diet and medicine, has antioxidant, anti-inflammatory, antimicrobial, and anticancer activities. On account of its antioxidant activity, MAG might protect cancer cells from free radical damage in photodynamic therapy (PDT) during which reactive oxygen species production was stimulated leading to irreversible tumor cell injury. In this study, the antioxidant activity of MAG was investigated and the influence of MAG on K562 cells in 5-aminolevulinic acid (ALA)-based PDT is demonstrated. The results showed that MAG could scavenge hydroxyl radical, superoxide anion, and hydrogen peroxide and inhibit the formation of malondialdehyde (MDA), but increase the amounts of singlet oxygen in cell-free systems. MAG inhibits cell proliferation and enhances cell apoptosis, lipid peroxidation, and DNA damage in ALA-PDT on K562 cells. NaN3, a singlet oxygen quencher, suppresses the MAG-induced cell apoptosis, lipid peroxidation, and DNA damage. In conclusion, MAG enhances the PDT-induced cytotoxicity in K562 cells and singlet oxygen was involved in this process. These results implied that the effect of antioxidants on PDT might be determined by its sensitization ability to singlet oxygen.

  S. A Moses , M. A Ali , S Zuohe , L Du Cuny , L. L Zhou , R Lemos , N Ihle , A. G Skillman , S Zhang , E. A Mash , G Powis and E. J. Meuillet
 

The phosphatidylinositol 3-kinase/AKT signaling pathway plays a critical role in activating survival and antiapoptotic pathways within cancer cells. Several studies have shown that this pathway is constitutively activated in many different cancer types. The goal of this study was to discover novel compounds that bind to the pleckstrin homology (PH) domain of AKT, thereby inhibiting AKT activation. Using proprietary docking software, 22 potential PH domain inhibitors were identified. Surface plasmon resonance spectroscopy was used to measure the binding of the compounds to the expressed PH domain of AKT followed by an in vitro activity screen in Panc-1 and MiaPaCa-2 pancreatic cancer cell lines. We identified a novel chemical scaffold in several of the compounds that binds selectively to the PH domain of AKT, inducing a decrease in AKT activation and causing apoptosis at low micromolar concentrations. Structural modifications of the scaffold led to compounds with enhanced inhibitory activity in cells. One compound, 4-dodecyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide, inhibited AKT and its downstream targets in cells as well as in pancreatic cancer cell xenografts in immunocompromised mice; it also exhibited good antitumor activity. In summary, a pharmacophore for PH domain inhibitors targeting AKT function was developed. Computer-aided modeling, synthesis, and testing produced novel AKT PH domain inhibitors that exhibit promising preclinical properties. [Cancer Res 2009;69(12):5073–81]

  S Zhang , J Lu , X Zhao , W Wu , H Wang , Q Wu , X Chen , W Fan , H Chen , F Wang , Z Hu , L Jin , Q Wei , H Shen , W Huang and D. Lu
 

Checkpoint kinase (CHEK) 2, a tumor suppressor gene, plays an essential role in the DNA damage checkpoint response cascade. We first investigated two polymorphisms in the proximal promoter of the CHEK2 gene and evaluated their associations with the risk of lung cancer in a case–control study using 500 incident lung cancer cases and 517 cancer-free controls. We found that CHEK2 rs2236141 –48 G > A was significantly associated with lung cancer risk (P = 0.0018). Similar results were obtained in a follow-up replication study in 575 lung cancer patients and 589 controls (P = 0.042). Quantitative polymerase chain reaction showed that individuals with the G allele had lower levels of CHEK2 transcripts in peripheral blood mononuclear cells and normal lung tissues. The –48 G->A variant eliminated a methylation site and thereby relieve the transcriptional repression of CHEK2. Therefore, this polymorphism affected downstream transcription through genetic and epigenetic modifications. Luciferase reporter assays demonstrated that the major G allele significantly attenuated reporter gene expression when methylated. Electrophoretic Mobility shift assays and surface plasmon resonance revealed that the methylated G allele increased transcription factor accessibility. We used in vivo chromatin immunoprecipitation to confirm that the relevant transcription factor was Sp1. Using lung tissue heterozygous for the G/A single-nucleotide polymorphism, we found that Sp1 acted as a repressor and had a stronger binding affinity for the G allele. These results support our hypothesis that the CHEK2 rs2236141 variant modifies lung cancer susceptibility in the Chinese population by affecting CHEK2 expression.

  S Zhang , Y. J Zhang , H. H Su , X. W Gao and Y. Y. Guo
 

The parasitoids of Cotton Bollworm Microplitis mediator (Hymenoptera: Braconidae) find their hosts through the odor released by stressed plants. In this study, preliminary characterization and isolation of cDNAs from male M. mediator antennal libraries identified 8 putative odorant-binding proteins (OBPs). Real-time polymerase chain reaction method was used to study the expression pattern of these isolated genes. Their gene expression profiles under a wide range of conditions indicated that only 4 OBP genes in M. mediator were antenna specific. The remaining 4 genes are either expressed ubiquitously or strictly regulated in specialized tissues or during different developmental stages. Some OBP genes were gender specific. These findings support that OBPs play dynamic roles during development of M. mediator and are likely to be involved in broader physiological functions.

  N Suematsu , C Ojaimi , F. A Recchia , Z Wang , Y Skayian , X Xu , S Zhang , P. M Kaminski , D Sun , M. S Wolin , G Kaley and T. H. Hintze
 

Rationale: Patients on a low salt (LS) diet have increased mortality.

Objective: To determine whether reduction in NO bioactivity may contribute to the LS-induced cardiac dysfunction and mortality.

Methods and Results: Adult male mongrel dogs were placed on LS (0.05% sodium chloride) for 2 weeks. Body weight (25.4±0.4 to 23.6±0.4 kg), left ventricular systolic pressure (137.0±3.4 to 124.0±6.7 mm Hg), and mean aortic pressure (111±3.1 to 98±4.3 mm Hg) decreased. Plasma angiotensin II concentration increased (4.4±0.7 to 14.8±3.7 pg/mL). Veratrine-induced (5 µg/kg) NO-mediated vasodilation was inhibited by 44% in LS; however, the simultaneous intravenous infusion of ascorbic acid or apocynin acutely and completely reversed this inhibition. In LS heart tissues, lucigenin chemiluminescence was increased 2.3-fold to angiotensin II (10–8 mol/L), and bradykinin (10–4 mol/L) induced reduction of myocardial oxygen consumption in vitro was decreased (40±1.3% to 16±6.3%) and completely restored by coincubation with tiron, tempol or apocynin. Switching of substrate uptake from free fatty acid to glucose by the heart was observed (free fatty acid: 8.97±1.39 to 4.53±1.12 µmol/min; glucose: 1.31±0.52 to 6.86±1.78 µmol/min). Western blotting indicated an increase in both p47phox (121%) and gp91phox (44%) as did RNA microarray analysis (433 genes changed) showed an increase in p47phox (1.6-fold) and gp91phox (2.0 fold) in the LS heart tissue.

Conclusions: LS diet induces the activation of the renin–angiotensin system, which increases oxidative stress via the NADPH oxidase and attenuates NO bioavailability in the heart.

  W Wu , W Zhang , R Qiao , D Chen , H Wang , Y Wang , S Zhang , G Gao , A Gu , J Shen , J Qian , W Fan , L Jin , B Han and D. Lu
 

Purpose: Platinum agents cause DNA cross-linking and adducts. Xeroderma pigmentosum group D (XPD) plays a key role in the nucleotide excision repair pathway of DNA repair. Genetic polymorphisms of XPD may affect the capacity to remove the deleterious DNA lesions in normal tissues and lead to greater treatment-related toxicity. This study aimed to investigate the association of three polymorphisms of XPD at codons 156, 312, and 711, with the occurrence of grade 3 or 4 toxicity in advanced non–small cell lung cancer patients.

Experimental Design: We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to genotype the three polymorphisms in 209 stage III and IV non–small cell lung cancer patients treated with platinum-based chemotherapy.

Results: The variant homozygotes of XPD p.Arg156Arg (rs238406) polymorphism were associated with a significantly increased risk of grade 3 or 4 hematologic toxicity (adjusted odds ratios, 3.24; 95% confidence interval, 1.35-7.78; P for trend = 0.009), and, more specifically, severe leukopenia toxicity (P for trend = 0.005). No statistically significant association was found for the three polymorphisms and grade 3 or 4 gastrointestinal toxicity. Consistent with these results of single-locus analysis, both the haplotype and the diplotype analyses revealed a protective effect of the haplotype "CG" (in the order of p.Arg156Arg-p.Asp312Asn) on the risk of grade 3 or 4 hematologic toxicity.

Conclusions: This investigation, for the first time, provides suggestive evidence of an effect of XPD p.Arg156Arg polymorphism on severe toxicity variability among platinum-treated non–small cell lung cancer patients.

  J. A Weber , D. H Baxter , S Zhang , D. Y Huang , K How Huang , M Jen Lee , D. J Galas and K. Wang
  BACKGROUND:

MicroRNAs (miRNAs) are small, noncoding RNAs that play an important role in regulating various biological processes through their interaction with cellular messenger RNAs. Extracellular miRNAs in serum, plasma, saliva, and urine have recently been shown to be associated with various pathological conditions including cancer.

METHODS:

With the goal of assessing the distribution of miRNAs and demonstrating the potential use of miRNAs as biomarkers, we examined the presence of miRNAs in 12 human body fluids and urine samples from women in different stages of pregnancy or patients with different urothelial cancers. Using quantitative PCR, we conducted a global survey of the miRNA distribution in these fluids.

RESULTS:

miRNAs were present in all fluids tested and showed distinct compositions in different fluid types. Several of the highly abundant miRNAs in these fluids were common among multiple fluid types, and some of the miRNAs were enriched in specific fluids. We also observed distinct miRNA patterns in the urine samples obtained from individuals with different physiopathological conditions.

CONCLUSIONS:

MicroRNAs are ubiquitous in all the body fluid types tested. Fluid type–specific miRNAs may have functional roles associated with the surrounding tissues. In addition, the changes in miRNA spectra observed in the urine samples from patients with different urothelial conditions demonstrates the potential for using concentrations of specific miRNAs in body fluids as biomarkers for detecting and monitoring various physiopathological conditions.

  S Zhang , M. B Feany , S Saraswati , J. T Littleton and N. Perrimon
  Sheng Zhang, Mel B. Feany, Sudipta Saraswati, J. Troy Littleton, and Norbert Perrimon

A polyglutamine expansion in the huntingtin (HTT) gene causes neurodegeneration in Huntington’s disease (HD), but the in vivo function of the native protein (Htt) is largely unknown. Numerous biochemical and in vitro studies have suggested a role for Htt in neuronal development, synaptic function and axonal trafficking. To test these models, we generated a null mutant in the putative Drosophila HTT homolog (htt, hereafter referred to asdhtt) and, surprisingly, found that dhtt mutant animals are viable with no obvious developmental defects. Instead, dhtt is required for maintaining the mobility and long-term survival of adult animals, and for modulating axonal terminal complexity in the adult brain. Furthermore, removing endogenous dhtt significantly accelerates the neurodegenerative phenotype associated with a Drosophila model of polyglutamine Htt toxicity (HD-Q93), providing in vivo evidence that disrupting the normal function of Htt might contribute to HD pathogenesis.

  W Junfang , Z Biao , Z Weijun , S Zhang , W Yinyin and K. Chen
  Background

In this study, we determined the prevalence of unmet need for hospitalization service and the characteristics of the elderly with this unmet need in Zhejiang province, China.

Methods

Data were collected from a random sample of 4046 Chinese aged 60 years and older in Zhejiang province. Based on the Andersen-Newman service utilization framework, multivariable logistic regression analysis was used to determine independent effects of these variables on the likelihood of having an unmet need for hospitalization service.

Results

Overall, the prevalence of unmet need was 16.2% for hospitalization service. Among predisposing factors, only educational level was statistically significant. Individuals with higher education were less likely to report unmet needs. Among enabling factors, residential area, social support, personal yearly income and personal healthcare expenditure were strongly associated with the presence of unmet need. Those with less enabling resources (e.g. residing in rural areas) were more likely to report unmet need [Odds ratio (OR) = 1.5–6.5]. All the need factors, except for physical function, were strongly associated with the presence of unmet need. Seniors in poorer health (e.g. in fair or poor health) were more likely to report unmet need than their counterparts in better health (OR = 1.5–2.8).

Conclusions

In spite of relatively high insurance coverage rates, unmet need for hospitalization service remains high among the elderly people of Zhejiang province in China. Application of comprehensive intervention strategies such as conducting health education, creating social support, promoting community participation and promoting inter-sectional cooperation may be more effective in reducing unmet need for hospitalization service.

  Y Zhong , Y Huang , T Zhang , C Ma , S Zhang , W Fan , H Chen , J Qian and D. Lu
 

O6-methylguanine-DNA methyltransferase is one of the rare proteins to directly remove alkylating agents in the human DNA direct reversal repair pathway. Its two common single-nucleotide polymorphisms, Leu84Phe and Ile143Val, had previously been identified to contribute to susceptibility of cancer. However, there are conflicting results in studies on the association of the two polymorphisms with cancer. Therefore, we conducted a meta-analysis to clarify the paradox with a large collected sample (13 069 cancer patients and 20 290 controls). We found significant association between the T allele (84Phe) and cancer risk, under the recessive genetic model [P = 0.023, odds ratio (OR) = 1.251, 95% confidence interval (CI) 1.031–1.517, Pheterogeneity = 0.270], TT versus CC comparison (P = 0.035, OR = 1.239, 95% CI 1.015–1.511, Pheterogeneity = 0.225) and TT versus CT comparison (P = 0.007, OR = 1.292, 95% CI 1.071–1.559, Pheterogeneity = 0.374), using the random-effect model. In the ethnicity subgroup analysis, a significant association with cancer among Caucasians was found under the recessive genetic model, homozygote comparison and TT versus TC comparison. In the tumour sites subgroup analysis, only the protective effects of Leu84Phe polymorphism were found in colorectal cancer, under CT versus CC comparison. No significant association between the G allele of Ile143Val and cancer risk was found. The G allele showed an increased lung cancer risk under the dominant genetic model and AG versus AA comparison in all Hardy–Weinberg equilibrium subjects, only when the fixed-effect model was used. However, it was insignificant in the random-effect model.

  K. L Sens , S Zhang , P Jin , R Duan , G Zhang , F Luo , L Parachini and E. H. Chen
 

Recent studies in Drosophila have implicated actin cytoskeletal remodeling in myoblast fusion, but the cellular mechanisms underlying this process remain poorly understood. Here we show that actin polymerization occurs in an asymmetric and cell type–specific manner between a muscle founder cell and a fusion-competent myoblast (FCM). In the FCM, a dense F-actin–enriched focus forms at the site of fusion, whereas a thin sheath of F-actin is induced along the apposing founder cell membrane. The FCM-specific actin focus invades the apposing founder cell with multiple finger-like protrusions, leading to the formation of a single-channel macro fusion pore between the two muscle cells. Two actin nucleation–promoting factors of the Arp2/3 complex, WASP and Scar, are required for the formation of the F-actin foci, whereas WASP but not Scar promotes efficient foci invasion. Our studies uncover a novel invasive podosome-like structure (PLS) in a developing tissue and reveal a previously unrecognized function of PLSs in facilitating cell membrane juxtaposition and fusion.

  S Zhang , M Rozell , R. K Verma , D. I Albu , D Califano , J VanValkenburgh , A Merchant , J Rangel Moreno , T. D Randall , N. A Jenkins , N. G Copeland , P Liu and D. Avram
 

CD8+ T lymphocytes mediate the immune response to viruses, intracellular bacteria, protozoan parasites, and tumors. We provide evidence that the transcription factor Bcl11b/Ctip2 controls hallmark features of CD8+ T cell immunity, specifically antigen (Ag)-dependent clonal expansion and cytolytic activity. The reduced clonal expansion in the absence of Bcl11b was caused by altered proliferation during the expansion phase, with survival remaining unaffected. Two genes with critical roles in TCR signaling were deregulated in Bcl11b-deficient CD8+ T cells, CD8 coreceptor and Plc1, both of which may contribute to the impaired responsiveness. Bcl11b was found to bind the E8I, E8IV, and E8V, but not E8II or E8III, enhancers. Thus, Bcl11b is one of the transcription factors implicated in the maintenance of optimal CD8 coreceptor expression in peripheral CD8+ T cells through association with specific enhancers. Short-lived Klrg1hiCD127lo effector CD8+ T cells were formed during the course of infection in the absence of Bcl11b, albeit in smaller numbers, and their Ag-specific cytolytic activity on a per-cell basis was altered, which was associated with reduced granzyme B and perforin.

  S Zhang , S. J Bursian , P. A Martin , H. M Chan , G Tomy , V. P Palace , G. J Mayne and J. W. Martin
 

Polybrominated diphenyl ethers (PBDEs) are widespread persistent and bioaccumulative environmental contaminants. Recent scientific attention has focused on the developmental toxicity of PBDE commercial mixtures following perinatal exposure of rodents; however, these studies do not necessarily predict toxicity to highly exposed top predators, such as mink (Mustela vison). Here we assessed the effects of environmentally relevant doses (0, 0.1, 0.5, and 2.5 ppm [wt/wt] in feed) of a technical pentabrominated diphenyl ether mixture, DE-71, on reproductive performance of mink and on development of offspring exposed perinatally and post-weaning until 33 weeks. A dietary concentration that causes no effects on reproduction in rodents, 2.5-ppm DE-71, resulted in complete reproductive failure in these mink, while whelping rates were not affected at all lower does. Developmental effects in offspring were evident in 33-week-old juveniles, which were more sensitive to effects than their respective dams. Juvenile thyroid hormone homeostasis was also much more sensitive compared to rodents, and at 0.5-ppm DE-71, total triiodothyronine (T3) was significantly decreased in all males and females, even despite a compensatory increase of total thyroxine (T4) in females. T4-outer-ring deiodinase activity, mainly contributed by type II deiodinase, was not affected at any dose for any life stage, but thyroid follicular epithelium cell height was elevated in the 0.5-ppm–treated juveniles (p = 0.057). Ethoxyresorufin O-deethylase activity was significantly induced in all offspring at 33 weeks, most likely as a consequence of polybrominated dioxin, furan, or biphenyl impurities in DE-71. Biomonitoring of wild mink in the Great Lakes region indicated that most populations had lower concentrations than what are expected to affect thyroid hormone homeostasis, but margins of safety are small and mink around Hamilton Harbour exceeded the no observed adverse effect level for T3 disruption.

 
 
 
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