Asian Science Citation Index is committed to provide an authoritative, trusted and significant information by the coverage of the most important and influential journals to meet the needs of the global scientific community.  
ASCI Database
308-Lasani Town,
Sargodha Road,
Faisalabad, Pakistan
Fax: +92-41-8815544
Contact Via Web
Suggest a Journal
 
Articles by H Zhang
Total Records ( 32 ) for H Zhang
  L Sun , X Shen , Y Liu , G Zhang , J Wei , H Zhang , E Zhang and F. Ma
 

The mechanism underlining human papillomaviruses (HPVs) causing cancer has been studied extensively, and it was concluded that the high-risk HPVs' E6 targeted and degraded tumor suppressor protein p53, leading to infected cells malignant transformation. In contrast, the low-risk HPVs only cause proliferative but non-invasive lesions of infected epithelia. Therefore, we hypothesized that low-risk HPVs' E6 might interact with p53 in a different pattern. We used a mammalian green fluorescent protein (GFP) expression system to express HPV-18E6 and HPV-6E6 fusion proteins in wild-type (wt) p53 cell lines, 293T and HEK293 cells, to investigate the traffic and location of E6s and p53. The results indicated GFP-18E6 was mainly expressed in nucleus, whereas GFP-6E6 was expressed exclusively in cytoplasm. Endogenous wt p53 was shown to be localized in the nuclei of cells transfected with GFP-18E6. Interestingly, for the first time, we observed that p53 was trapped in the cytoplasm and never translocated into the cell nuclei transfected with GFP-6E6. In conclusion, HPV-6E6 was responsible for the cytoplasmic localization of p53. Therefore, our experiments provide a new insight into the pathogenesis of HPV.

  L Ji , F Fu , L Zhang , W Liu , X Cai , Q Zheng , H Zhang and F. Gao
 

It is well known that insulin possesses a cardioprotective effect and that insulin resistance is closely related to cardiovascular diseases. Peroxynitrite (ONOO) formation may trigger oxidative/nitrative stress and represent a major cytotoxic effect in heart diseases. This study was designed to investigate whether insulin attenuates ONOO generation and oxidative/nitrative stress in acute myocardial ischemia/reperfusion (MI/R). Adult male rats were subjected to 30 min of myocardial ischemia and 3 h of reperfusion. Rats randomly received vehicle, insulin, or insulin plus wortmannin. Arterial blood pressure and left ventricular pressure were monitored throughout the experiment. Insulin significantly improved cardiac functions and reduced myocardial infarction, apoptotic cell death, and blood creatine kinase/lactate dehydrogenase levels following MI/R. Myocardial ONOO formation was significantly attenuated after insulin treatment. Moreover, insulin resulted in a significant increase in Akt and endothelial nitric oxide (NO) synthase (eNOS) phosphorylation, NO production, and antioxidant capacity in ischemic/reperfused myocardial tissue. On the other hand, insulin markedly reduced MI/R-induced inducible NOS (iNOS) and gp91phox expression in cardiac tissue. Inhibition of insulin signaling with wortmannin not only blocked the cardioprotection of insulin but also markedly attenuated insulin-induced antioxidative/antinitrative effect. Furthermore, the suppression on ONOO formation by either insulin or an ONOO scavenger uric acid reduced myocardial infarct size in rats subjected to MI/R. We concluded that insulin exerts a cardioprotective effect against MI/R injury by blocking ONOO formation. Increased physiological NO production (via eNOS phosphorylation) and superoxide anion reduction contribute to the antioxidative/antinitrative effect of insulin, which can be reversed by inhibiting phosphatidylinositol 3'-kinase. These results provide important novel information on the mechanisms of cardiovascular actions of insulin.

  L Shi , C Mao , F Zeng , J Hou , H Zhang and Z. Xu
 

Angiotensin (Ang) II plays a critical role in cardiovascular homeostasis and neuroendocrine regulation. Little is known about whether central angiotensin-converting enzyme (ACE) is functional in the fetal brain. We investigated cardiovascular and neuroendocrinological responses to intracerebroventricular (icv) application of Ang I in the chronically prepared near-term ovine fetus in utero and examined the action sites marked by c-fos expression in the fetal hypothalamus. ACE mRNA was detected in the specific central areas. Intracerebroventricular Ang I significantly increased fetal blood pressure and c-fos expression in the supraoptic nuclei (SON) and the paraventricular nuclei (PVN) in the hypothalamus, accompanied by an increase of fetal plasma arginine vasopressin (AVP). Double labeling demonstrated that AVP neurons in the fetal SON and PVN were expressing c-fos. Captopril, an inhibitor of ACE, significantly suppressed fetal pressor responses and plasma AVP. Double labeling experiments showed colocalization of AT1 receptor (AT1R) and c-fos expression in both SON and PVN following icv Ang I. The results indicate that central endogenous ACE has been functional at least at the last third of gestation and the endogenous brain renin-angiotensin system-mediated pressor responses and AVP release via AT1Rs by acting at the sites consistent with the cardiovascular network in the hypothalamus.

  J Yang , Y Park , H Zhang , X Xu , G. A Laine , K. C Dellsperger and C. Zhang
 

We hypothesized that the interaction between tumor necrosis factor- (TNF-)/nuclear factor-B (NF-B) via the activation of IKK-β may amplify one another, resulting in the evolution of vascular disease and insulin resistance associated with diabetes. To test this hypothesis, endothelium-dependent (ACh) and -independent (sodium nitroprusside) vasodilation of isolated, pressurized coronary arterioles from mLeprdb (heterozygote, normal), Leprdb (homozygote, diabetic), and Leprdb mice null for TNF- (dbTNF–/dbTNF–) were examined. Although the dilation of vessels to sodium nitroprusside was not different between Leprdb and mLeprdb mice, the dilation to ACh was reduced in Leprdb mice. The NF-B antagonist MG-132 or the IKK-β inhibitor sodium salicylate (NaSal) partially restored nitric oxide-mediated endothelium-dependent coronary arteriolar dilation in Leprdb mice, but the responses in mLeprdb mice were unaffected. The protein expression of IKK- and IKK-β were higher in Leprdb than in mLeprdb mice; the expression of IKK-β, but not the expression of IKK-, was attenuated by MG-132, the antioxidant apocynin, or the genetic deletion of TNF- in diabetic mice. Leprdb mice showed an increased insulin resistance, but NaSal improved insulin sensitivity. The protein expression of TNF- and NF-B and the protein modification of phosphorylated (p)-IKK-β and p-JNK were greater in Leprdb mice, but NaSal attenuated TNF-, NF-B, p-IKK-β, and p-JNK in Leprdb mice. The ratio of p-insulin receptor substrate (IRS)-1 at Ser307 to IRS-1 was elevated in Leprdb compared with mLeprdb mice; both NaSal and the JNK inhibitor SP-600125 reduced the p-IRS-1-to-IRS-1 ratio in Leprdb mice. MG-132 or the neutralization of TNF- reduced superoxide production in Leprdb mice. In conclusion, our results indicate that the interaction between NF-B and TNF- signaling induces the activation of IKK-β and amplifies oxidative stress, leading to endothelial dysfunction in type 2 diabetes.

  M. F Morris , Y Zhang , H Zhang , J. C Prowda , D. N Silvers , R. A Fawwaz and M. R. Prince
 

OBJECTIVE. The objective of this article is to illustrate the spectrum of imaging findings with photographic and histopathologic correlation in patients with biopsy-proven nephrogenic systemic fibrosis (NSF).

CONCLUSION. Features of NSF may be evident on the patient's skin as well as on routine imaging studies, although these imaging findings are nonspecific and are more likely to occur with other diseases.

  C McCabe , C Kirchner , H Zhang , J Daley and D. N. Fisman
 

Background  Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality worldwide. Clinical practice guidelines for empirical CAP treatment, formulated jointly by the Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS), remain controversial and inconsistently applied. We evaluated the impact of guideline-concordant therapy on in-hospital survival and other outcomes using a large database including adults treated for CAP in both community and tertiary care hospitals.

Methods  We evaluated the association between in-hospital survival and guideline-concordant therapy using logistic regression models. Time until discharge from hospital and discontinuation of parenteral therapy were evaluated using survival analysis.

Results  Of 54 619 non–intensive care unit inpatients with CAP hospitalized at 113 community hospitals and tertiary care centers, 35 477 (65%) received initial guideline-concordant therapy. After adjustment for severity of illness and other confounders, guideline-concordant therapy was associated with decreased in-hospital mortality (odds ratio [OR], 0.70; 95% confidence interval [CI], 0.63-0.77), sepsis (OR, 0.83; 95% CI, 0.72-0.96), and renal failure (OR, 0.79; 95% CI, 0.67-0.94), and reduced both length of stay and duration of parenteral therapy by approximately 0.6 days (P < .001 for both comparisons). These findings were robust with alternate definitions of "concordance" and were linked to treatment with fluoroquinolone or macrolide agents.

Conclusions  Guideline-concordant therapy for CAP is associated with improved health outcomes and diminished resource use in adults. The mechanisms underlying this finding remain speculative and warrant further study, but our findings nonetheless support compliance with CAP clinical practice guidelines as a benchmark of quality of care.

  M. C Royer , H Zhang , C. Y Fan and M. S. Kokoska
 

Objectives  To determine the relationship between hOGG1 loss of heterozygosity (LOH), Hashimoto thyroiditis (HT), and papillary thyroid cancer (PTC). Hashimoto thyroiditis is an autoimmune mediated chronic inflammatory disease previously shown to coexist with papillary PTC. To further define the relationship between HT and PTC, we report an analysis of hOGG1, a major repair gene for free radical–induced oxidative DNA damages, in thyroidectomy specimens.

Design  Tissue samples from 20 cases of PTC, 20 cases of HT, and 15 cases of benign goiter were included in this study. Samples of DNA collected from laser-capture microdissection of thyroidectomy specimens were analyzed for hOGG1 LOH by polymerase chain reaction (PCR) amplification using 5 fluorescent-labeled microsatellite markers followed by fragment analysis.

Setting  A university tertiary care center and regional veterans' hospital.

Patients  Fifty-five patients undergoing partial or total thyroidectomies for various indications (PTC, HT, or goiter).

Interventions  Pathology specimens were analyzed by laser capture microdissection and PCR for hOGG1.

Main Outcome Measure  The presence of hOGG1 in all thyroid specimens.

Results  Amplification by PCR was successful for all 5 markers in 18 cases of PTC, 15 cases of HT, and 12 cases of benign thyroid. Among these samples, hOGG1 LOH was found in 17 of 18 PTC specimens (94%), 11 of 15 HT specimens (73%), and 1 of 12 benign goiter specimens (8%).

Conclusions  hOGG1 LOH is strongly associated with PTC and HT but not with benign thyroid. We hypothesize that thyroid follicular epithelia accumulate aberrant genetic changes in long-standing HT, which may represent a precursor lesion of PTC.

  J Liu , H Zhang , Z Li , T. K Hailemariam , M Chakraborty , K Jiang , D Qiu , H. H Bui , D. A Peake , M. S Kuo , R Wadgaonkar , G Cao and X. C. Jiang
 

Background— It has been proposed that plasma sphingomyelin (SM) plays a very important role in plasma lipoprotein metabolism and atherosclerosis. Sphingomyelin synthase (SMS) is the last enzyme for SM de novo biosynthesis. Two SMS genes, SMS1 and SMS2, have been cloned and characterized.

Methods and Results— To evaluate the in vivo role of SMS2 in SM metabolism, we prepared SMS2 knockout (KO) and SMS2 liver-specific transgenic (LTg) mice and studied their plasma SM and lipoprotein metabolism. On a chow diet, SMS2 KO mice showed a significant decrease in plasma SM levels (25%, P<0.05), but no significant changes in total cholesterol, total phospholipids, or triglyceride, compared with wild-type (WT) littermates. On a high-fat diet, SMS2 KO mice showed a decrease in plasma SM levels (28%, P<0.01), whereas SMS2LTg mice showed a significant increase in those levels (29%, P<0.05), but no significant changes in other lipids, compared with WT littermates. Atherogenic lipoproteins from SMS2LTg mice displayed a significantly stronger tendency toward aggregation after mammalian sphingomyelinase treatment, compared with controls. Moreover, SMS2 deficiency significantly increased plasma apoE levels (2.0-fold, P<0.001), whereas liver-specific SMS2 overexpression significantly decreased those levels (1.8-fold, P<0.01). Finally, SMS2 KO mouse plasma promoted cholesterol efflux from macrophages, whereas SMS2LTg mouse plasma prevented it.

Conclusions— We therefore believe that regulation of liver SMS2 activity could become a promising treatment for atherosclerosis.

  D. J Englot , L Yang , H Hamid , N Danielson , X Bai , A Marfeo , L Yu , A Gordon , M. J Purcaro , J. E Motelow , R Agarwal , D. J Ellens , J. D Golomb , M. C. F Shamy , H Zhang , C Carlson , W Doyle , O Devinsky , K Vives , D. D Spencer , S. S Spencer , C Schevon , H. P Zaveri and H. Blumenfeld
 

Impaired consciousness requires altered cortical function. This can occur either directly from disorders that impair widespread bilateral regions of the cortex or indirectly through effects on subcortical arousal systems. It has therefore long been puzzling why focal temporal lobe seizures so often impair consciousness. Early work suggested that altered consciousness may occur with bilateral or dominant temporal lobe seizure involvement. However, other bilateral temporal lobe disorders do not impair consciousness. More recent work supports a ‘network inhibition hypothesis’ in which temporal lobe seizures disrupt brainstem–diencephalic arousal systems, leading indirectly to depressed cortical function and impaired consciousness. Indeed, prior studies show subcortical involvement in temporal lobe seizures and bilateral frontoparietal slow wave activity on intracranial electroencephalography. However, the relationships between frontoparietal slow waves and impaired consciousness and between cortical slowing and fast seizure activity have not been directly investigated. We analysed intracranial electroencephalography recordings during 63 partial seizures in 26 patients with surgically confirmed mesial temporal lobe epilepsy. Behavioural responsiveness was determined based on blinded review of video during seizures and classified as impaired (complex-partial seizures) or unimpaired (simple-partial seizures). We observed significantly increased delta-range 1–2 Hz slow wave activity in the bilateral frontal and parietal neocortices during complex-partial compared with simple-partial seizures. In addition, we confirmed prior work suggesting that propagation of unilateral mesial temporal fast seizure activity to the bilateral temporal lobes was significantly greater in complex-partial than in simple-partial seizures. Interestingly, we found that the signal power of frontoparietal slow wave activity was significantly correlated with the temporal lobe fast seizure activity in each hemisphere. Finally, we observed that complex-partial seizures were somewhat more common with onset in the language-dominant temporal lobe. These findings provide direct evidence for cortical dysfunction in the form of bilateral frontoparietal slow waves associated with impaired consciousness in temporal lobe seizures. We hypothesize that bilateral temporal lobe seizures may exert a powerful inhibitory effect on subcortical arousal systems. Further investigations will be needed to fully determine the role of cortical-subcortical networks in ictal neocortical dysfunction and may reveal treatments to prevent this important negative consequence of temporal lobe epilepsy.

  Y He , H Zhang , J Yin , J Xie , X Tan , S Liu , Q Zhang , C Li , J Zhao , H Wang and G. Cao
 

Genetic predisposition of nuclear factor-kappa B (NF-B)-signaling pathways linking inflammation to hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) remains unresolved. We conducted a case–control study to determine the associations of the polymorphisms within the promoter regions of NFKB1 encoding NF-B1 and NFKBIA encoding IkappaBalpha with the development of HCC. A total of 404 healthy controls, 482 non-HCC subjects with HBV infection and 202 patients with HCC were included. NFKB1 –94ATTG2 allele and GG allele in the 3'-untranslated region of NFKBIA were more prevalent in HCC patients than in the healthy controls. NFKBIA –826CT and NFKBIA –881AG allelic carriages were more prevalent in HCC patients than in the non-HCC subjects with HBV infection. The estimated haplotype frequency of NFKBIA promoter –881G–826T–519C was significantly higher in the patients with HCC than in the HBV-infected subjects without HCC (odds ratio = 3.142, P = 0.002). As compared with the HBV-infected subjects without HCC, NFKBIA –826 T and NFKBIA –881AG allelic carriages were only associated with HCC risk in the subjects with HBV genotype C. The association of NFKBIA –881AG allelic carriage with HCC risk was not affected by liver cirrhosis (LC) status, alanine aminotransferase level and hepatitis B e antigen status. By multivariate regression analysis, NFKB1 –94ATTG2, NFKBIA –826T, NFKBIA –881AG and HBV genotype C were independently associated with an increased risk of HCC. In conclusion, NFKB1 –94ATTG2 allele and haplotype –881G–826T–519C in NFKBIA promoter were associated with hepatocarcinogenesis. NFKBIA –826T and –881AG were associated with the risk of HCC in the subjects infected with HBV genotype C.

  J Liu , C Huan , M Chakraborty , H Zhang , D Lu , M. S Kuo , G Cao and X. C. Jiang
 

Rationale: Sphingomyelin synthase (SMS)2 contributes to de novo sphingomyelin (SM) biosynthesis and plasma membrane SM levels. SMS2 deficiency in macrophages diminishes nuclear factor B and mitogen-activated protein kinase activation induced by inflammatory stimuli.

Objective: The effects of SMS2 deficiency on the development of atherosclerosis are investigated.

Methods and Results: We measured cholesterol efflux from macrophages of wild-type (WT) and SMS2 knockout (KO) mice. We transplanted SMS2 KO mouse bone marrow into low-density lipoprotein (LDL) receptor (LDLr) knockout mice (SMS2–/–->LDLr–/–), creating a mouse model of SMS2 deficiency in the macrophages. We found that SMS2 deficiency caused significant induction of cholesterol efflux in vitro and in vivo. Moreover, we found that SMS2 KO mice had less interleukin-6 and tumor necrosis factor in the circulation before and after endotoxin stimulation, compared with controls. More importantly, after 3 months on a western-type diet, SMS2–/–->LDLr–/– mice showed decreased atherosclerotic lesions in the aortic arch, root (57%, P<0.001), and the entire aorta (42%, P<0.01), compared with WT->LDLr–/– mice. Analysis of plaque morphology revealed that SMS2–/–->LDLr–/– mice had significantly less necrotic core area (71%, P<0.001), less macrophage content (37%, P<0.01), and more collagen content (35%, P<0.05) in atherosclerotic lesions. We also found that SMS2–/–->LDLr–/– mice had significantly lower free cholesterol and cholesteryl ester levels in the brachiocephalic artery than WT->LDLr–/– mice (33 and 52%, P<0.01 and P<0.001, respectively).

Conclusions: SMS2 deficiency in the macrophages reduces atherosclerosis in mice. Macrophage SMS2 is thus a potential therapeutic target for treatment of this disease.

  S Wang , H Zhang , X Dai , R Sealock and J. E. Faber
  Rationale:

Collaterals are arteriole-to-arteriole anastomoses that connect adjacent arterial trees. They lessen ischemic tissue injury by serving as endogenous bypass vessels when the trunk of 1 tree becomes narrowed by vascular disease. The number and diameter ("extent") of native (preexisting) collaterals, plus their amount of lumen enlargement (growth/remodeling) in occlusive disease, show remarkably wide variation among inbred mouse strains (eg, C57BL/6 and BALB/c), resulting in large differences in tissue injury in models of occlusive disease. Evidence suggests similar large differences exist among healthy humans.

Objective:

To identify candidate loci responsible for genetic-dependent collateral variation.

Methods and Results:

Cerebral collateral number and diameter were determined in 221 C57BL/6xBALB/c F2 progeny, followed by linkage analysis to identify quantitative trait loci (QTL) for collateral number and diameter. Four QTL were obtained for collateral number, including epistasis between 2 loci. A QTL that was identical to the strongest QTL for collateral number on chromosome 7 (logarithm of the odds [LOD]=29, effect size=37%) was also mapped for collateral diameter (LOD=17, effect size=30%). Chromosome substitution strain analysis confirmed this locus. We also obtained a unique QTL on chromosome 11 for collateral remodeling after middle cerebral artery occlusion. Association mapping within the chromosome 7 QTL interval using collateral traits measured for 15 inbred strains delineated 172-kbp (P=0.00002) and 290-kbp (P=0.0004) regions on chromosome 7 containing 2 and 7 candidate genes, respectively.

Conclusions:

We conclude that collateral extent and remodeling are unique, highly heritable complex traits, with 1 QTL predominantly affecting native collateral number and diameter.

  R Kumar , H Zhang , C Holm , R. K Vadlamudi , G Landberg and S. K. Rayala
 

Purpose: Tamoxifen is one of many standard therapeutic options currently available for estrogen receptor-–positive breast cancer patients. Emerging data have suggested that levels of estrogen receptor coregulatory proteins play a significant role in acquiring resistance to antiestrogen action. It has been suggested that high levels of estrogen receptor coactivators and its mislocalization may enhance the estrogen agonist activity of tamoxifen and contribute to tamoxifen resistance.

Experimental Design: In an effort to understand the impact of nongenomic signaling and its contribution to hormone resistance in a whole-animal setting, we generated a transgenic mouse expressing a cytoplasmic version of proline-, glutamic acid–, and leucine-rich protein–1 (PELP1) mutant defective in its nuclear translocation (PELP1-cyto) and implanted these mice with tamoxifen pellets to assess its responsiveness.

Results: We show that mammary glands from these mice developed widespread hyperplasia with increased cell proliferation and enhanced activation of mitogen-activated protein kinase and AKT as early as 12 weeks of age. Treatment with tamoxifen did not inhibit this hyperplasia; instead, such treatment exaggerated hyperplasia with an enhanced degree of alteration, indicative of hypersensitivity to tamoxifen. Analysis of molecular markers in the transgenic mammary glands from the tamoxifen-treated transgenic mice showed higher levels of proliferation markers proliferating cell nuclear antigen and activated mitogen-activated protein kinase than in untreated PELP1-cyto cell-derived mice. We also found that nude mice with MCF-7/PELP1-cyto cell-derived tumor xenografts did not respond to tamoxifen. Using immunohistochemical analysis, we found that 43% of human breast tumor samples had high levels of cytoplasmic PELP1, which shows a positive correlation between tumor grade and proliferation. Patients whose tumors had high levels of cytoplasmic PELP1 exhibited a tendency to respond poorly to tamoxifen compared with patients whose tumors had low levels of cytoplasmic PELP1.

Conclusions: These findings suggest that PELP1 localization could be used as a determinant of hormone sensitivity or vulnerability. The establishment of the PELP1-cyto transgenic mouse model is expected to facilitate the development of preclinical approaches for effective intervention of breast tumors using cytoplasmic coregulators and active nongenomic signaling.

  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.

  W Zhang , K Sun , Y Yang , H Zhang , F. B Hu and R. Hui
 

Background: Hyperuricemia has been positively associated with hypertension, but whether this association is independent of adiposity and other cardiovascular risk factors remains a matter of debate.

Methods: We conducted a community-based prospective cohort study comprising 7220 participants (mean age 37 years; 73.8% men) in the Qingdao Port Health and Nutrition Examination Survey in China, who were free from hypertension at study entry in 1999–2000. During 4-year follow-up, 1370 men (19.0%) and 208 women (11.0%) had developed hypertension.

Results: After adjustment for age, body mass index, and other covariates, the relative risks (RRs) of developing hypertension comparing the highest and lowest uric acid quartiles were 1.55 (95% CI 1.10–2.19; P for trend <0.001) for men and 1.91 (1.12–3.25; P for trend <0.001) for women. After additional adjustment for abdominal obesity, the RRs comparing the participants in the highest and lowest quartiles of uric acid were 1.39 (1.16–1.68; P for trend 0.003) for men and 1.85 (1.06–3.24; P for trend 0.006) for women. In joint analysis, compared with those in the lowest uric acid quartile and without abdominal obesity, participants who were in the highest quartile and also had abdominal obesity had a 3.0- and 3.4-fold greater risk of incident hypertension (1.56–3.97 for men and 2.10–3.81 for women, respectively).

Conclusions: These data suggest a positive association between plasma uric acid and incidence of hypertension during short-term follow-up in a Chinese population. The association between hyperuricemia and hypertension was partly mediated by abdominal obesity.

  P Olson , J Lu , H Zhang , A Shai , M. G Chun , Y Wang , S. K Libutti , E. K Nakakura , T. R Golub and D. Hanahan
 

While altered expression of microRNAs (miRs) in tumors has been well documented, it remains unclear how the miR transcriptome intersects neoplastic progression. By profiling the miR transcriptome we identified miR expression signatures associated with steps in tumorigenesis and the acquisition of hallmark capabilities in a prototypical mouse model of cancer. Metastases and a rare subset of primary tumors shared a distinct miR signature, implicating a discrete lineage for metastatic tumors. The miR-200 family is strongly down-regulated in metastases and met-like primary tumors, thereby relieving repression of the mesenchymal transcription factor Zeb1, which in turn suppresses E-cadherin. Treatment with a clinically approved angiogenesis inhibitor normalized angiogenic signature miRs in primary tumors, while altering expression of metastatic signature miRs similarly to liver metastases, suggesting their involvement in adaptive resistance to anti-angiogenic therapy via enhanced metastasis. Many of the miR changes associated with specific stages and hallmark capabilities in the mouse model are similarly altered in human tumors, including cognate pancreatic neuroendocrine tumors, implying a generality.

  H Zhang , Y. J Hou , S. Y Han , E. C Zhang , K Huebner and J. Zhang
 

The mammalian Nit1 protein is homologous to plant and bacterial nitrilases. In flies and worms, Nit1 is fused to the 5' end of Fhit, suggesting that Nit1 may functionally interact with the Fhit pathway. Fhit has been shown to play a role of a tumor suppressor. Somatic loss of Fhit in human tissues is associated with a wide variety of cancers. Deletion of Fhit results in a predisposition to induced and spontaneous tumors in mice. It has been suggested that Nit1 collaborates with Fhit in tumor suppression. Similar to mice lacking Fhit, Nit1-deficient mice are more sensitive to carcinogen-induced tumors. It was previously shown that ectopic expression of Nit1 or Fhit led to caspase activation and apoptosis, and that both proteins may play a role in DNA damage-induced apoptosis. In this study, we analyzed the physiological function of Nit1 in T cells using Nit1-knockout mice. Nit1-deficient T cells can undergo apoptosis induced by DNA damage due to irradiation and chemical treatment. However, apoptosis induced by Fas or Ca++ signals appeared to be compromised. Additionally, Nit1 deficiency resulted in T cell hyperproliferative responses induced by TCR stimulation. The expressions of T cell activation markers were elevated in Nit1–/– T cells. There was a spontaneous cell cycle entry and enhanced cell cycle progression in Nit1–/– T cells. These data indicate that Nit1 is a novel negative regulator in primary T cells.

  S Liu , H Zhang , C Gu , J Yin , Y He , J Xie and G. Cao
  Background

The association between hepatitis B virus (HBV) mutations and hepatocarcinogenesis remains controversial because of conflicting data in the literature. We conducted a meta-analysis of case–control and cohort studies to examine HBV PreS, enhancer II (EnhII), basal core promoter (BCP), and precore mutations in relation to the risk of hepatocellular carcinoma (HCC).

Methods

We searched databases for studies of these associations that were published in English or Chinese up to August 31, 2008. HBV mutation–specific odds ratios and relative risks were pooled by use of a random-effects model and stratified by potential confounders. All statistical tests were two-sided.

Results

Of the 43 studies included in this meta-analysis, 40 used a case–control design. The 43 studies evaluated a total of 11 582 HBV-infected participants, of whom 2801 had HCC. Statistically significant summary odds ratios of HCC were obtained for any PreS mutation (3.77, 95% confidence interval [CI] = 2.57 to 5.52), C1653T in EnhII (2.76, 95% CI = 2.09 to 3.64), T1753V (2.35, 95% CI = 1.63 to 3.40), and A1762T/G1764A in BCP (3.79, 95% CI = 2.71 to 5.29). PreS mutations were more strongly associated with an increased risk of HCC in subjects who were infected with HBV genotype C than in those who were infected with HBV genotype B, whereas the opposite was true for A1762T/G1764A. C1653T, T1753V, and A1762T/G1764A were more strongly associated with an increased risk of HCC in hepatitis B e antigen (HBeAg)–positive subjects than in HBeAg-negative subjects. PreS mutations, C1653T, T1753V, and A1762T/G1764A accumulated during the progression of chronic HBV infection from the asymptomatic carrier state to HCC (Ptrend < .001 for each mutation). PreS mutations, C1653T, C1653T + T1753V, and A1762T/G1764A-based combinations of mutations had specificities greater than 80% for the prediction of HCC. The precore mutations G1896A and C1858T were not associated with the risk of HCC, regardless of HBeAg status and HBV genotype.

Conclusions

HBV PreS mutations, C1653T, T1753V, and A1762T/G1764A are associated with an increased risk of HCC. These mutations alone and in combination may be predictive for hepatocarcinogenesis.

  Y Zhang , X Li , J Qi , J Wang , X Liu , H Zhang , S. C Lin and A. Meng
 

The Rho-associated serine/threonine kinases Rock1 and Rock2 play important roles in cell contraction, adhesion, migration, proliferation and apoptosis. Here we report that Rock2 acts as a negative regulator of the TGFβ signaling pathway. Mechanistically, Rock2 binds to and accelerates the lysosomal degradation of TGFβ type I receptors internalized from the cell surface in mammalian cells. The inhibitory effect of Rock2 on TGFβ signaling requires its kinase activity. In zebrafish embryos, injection of rock2a mRNA attenuates the expression of mesodermal markers during late blastulation and blocks the induction of mesoderm by ectopic Nodal signals. By contrast, overexpression of a dominant negative form of zebrafish rock2a, dnrock2a, has an opposite effect on mesoderm induction, suggesting that Rock2 proteins are endogenous inhibitors for mesoderm induction. Thus, our data have unraveled previously unidentified functions of Rock2, in controlling TGFβ signaling as well as in regulating embryonic patterning.

  H Zhang , M Li , X Zheng , Y Sun , Z Wen and X. Zhao
 

In normal endometrium, stromal factors regulate the growth of epithelial cells. However, epithelial cells in endometriotic lesions display increased proliferation and decreased apoptosis. This work tested the hypothesis that in endometriosis stromal cells lose the ability to regulate survival signaling and cell growth in epithelial cells. Primary normal, endometriotic eutopic and ectopic epithelial cells were cultured in the presence of medium conditioned by normal, eutopic and ectopic endometriotic endometrial stromal cells. Endometriotic epithelial cells showed higher Survivin expression than normal epithelial cells. Conditioned medium (CM) from normal or eutopic endometriotic stromal cells significantly inhibited the Survivin expression and AKt phosphorylation in normal or eutopic endometriotic epithelial cells. However, CM from ectopic endometriotic stromal cells did not have an inhibitory effect on normal or ectopic endometriotic epithelial cells. Inhibition of AKt phosphorylation and Survivin expression in normal or eutopic endometriotic epithelial cells in the presence of stromal factors from normal or eutopic endometriotic stromal cells was enhanced by progesterone, whereas progesterone had little effect in the presence of stromal factors from ectopic endometriotic stromal cells. The inability of ectopic endometriotic stromal cells to regulated PI3K/AKt/Survivin signaling and mediate the progesterone response in endometriotic epithelial cells may facilitate epithelial cell proliferation in endometriosis and promote the survival of endometriotic lesions.

  W. x Liao , L Feng , H Zhang , J Zheng , T. R Moore and D. b. Chen
 

On vascular endothelial growth factor (VEGF) stimulation, both VEGF R1 and R2 receptors were phosphorylated in ovine fetoplacental artery endothelial (oFPAE) cells. Treatment with VEGF stimulated both time- and dose-dependent activation of ERK2/1 in oFPAE cells. VEGF-induced ERK2/1 activation was mediated by VEGFR2, but not VEGFR1, and was linked to intracellular calcium, protein kinase C, and Raf-1. VEGF stimulated oFPAE cell proliferation, migration, and tube formation in vitro. Blockade of ERK2/1 pathway attenuated VEGF-induced cell proliferation and tube formation but failed to inhibit migration in oFPAE cells. Disruption of caveolae by cholesterol depletion with methyl-β-cyclodextrin or by down-regulation of its structural protein caveolin-1 blunted VEGF-induced ERK2/1 activation, proliferation, and tube formation in oFPAE cells, indicating an essential role of integral caveolae in these VEGF-induced responses. Adenoviral overexpression of caveolin-1 and addition of a caveolin scaffolding domain peptide also inhibited VEGF-stimulated ERK2/1 activation, cell proliferation, and tube formation in oFPAE cells. Furthermore, molecules comprising the ERK2/1 signaling module, including VEGFR2, protein kinase C, Raf-1, MAPK kinase 1/2, and ERK2/1, resided with caveolin-1 in caveolae. VEGF transiently stimulated ERK2/1 activation in the caveolae similarly as in intact cells. Caveolae disruption greatly diminished ERK2/1 activation by VEGF in oFPAE cell caveolae. We conclude that caveolae function as a platform for compartmentalizing the VEGF-induced ERK2/1 signaling module. Caveolin-1 and caveolae play a paradoxical role in regulating VEGF-induced ERK2/1 activation and in vitro angiogenesis as evidenced by the similar inhibitory effects of down-regulation and overexpression of caveolin-1 and disruption of caveolae in oFPAE cells.

  H Zhang and J. Ogas
 

The developmental program of seeds is promoted by master regulators that are expressed in a seed-specific manner. Ectopic expression studies reveal that expression of these master regulators and other transcriptional regulators is sufficient to promote seed-associated traits, including generation of somatic embryos. Recent work highlights the importance of chromatin-associated factors in restricting expression of seed-specific genes, in particular PcG proteins and ATP-dependent remodelers. This review summarizes what is known regarding factors that promote zygotic and/or somatic embryogenesis and the chromatin machinery that represses their expression. Characterization of the regulation of seed-specific genes reveals that plant chromatin-based repression systems exhibit broad conservation with and surprising differences from animal repression systems.

  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.

  H Zhang , X Chen , W. B Bollag , R. J Bollag , D. J Sheehan and C. S. Chew
 

Lasp1 is an actin-binding, signaling pathway-regulated phosphoprotein that is overexpressed in several cancers. siRNA knockdown in cell lines retards cell migration, suggesting the possibility that Lasp1 upregulation influences cancer metastasis. Herein, we utilized a recently developed gene knockout model to assess the role of Lasp1 in modulating nontransformed cell functions. Wound healing and tumor initiation progressed more rapidly in Lasp1–/– mice compared with Lasp1+/+ controls. Embryonic fibroblasts (MEFs) derived from Lasp1–/– mice also migrated more rapidly in vitro. These MEFs characteristically possessed increased focal adhesion numbers and displayed more rapid attachment compared with wild-type MEFs. Differential microarray analyses revealed alterations in message expression for proteins implicated in cell migration, adhesion, and cytoskeletal organization. Notably, the focal adhesion protein, lipoma preferred partner (LPP), a zyxin family member and putative Lasp1 binding protein, was increased about twofold. Because LPP gene disruption reduces cell migration, we hypothesize that LPP plays a role in enhancing the migratory capacity of Lasp1–/– MEFs, perhaps by modifying the subcellular localization of other motility-associated proteins. The striking contrast in the functional effects of loss of Lasp1 in innate cells compared with cell lines reveals distinct differences in mechanisms of motility and attachment in these models.

  C Jiang , H Zhang , W Zhang , W Kong , Y Zhu , Q Xu , Y Li and X. Wang
 

Adipokines may represent a mechanism linking insulin resistance to cardiovascular disease. We showed previously that homocysteine (Hcy), an independent risk factor for cardiovascular disease, can induce the expression and secretion of resistin, a novel adipokine, in vivo and in vitro. Since vascular smooth muscle cell (VSMC) migration is a key event in vascular disease, we hypothesized that adipocyte-derived resistin is involved in Hcy-induced VSMC migration. To confirm our hypothesis, Sprague-Dawley rat aortic SMCs were cocultured with Hcy-stimulated primary rat epididymal adipocytes or treated directly with increasing concentrations of resistin for up to 24 h. Migration of VSMCs was investigated. Cytoskeletal structure and cytoskeleton-related proteins were also detected. The results showed that Hcy (300–500 µM) increased migration significantly in VSMCs cocultured with adipocytes but not in VSMC cultured alone. Resistin alone also significantly increased VSMC migration in a time- and concentration-dependent manner. Resistin small interfering RNA (siRNA) significantly attenuated VSMC migration in the coculture system, which indicated that adipocyte-derived resistin mediates Hcy-induced VSMC migration. On cell spreading assay, resistin induced the formation of focal adhesions near the plasma membrane, which suggests cytoskeletal rearrangement via an 5β1-integrin-focal adhesion kinase/paxillin-Ras-related C3 botulinum toxin substrate 1 (Rac1) pathway. Our data demonstrate that Hcy promotes VSMC migration through a paracrine or endocrine effect of adipocyte-derived resistin, which provides further evidence of the adipose-vascular interaction in metabolic disorders. The migratory action exerted by resistin on VSMCs may account in part for the increased incidence of restenosis in diabetic patients.

  H Zhang , D Zhao , Z Wang and D. Zheng
 

Although there is increasing evidence that the ATP sensitive potassium channel (KATP) opener exhibits neuroprotective effects against ischaemic neural damage, little is known about the mechanism. Mitochondria play a key role in apoptosis by releasing many important factors, including cytochrome c and apoptosis-inducing factor, which in turn initiate the caspase-dependent and -independent mitochondrial pathway, respectively. In the present study, we sought to determine the locus that KATP opener uses to mediate this protection in PC12 cells. We found that pre-treatment of PC12 cells with diazoxide (DZX), a mitochondrial ATP sensitive potassium channel (mitoKATP) opener, dose-dependently increased cell viability under conditions of oxygen glucose deprivation (OGD). The protective effect of this pre-conditioning was attenuated by 5-hydroxydecanoic acid, a selective mitoKATP blocker. The results showed that DZX inhibits the release of cytochrome c, the activation of caspase-3 and the release of AIF evoked by OGD. Taken together, our results demonstrate for the first time that activation of the mitoKATP channel elicits protective effects against OGD-induced cell apoptosis by caspase-dependent and -independent mitochondrial pathways.

  H Zhang , R. L Eoff , I. D Kozekov , C. J Rizzo , M Egli and F. P. Guengerich
 

Previous work has shown that Y-family DNA polymerases tolerate large DNA adducts, but a substantial decrease in catalytic efficiency and fidelity occurs during bypass of N2,N2-dimethyl (Me2)-substituted guanine (N2,N2-Me2G), in contrast to a single methyl substitution. Therefore, it is unclear why the addition of two methyl groups is so disruptive. The presence of N2,N2-Me2G lowered the catalytic efficiency of the model enzyme Sulfolobus solfataricus Dpo4 16,000-fold. Dpo4 inserted dNTPs almost at random during bypass of N2,N2-Me2G, and much of the enzyme was kinetically trapped by an inactive ternary complex when N2,N2-Me2G was present, as judged by a reduced burst amplitude (5% of total enzyme) and kinetic modeling. One crystal structure of Dpo4 with a primer having a 3'-terminal dideoxycytosine (Cdd) opposite template N2,N2-Me2G in a post-insertion position showed Cdd folded back into the minor groove, as a catalytically incompetent complex. A second crystal had two unique orientations for the primer terminal Cdd as follows: (i) flipped into the minor groove and (ii) a long pairing with N2,N2-Me2G in which one hydrogen bond exists between the O-2 atom of Cdd and the N-1 atom of N2,N2-Me2G, with a second water-mediated hydrogen bond between the N-3 atom of Cdd and the O-6 atom of N2,N2-Me2G. A crystal structure of Dpo4 with dTTP opposite template N2,N2-Me2G revealed a wobble orientation. Collectively, these results explain, in a detailed manner, the basis for the reduced efficiency and fidelity of Dpo4-catalyzed bypass of N2,N2-Me2G compared with mono-substituted N2-alkyl G adducts.

 
 
 
Copyright   |   Desclaimer   |    Privacy Policy   |   Browsers   |   Accessibility