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Articles by C Wang
Total Records ( 21 ) for C Wang
  A. S Gershon , C Wang , A. S Wilton , R Raut and T. To

Background  Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease with a prevalence of more than 10% worldwide among adults 40 years and older. Whether this amount has been increasing, decreasing, or stable over time remains unknown.

Methods  A longitudinal cohort study using population-based, health administrative data from 1991 to 2007 was conducted in Ontario, Canada. Individuals with COPD were identified using a previously validated health administrative case definition of COPD. Annual COPD prevalence, incidence, and all-cause mortality rates were estimated from 1996 to 2007.

Results  The prevalence of COPD increased by 64.8% between 1996 and 2007. The age- and sex-standardized COPD prevalence rate increased from 7.8% to 9.5%, representing a relative increase of 23.0% (P < .001). The age- and sex-standardized incidence decreased from 11.8 per 1000 adults to 8.5 per 1000 adults, representing a relative decrease of 28.3% (P < .001). Finally, the age- and sex-standardized all-cause mortality rate decreased from 5.7% to 4.3%, representing a relative decrease of 24.0% (P < .001).

Conclusions  Our findings indicate a substantial increase in COPD prevalence in the last decade, with more of the burden being shifted from men to women. Effective clinical and public health strategies are needed to prevent COPD and manage the increasing number of people living longer with this disease.

  F Li , P Yang , X Liu , C Wang , S Hou and A. Kijlstra

Objectives  To analyze the expression and potential role of interleukin (IL) 21 in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease.

Methods  Blood samples were obtained from patients with VKH disease and from healthy control subjects. Serum IL-21 level and IL-21 messenger RNA (mRNA) expression by peripheral blood mononuclear cells (PBMCs) were determined by enzyme-linked immunosorbent assay and by reverse transcriptase–polymerase chain reaction, respectively. Interleukin 17 and interferon levels in the supernatants of PBMCs and CD4+ T cells cultured with anti-CD3 and anti-CD28 antibodies in the presence or absence of recombinant IL-21 were detected by enzyme-linked immunosorbent assay.

Results  The results showed a significantly increased serum IL-21 level, as well as higher IL-21 mRNA expression by PBMCs, in patients having chronic or recurrent active VKH disease compared with patients having inactive VKH disease and with controls. In vitro experiments showed that recombinant IL-21 significantly increased IL-17 production by PBMCs and by CD4+ T cells from patients and from controls. However, recombinant IL-21 did not affect interferon expression by PBMCs or by CD4+ T cells.

Conclusion  Interleukin 21 may be involved in the pathogenesis of chronic or recurrent VKH disease, possibly by promoting IL-17 secretion.

Clinical Relevance  Findings from the present study suggest that IL-21 may be a potential target in the development of therapy for VKH disease.

  W Li , C Wang , S. K Juhn , F. G Ondrey and J. Lin

Objectives  To characterize the expression of fibroblast growth factor binding protein (FGF-BP) messenger RNA (mRNA) in head and neck squamous cell carcinoma (HNSCC) and to study the association of FGF-BP with vascularity.

Design  The expression of FGF-BP mRNA in HNSCC was studied in 35 primary and 8 metastatic HNSCC specimens and 7 control tissues using in situ hybridization and reverse transcriptase–polymerase chain reaction (RT-PCR). Microvessels in tumor specimens were identified with endothelial cell markers (von Willebrand factor [vWF] and CD34-specific antibodies). Correlates between FGF-BP and microvessel counts were evaluated statistically.

Setting  University of Minnesota Hospitals and Clinics.

Patients  Forty-two surgically treated patients with HNSCC.

Interventions  The patients were routinely treated in the study hospitals and clinics.

Main Outcome Measures  The expression of FGF-BP and angiogenesis in tumors were evaluated.

Results  In situ hybridization and RT-PCR demonstrated that FGF-BP mRNA transcripts were expressed in 34 of 35 primary HNSCC specimens and 5 of 8 metastatic tumor specimens but not in adjacent control tissues. The microvessel counts in HNSCC specimens were closely related to the expression level of FGF-BP (P < .001).

Conclusion  The expression of FGF-BP is statistically linked to the angiogenesis of HNSCC, suggesting that FGF-BP participates in the angiogenesis of HNSCC.

  C Wang , A Guttmann , T To and P. T. Dick

Objective  To quantify the effect of socioeconomic status (SES) on health outcomes during the first year after newborn discharge among infants with complex chronic conditions (CCCs) insured through a universal health plan.

Design  Longitudinal, population-based cohort study.

Setting  Ontario, Canada.

Participants  Infants born in hospitals from April 1, 1996, through March 31, 2000. Infants with CCCs were identified from their newborn discharge records. Neighborhood income quintiles were obtained by linking participants' postal codes to census data.

Main Outcome Measures  Mortality and hospital admissions in the first year after newborn discharge. Logistic and Poisson regression analyses were used to examine the relationship between neighborhood income quintiles and outcomes, adjusting for important covariates such as low birth weight and rural residence.

Results  A total of 512 768 infants were included, of whom 2.3% had CCCs at newborn discharge. Infants with CCCs accounted for 37.8% of deaths and 11.0% of hospitalizations during the first year after the newborn discharge. Infants with CCCs living in the lowest-income neighborhoods had a 1.26-fold higher mortality risk (95% confidence interval, 0.83-1.90; P = .28) and a 1.24-fold higher hospitalization rate (1.09-1.40; P < .001) compared with those living in the highest-income neighborhoods. Although the income gradients associated with mortality and hospitalization were less pronounced among infants with CCCs compared with infants without CCCs, the absolute interquintile risk differences attributable to SES were higher among infants with CCCs.

Conclusions  Despite universal health insurance, SES-related inequality affects hospitalization and, possibly, mortality rates among medically vulnerable infants.

  M Zhang , L Zhang , J Zou , C Yao , H Xiao , Q Liu , J Wang , D Wang , C Wang and Z. Guo

Motivation: According to current consistency metrics such as percentage of overlapping genes (POG), lists of differentially expressed genes (DEGs) detected from different microarray studies for a complex disease are often highly inconsistent. This irreproducibility problem also exists in other high-throughput post-genomic areas such as proteomics and metabolism. A complex disease is often characterized with many coordinated molecular changes, which should be considered when evaluating the reproducibility of discovery lists from different studies.

Results: We proposed metrics percentage of overlapping genes-related (POGR) and normalized POGR (nPOGR) to evaluate the consistency between two DEG lists for a complex disease, considering correlated molecular changes rather than only counting gene overlaps between the lists. Based on microarray datasets of three diseases, we showed that though the POG scores for DEG lists from different studies for each disease are extremely low, the POGR and nPOGR scores can be rather high, suggesting that the apparently inconsistent DEG lists may be highly reproducible in the sense that they are actually significantly correlated. Observing different discovery results for a disease by the POGR and nPOGR scores will obviously reduce the uncertainty of the microarray studies. The proposed metrics could also be applicable in many other high-throughput post-genomic areas.

  M. B Thomsen , C Wang , N Ozgen , H. G Wang , M. R Rosen and G. S. Pitt

Complex modulation of voltage-gated Ca2+ currents through the interplay among Ca2+ channels and various Ca2+-binding proteins is increasingly being recognized. The K+ channel interacting protein 2 (KChIP2), originally identified as an auxiliary subunit for KV4.2 and a component of the transient outward K+ channel (Ito), is a Ca2+-binding protein whose regulatory functions do not appear restricted to KV4.2. Consequently, we hypothesized that KChIP2 is a direct regulator of the cardiac L-type Ca2+ current (ICa,L). We found that ICa,L density from KChIP2–/– myocytes is reduced by 28% compared to ICa,L recorded from wild-type myocytes (P<0.05). This reduction in current density results from loss of a direct effect on the Ca2+ channel current, as shown in a transfected cell line devoid of confounding cardiac ion currents. ICa,L regulation by KChIP2 was independent of Ca2+ binding to KChIP2. Biochemical analysis suggested a direct interaction between KChIP2 and the CaV1.2 1C subunit N terminus. We found that KChIP2 binds to the N-terminal inhibitory module of 1C and augments ICa,L current density without increasing CaV1.2 protein expression or trafficking to the plasma membrane. We propose a model in which KChIP2 impedes the N-terminal inhibitory module of CaV1.2, resulting in increased ICa,L. In the context of recent reports that KChIP2 modulates multiple KV and NaV currents, these results suggest that KChIP2 is a multimodal regulator of cardiac ionic currents.

  M. L Steigner , D Mitsouras , A. G Whitmore , H. J Otero , C Wang , O Buckley , N. A Levit , A. Z Hussain , T Cai , R. T Mather , O Smedby , M. F DiCarli and F. J. Rybicki

Background— To define and evaluate coronary contrast opacification gradients using prospectively ECG-gated single heart beat 320-detector row coronary angiography (CTA).

Methods and Results— Thirty-six patients with normal coronary arteries determined by 320x0.5-mm detector row coronary CTA were retrospectively evaluated with customized image postprocessing software to measure Hounsfield Units at 1-mm intervals orthogonal to the artery center line. Linear regression determined correlation between mean Hounsfield Units and distance from the coronary ostium (regression slope defined as the distance gradient Gd), lumen cross-sectional area (Ga), and lumen short-axis diameter (Gs). For each gradient, differences between the 3 coronary arteries were analyzed with ANOVA. Linear regression determined correlations between measured gradients, heart rate, body mass index, and cardiac phase. To determine feasibility in lesions, all 3 gradients were evaluated in 22 consecutive patients with left anterior descending artery lesions ≥50% stenosis. For all 3 coronary arteries in all patients, the gradients Ga and Gs were significantly different from zero (P<0.0001), highly linear (Pearson r values, 0.77 to 0.84), and had no significant difference between the left anterior descending, left circumflex, and right coronary arteries (P>0.503). The distance gradient Gd demonstrated nonlinearities in a small number of vessels and was significantly smaller in the right coronary artery when compared with the left coronary system (P<0.001). Gradient variations between cardiac phases, heart rates, body mass index, and readers were low. Gradients in patients with lesions were significantly different (P<0.021) than in patients considered normal by CTA.

Conclusions— Measurement of contrast opacification gradients from temporally uniform coronary CTA demonstrates feasibility and reproducibility in patients with normal coronary arteries. For all patients, the gradients defined with respect to the coronary lumen cross-sectional area and short-axis diameters are highly linear, not significantly influenced by the coronary artery (left anterior descending artery versus left circumflex versus right coronary artery), and have only small variation with respect to patient parameters. Preliminary evaluation of gradients across coronary artery lesions is promising but requires additional study.

  C Zhang , C Wang , X Chen , C Yang , K Li , J Wang , J Dai , Z Hu , X Zhou , L Chen , Y Zhang , Y Li , H Qiu , J Xing , Z Liang , B Ren , K Zen and C. Y. Zhang

Sensitive and specific biomarkers for the early detection of esophageal squamous cell carcinoma (ESCC) are urgently needed to reduce the high morbidity and mortality of the disease. The discovery of serum microRNAs (miRNAs) and their unique concentration profiles in patients with various diseases makes them attractive, novel noninvasive biomarkers for tumor diagnosis. In this study, we investigated the serum miRNA profile in ESCC patients to develop a novel diagnostic ESCC biomarker.


Serum samples were taken from 290 ESCC patients and 140 age- and sex-matched controls. Solexa sequencing technology was used for an initial screen of miRNAs in serum samples from 141 patients and 40 controls. A hydrolysis probe–based stem–loop quantitative reverse-transcription PCR (RT-qPCR) assay was conducted in the training and verification phases to confirm the concentrations of selected miRNAs in serum samples from 149 patients and 100 controls.


The Solexa sequencing results demonstrated marked upregulation of 25 serum miRNAs in ESCC patients compared with controls. RT-qPCR analysis identified a profile of 7 serum miRNAs (miR-10a, miR-22, miR-100, miR-148b, miR-223, miR-133a, and miR-127-3p) as ESCC biomarkers. The area under the ROC curve for the selected miRNAs ranged from 0.817 to 0.949, significantly higher than for carcinoembryonic antigen (0.549; P < 0.0005). More importantly, this panel of 7 miRNAs clearly distinguished stage I/II ESCC patients from controls.


This panel of 7 serum miRNAs holds promise as a novel blood-based biomarker for the diagnosis of ESCC.

  Y Wu , L Yang , T Su , C Wang , G Liu and X. m. Li

Background and objectives: Although a renal biopsy is indispensable for depicting the severity of pathologic lesions in drug-induced tubulointerstitial nephritis (DTIN), it is not acceptable in some cases and cannot be performed serially because of its invasive nature. Therefore, the discovery of noninvasive markers that are closely related to the pathology of DTIN is of great value.

Design, setting, participants, & measurements: In this study, the urinary levels of monocyte chemotactic peptide-1 (MCP-1), neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-β-d-glucosaminidase, and 1-microglobulin were measured in 40 DTIN subjects, and the performances of these parameters for distinguishing different pathologic lesions were compared.

Results: Linear correlation and receiver operating characteristic curve analyses showed that urinary MCP-1 levels were able to identify serious interstitial edema and inflammatory infiltration with greater accuracy than the other biomarkers (r = 0.501, P < 0.001 and r = 0.768, P < 0.001, respectively), whereas urinary NGAL levels showed the highest correlation coefficient with tubular atrophy (r = 0.692, P < 0.001).

Conclusions: These results suggest that these biomarker levels were higher in patients with DTIN than in controls. Urinary MCP-1 levels correlated and were predictive of the gradated severity of acute lesions in DTIN, whereas the roles of NGAL and 1-microglobulin in chronic alterations require further study.

  C Wang , K. C Chang , G Somers , D Virshup , B. T Ang , C Tang , F Yu and H. Wang
  Cheng Wang, Kai Chen Chang, Gregory Somers, David Virshup, Beng Ti Ang, Carol Tang, Fengwei Yu, and Hongyan Wang

Drosophila larval brain neural stem cells, also known as neuroblasts, divide asymmetrically to generate a self-renewing neuroblast and a ganglion mother cell (GMC) that divides terminally to produce two differentiated neurons or glia. Failure of asymmetric cell division can result in hyperproliferation of neuroblasts, a phenotype resembling brain tumors. Here we have identified Drosophila Protein phosphatase 2A (PP2A) as a brain tumor-suppressor that can inhibit self-renewal of neuroblasts. Supernumerary larval brain neuroblasts are generated at the expense of differentiated neurons in PP2A mutants. Neuroblast overgrowth was observed in both dorsomedial (DM)/posterior Asense-negative (PAN) neuroblast lineages and non-DM neuroblast lineages. The PP2A heterotrimeric complex, composed of the catalytic subunit (Mts), scaffold subunit (PP2A-29B) and a B-regulatory subunit (Tws), is required for the asymmetric cell division of neuroblasts. The PP2A complex regulates asymmetric localization of Numb, Pon and Atypical protein kinase C, as well as proper mitotic spindle orientation. Interestingly, PP2A and Polo kinase enhance Numb and Pon phosphorylation. PP2A, like Polo, acts to prevent excess neuroblast self-renewal...

  T Ramesh , A. N Lyon , R. H Pineda , C Wang , P. M. L Janssen , B. D Canan , A. H. M Burghes and C. E. Beattie
  Tennore Ramesh, Alison N. Lyon, Ricardo H. Pineda, Chunping Wang, Paul M. L. Janssen, Benjamin D. Canan, Arthur H. M. Burghes, and Christine E. Beattie

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that, for ~80% of patients, is fatal within five years of diagnosis. To better understand ALS, animal models have been essential; however, only rodent models of ALS exhibit the major hallmarks of the disease. Here, we report the generation of transgenic zebrafish overexpressing mutant Sod1. The construct used to generate these lines contained the zebrafish sod1 gene and ~16 kb of flanking sequences. We generated lines expressing the G93R mutation, as well as lines expressing wild-type Sod1. Focusing on two G93R lines, we found that they displayed the major phenotypes of ALS. Changes at the neuromuscular junction were observed at larval and adult stages. In adulthood the G93R mutants exhibited decreased endurance in a swim tunnel test. An analysis of muscle revealed normal muscle force, however, at the end stage the fish exhibited motoneuron loss, muscle atrophy, paralysis and premature death. These phenotypes were more severe in lines expressing higher levels of mutant Sod1 and were absent in lines overexpressing wild-type Sod1. Thus, we have generated a vertebrate model of ALS to complement existing mammal models.

  W. P Williams , E. M Gibson , C Wang , S Tjho , N Khattar , G. E Bentley , K Tsutsui and L. J. Kriegsfeld

Circadian rhythms impact a variety of behavioral and physiological functions contributing to longevity and successful reproduction. In their natural environments, individuals of a species are faced with a multitude of challenges and the coordination of internal processes and behavior with external pressures has been hypothesized to be an important target of natural selection. Several lines of evidence from cyanobacteria, Drosophila, and plants provide strong support for an important role of the circadian clock in survival and reproductive success. Similarly in mammals, disruptions in circadian function markedly impact reproduction and lifespan. The present review discusses research outlining the proximate and ultimate mechanisms responsible for the central and peripheral control of the reproductive axis. Because precise temporal coordination of the endocrine system is particularly crucial for reproduction by females, the present overview focuses on the role of circadian timing in this sex.

  C Wang , D. C Popescu , C Wu , J Zhu , W Macklin and Y. Wang

We describe a novel fluorescent dye, 3-(4-aminophenyl)-2H-chromen-2-one (termed case myelin compound or CMC), that can be used for in situ fluorescent imaging of myelin in the vertebrate nervous system. When administered via intravenous injection into the tail vein, CMC selectively stained large bundles of myelinated fibers in both the central nervous system (CNS) and the peripheral nervous system (PNS). In the CNS, CMC readily entered the brain and selectively localized in myelinated regions such as the corpus callosum and cerebellum. CMC also selectively stained myelinated nerves in the PNS. The staining patterns of CMC in a hypermyelinated mouse model were consistent with immunohistochemical staining. Similar to immunohistochemical staining, CMC selectively bound to myelin sheaths present in the white matter tracts. Unlike CMC, conventional antibody staining for myelin basic protein also stained oligodendrocyte cytoplasm in the striatum as well as granule layers in the cerebellum. In vivo application of CMC was also demonstrated by fluorescence imaging of myelinated nerves in the PNS. (J Histochem Cytochem 58:611–621, 2010)

  C Wang , G Xie , B Cheng , L Du , L Shi , L Tan , Q Shu and X. Fang

Pediatric Risk of Mortality (PRISM), Pediatric Index of Mortality (PIM) and PIM2 could be applicable to the subset of term neonates has not been well investigated. The purpose of this study is to access and compare the performance of these scoring systems in predicting mortality probability in term Chinese neonates with critical illness. PRISM, PIM and PIM2 scores were calculated prospectively during a 1-year period on 243 neonates admitted to the neonatal intensive care unit (NICU) in the Children’s Hospital of Zhejiang University in China. Of these, 36 neonates (14.81%) died in the NICU, while the mortality rates estimated by PRISM, PIM and PIM2 were 16.19, 14.58 and 11.12%, respectively. The area under the receiver-operating characteristic (ROC) curve [95% confidence intervals (CIs)] were 0.834 (0.767–0.902), 0.851 (0.786–0.916) and 0.854 (0.790–0.918) for PRISM, PIM and PIM2, respectively. The Hosmer–Lemeshow test gave a chi-square of 1.35 (p = 0.930) for PRISM, 1.03 (p = 0.960) for PIM and 4.58 (p = 0.469) for PIM2. The standardized mortality rates (SMRs) (95% CI) using PRISM, PIM and PIM2 were 0.92 (0.79–1.08), 1.02 (0.88–1.20) and 1.33 (1.13–1.62), respectively. Although PRISM, PIM and PIM2 have displayed good discrimination and calibration in the present setting, PIM is considered as the most accurate and appropriate tool for predicting mortality in the studied NICU.

  A Van Deusen , A Hyland , M. J Travers , C Wang , C Higbee , B. A King , T Alford and K. M. Cummings

With the increasing normative trend of clean indoor air laws prohibiting smoking in public places such as worksites and restaurants, the home is becoming the primary source of secondhand smoke (SHS) exposure. However, little empirical data indicate how SHS is distributed throughout homes and whether smoking in segregated areas offers protection. This project studied real-time data on levels of SHS in 9 homes in which smoking was permitted and in 3 smoke-free homes. Active sampling monitors were used to assess levels of PM2.5, a marker for SHS, over a 3-day period. In smoking homes, one monitor was placed in the primary smoking area and another in a distal location, where smoking generally did not occur. Participants logged smoking and other activities that could affect air quality. In smoking homes, without assuming normality, the mean PM2.5 level for the primary smoking areas was statistically significantly higher than that for distal areas (84 and 63 µg/m3, respectively). Both levels far surpassed the U.S. Environmental Protection Agency's annual standard of 15 µg/m3 for outdoor air quality. By contrast, the smoke-free home mean was 9 µg/m3, similar to outdoor air quality. These results suggest that the air in smoking homes was several times more polluted than that in smoke-free homes, regardless of where the measurements were taken, meaning that efforts to confine smoking to only part of the home offer no protection for people anywhere inside the home. Household members can be protected by implementing a smoke-free home policy.

  J Jia , C Wang , Z Shi , J Zhao , Y Jia , Z Zhao Hui , X Li , Z Chen and P. Zhu

Objective. To explore the therapeutic potential of CD147/HAb18 mAb in the treatment of RA in severe combined immunodeficiency (SCID) mice engrafted with human cartilage and rheumatoid synovium tissue (SCID-HuRAg).

Methods. SCID-HuRAg mice were treated separately with CD147/HAb18 mAb, anti-TNF- mAb or a combination of both. The mice in control group were treated with anti-Japanese encephalitis virus mAb. The volume of engrafts was measured and the number of inflammatory cells and cartilage erosion score were examined. Expression of MMP-2, -3 and -9 was determined by immunohistochemistry. Human inflammatory cytokine levels in mouse sera were assessed using cytometric bead array kit.

Results. The volume of engrafts decreased significantly in SCID-HuRAg mice treated separately with anti-CD147 mAb or anti-TNF- mAb, and in the mice treated with anti-CD147 mAb plus anti-TNF- mAb (P < 0.05). Significant reduction was observed in cartilage erosion score in anti-CD147 treatment group and combined treatment group (P < 0.05). Immunohistochemical analysis showed that expression of MMP-2, -3 and -9 was lower in the anti-CD147 treatment group and combined treatment group than in the control mAb group (P < 0.05). Moreover, the level of TNF-, IL-6 and -8 in CD147 mAb group showed a significant decrease compared with that of the control mAb group (P < 0.05).

Conclusions. CD147/HAb18 mAb can reduce cartilage erosion and synovitis by inhibition of the MMPs and reduction of inflammatory cytokines in SCID-HuRAg mice, which suggests that CD147/HAb18 mAb is a promising treatment option for RA patients.

  G Fan , C Feng , Y Li , C Wang , J Yan , W Li , J Feng , X Shi and Y. Bi

Background: We carried out animal experiments based on the orthogonal design L8(27) setting seven factors with two different levels of each and 10 groups of rats. The nutrients tested were tyrosine, glycine, methionine, taurine, ascorbic acid, thiamine and zinc.

Objectives: The objective of this study was to explore the optimal combinations of nutrients for prevention or amelioration of lead-induced learning and memory impairment.

Methods: Rats were supplemented with nutrients by gavage once a day in two experiments: one was simultaneous nutrient supplementation with lead acetate administration (800 mg l–1) for 8 weeks (prophylactic supplementation) and the other was nutrient supplementation for 4 weeks after the cessation of 4 weeks of lead administration (remedial supplementation). Morris water maze was initiated at ninth week. Rats were terminated for assays of levels of Pb in blood, activities of superoxide dismutase (SOD) and nitric oxide synthase (NOS) in hippocampus, levels of nitric oxide (NO) in hippocampus and expressions of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and cyclic adenosine monophosphate (cAMP) response element-binding protein messenger RNA in hippocampus.

Results: Results showed that in prophylactic supplementation, methionine, taurine, zinc, ascorbic acid and glycine were the effective preventive factors for decreasing prolonged escape latency, increasing SOD and NOS activities and NO levels in the hippocampus, respectively. On the other hand, in remedial supplementation, taurine was the effective factor for reversing Pb-induced decrease in activities of SOD, NOS and levels of NO.

Conclusions: In conclusion, the optimum combinations of nutrients appear to be methionine, taurine, zinc, ascorbic acid and glycine for the prevention of learning and memory impairment, while taurine and thiamine appear to be the effective factors for reversing Pb neurotoxicity.

  C Wang , R Qi , N Li , Z Wang , H An , Q Zhang , Y Yu and X. Cao

Notch signaling plays a critical role in regulating cell proliferation, differentiation, and apoptosis. Our previous study showed that overexpression of Notch1 could inhibit human hepatocellular carcinoma (HCC) cell growth by arresting the cell cycle and inducing apoptosis. HCC cells are resistant to apoptotic induction by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), so new therapeutic approaches have been explored to sensitize HCC cells to TRAIL-induced apoptosis. We are wondering whether and how Notch1 signaling can enhance the sensitivity of HCC cells to TRAIL-induced apoptosis. In this study, we found that overexpression of ICN, the constitutive activated form of Notch1, up-regulated p53 protein expression in HCC cells by inhibiting proteasome degradation. p53 up-regulation was further observed in human primary hepatocellular carcinoma cells after activation of Notch signaling. Inhibition of the Akt/Hdm2 pathway by Notch1 signaling was responsible for the suppression of p53 proteasomal degradation, thus contributing to the Notch1 signaling-mediated up-regulation of p53 expression. Accordingly, Notch1 signaling could make HCC cells more sensitive to TRAIL-induced apoptosis, whereas Notch1 signaling lost the synergistic promotion of TRAIL-induced apoptosis in p53-silenced HepG2 HCC cells and p53-defective Hep3B HCC cells. The data suggest that enhancement of TRAIL-induced apoptosis by Notch1 signaling is dependent upon p53 up-regulation. Furthermore, Notch1 signaling could enhance DR5 expression in a p53-dependent manner. Taken together, Notch1 signaling sensitizes TRAIL-induced apoptosis in HCC cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating p53-dependent DR5 expression. Thus, our results suggest that activation of Notch1 signaling may be a promising approach to improve the therapeutic efficacy of TRAIL-resistant HCC.

  F Zhang , S Tsai , K Kato , D Yamanouchi , C Wang , S Rafii , B Liu and K. C. Kent

Bone marrow-derived progenitor cells have recently been shown to be involved in the development of intimal hyperplasia after vascular injury. Transforming growth factor-β (TGF-β) has profound stimulatory effects on intimal hyperplasia, but it is unknown whether these effects involve progenitor cell recruitment. In this study we found that although TGF-β had no direct effect on progenitor cell recruitment, conditioned media derived from vascular smooth muscle cells (VSMC) stimulated with TGF-β induced migration of both total bone marrow (BM) cells and BM-mesenchymal stem cells (MSC) and also induced MSC differentiation into smooth muscle like cells. Furthermore, overexpression of the signaling molecule Smad3 in VSMC via adenovirus-mediated gene transfer (AdSmad3) enhanced the TGF-β's chemotactic effect. Microarray analysis of VSMC stimulated by TGF-β/AdSmad3 revealed monocyte chemoattractant protein-1 (MCP-1) as a likely factor responsible for progenitor cell recruitment. We then demonstrated that TGF-β through Smad3 phosphorylation induced a robust expression of MCP-1 in VSMC. Recombinant MCP-1 mimicked the stimulatory effect of conditioned media on BM and MSC migration. In the rat carotid injury model, Smad3 overexpression significantly increased MCP-1 expression after vascular injury, consistent with our in vitro results. Interestingly, TGF-β/Smad3-induced MCP-1 was completely blocked by both Ro-32-0432 and rotterlin, suggesting protein kinase C- (PKC) may play a role in TGF-β/Smad3-induced MCP-1 expression. In summary, our data demonstrate that TGF-β, through Smad3 and PKC, stimulates VSMC production of MCP-1, which is a chemoattractant for bone marrow-derived cells, specifically MSC. Manipulation of this signaling system may provide a novel approach to inhibition of intimal hyperplasia.

  S. M Jin , M Lazarou , C Wang , L. A Kane , D. P Narendra and R. J. Youle

PINK1 is a mitochondrial kinase mutated in some familial cases of Parkinson’s disease. It has been found to work in the same pathway as the E3 ligase Parkin in the maintenance of flight muscles and dopaminergic neurons in Drosophila melanogaster and to recruit cytosolic Parkin to mitochondria to mediate mitophagy in mammalian cells. Although PINK1 has a predicted mitochondrial import sequence, its cellular and submitochondrial localization remains unclear in part because it is rapidly degraded. In this study, we report that the mitochondrial inner membrane rhomboid protease presenilin-associated rhomboid-like protein (PARL) mediates cleavage of PINK1 dependent on mitochondrial membrane potential. In the absence of PARL, the constitutive degradation of PINK1 is inhibited, stabilizing a 60-kD form inside mitochondria. When mitochondrial membrane potential is dissipated, PINK1 accumulates as a 63-kD full-length form on the outer mitochondrial membrane, where it can recruit Parkin to impaired mitochondria. Thus, differential localization to the inner and outer mitochondrial membranes appears to regulate PINK1 stability and function.

  B. C Betz , K. L Jordan Williams , C Wang , S. G Kang , J Liao , M. R Logan , C. H Kim and E. J. Taparowsky

Batf belongs to the activator protein 1 superfamily of basic leucine zipper transcription factors that includes Fos, Jun, and Atf proteins. Batf is expressed in mouse T and B lymphocytes, although the importance of Batf to the function of these lineages has not been fully investigated. We generated mice (BatfZ/Z) in which Batf protein is not produced. BatfZ/Z mice contain normal numbers of B cells but show reduced numbers of peripheral CD4+ T cells. Analysis of CD4+ T helper (Th) cell subsets in BatfZ/Z mice demonstrated that Batf is required for the development of functional Th type 17 (Th17), Th2, and follicular Th (Tfh) cells. In response to antigen immunization, germinal centers were absent in BatfZ/Z mice and the maturation of Ig-secreting B cells was impaired. Although adoptive transfer experiments confirmed that this B cell phenotype can be driven by defects in the BatfZ/Z CD4+ T cell compartment, stimulation of BatfZ/Z B cells in vitro, or by a T cell–independent antigen in vivo, resulted in proliferation but not class-switch recombination. We conclude that loss of Batf disrupts multiple components of the lymphocyte communication network that are required for a robust immune response.

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