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1.  Synergistic Impaired Effect between Smoking and Manganese Dust Exposure on Pulmonary Ventilation Function in Guangxi Manganese-Exposed Workers Healthy Cohort (GXMEWHC) 
PLoS ONE  2015;10(2):e0116558.
Purpose
The aims of this study were to investigate the effects of manganese (Mn) dust exposure on lung functions and evaluate the potential synergistic effect between smoking and Mn dust exposure among refinery workers.
Methods
A retrospective study including 1658 workers in a ferromanganese refinery was conducted, with subjects who were from the Guangxi manganese-exposed workers healthy cohort (GXMEWHC). Based on the Mn manganese cumulative exposure index (Mn-CEI), all subjects were divided into the low exposure group (n = 682) and the high exposure group (n = 976). A pulmonary function test was performed using an electronic spirometer, including the values and percentages of FVC, FEV1, FEV1/FVC, MMEF, PEFR, MVV, respectively.
Results
No significant effect of Mn dust exposure on the pulmonary function was found in the female workers (all p>0.05). However, there was an obvious decrease in the male workers in the high exposure group compared with those in the low exposure group (FVC -60 ml, FEV1 -120 ml, MMEF -260 ml/s, MVV -5.06 L, all p<0.05). In the high exposure group, the reduction in FVC% predicted, MMEF and MMEF% predicted was 1.0%, 210 mL/s, and 4.9%, respectively. In particular, among the exposed subjects smokers had a statistically significant decrease in lung function compared with non-smokers and the reduction in FVC% predicted, MMEF and MMEF% predicted was 1.0%, 210 mL/s, and 4.9%, respectively (p<0.05). Partial correlation analysis showed that there was also negative correlation between Mn-CEI and decreased changes in MMEF (r = -0.159, p = 0.018) and also MMEF% predicted (r = -0.163, p = 0.015).
Conclusions
Mn dust can impair the pulmonary ventilation function of male workers but not females, and individual smoking habits and manganese exposure had a synergistic effect on the lung function decrease.
doi:10.1371/journal.pone.0116558
PMCID: PMC4321994  PMID: 25664879
2.  Increased adenosine levels contribute to ischemic kidney fibrosis in the unilateral ureteral obstruction model 
Renal interstitial fibrosis (RIF) occurs as a result of chronic kidney disease (CKD) and is a common pathway leading to end-stage renal failure. Renal tissue hypoxia and ischemia are present during CKD. Adenosine (ADO) is an important signaling molecule induced under ischemic and hypoxic conditions. In the present study, the association between ADO and RIF was investigated using a mouse model, with the aim of obtaining important information relevant to the prevention and treatment of RIF. A unilateral ureteral obstruction (UUO) model of RIF was established in mice. A total of 44 male mice were randomly divided into sham, model and intervention groups, and samples were collected on days 1, 3, 7, and 14 after modeling. These were collected to detect hypoxia and changes in ADO concentration in obstructed renal tissue as well as to analyze the pathological changes and degree of RIF in the renal tissue. Changes in the levels of collagen deposition and profibrogenic factors in renal tissues were analyzed following intervention with an ADO receptor blocker. Following the UUO procedure, continuous hypoxia was present in the obstructed renal tissue, accompanied by an increased ADO concentration. Tubular injury and interstitial fibrosis progressively increased over time following the UUO procedure. The mRNA expression levels of tissue tumor growth factor β1 (TGF-β1) and α1(I) procollagen were significantly increased. Subsequent to the ADO pathway being blocked by 8-(p-sulfophenyl)-theophylline, tubular injury and interstitial fibrosis were reduced and the expression of related cytokines was decreased. Increased ADO levels were induced by hypoxia, causing the development of RIF. Following the blocking of the ADO pathway, renal damage was deferred and renal functions were protected.
doi:10.3892/etm.2015.2177
PMCID: PMC4316984  PMID: 25667621
adenosine; α-smooth muscle actin; cytokines; renal interstitial fibrosis; unilateral ureteral obstruction model
3.  Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice*  
Background and aims: Ingestion of paraquat (PQ), a widely used herbicide, can cause severe toxicity in humans, leading to a poor survival rate and prognosis. One of the main causes of death by PQ is PQ-induced pulmonary fibrosis, for which there are no effective therapies. The aim of this study was to evaluate the effects of rapamycin (RAPA) on inhibiting PQ-induced pulmonary fibrosis in mice and to explore its possible mechanisms. Methods: Male C57BL/6J mice were exposed to either saline (control group) or PQ (10 mg/kg body weight, intraperitoneally; test group). The test group was divided into four subgroups: a PQ group (PQ-exposed, non-treated), a PQ+RAPA group (PQ-exposed, treated with RAPA at 1 mg/kg intragastrically), a PQ+MP group (PQ-exposed, treated with methylprednisolone (MP) at 30 mg/kg intraperitoneally), and a PQ+MP+RAPA group (PQ-exposed, treated with MP at 30 mg/kg intraperitoneally and with RAPA at 1 mg/kg intragastrically). The survival rate and body weight of all the mice were recorded every day. Three mice in each group were sacrificed at 14 d and the rest at 28 d after intoxication. Lung tissues were excised and stained with hematoxylin-eosin (H&E) and Masson’s trichrome stain for histopathological analysis. The hydroxyproline (HYP) content in lung tissues was detected using an enzyme-linked immunosorbent assay (ELISA) kit. The expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) in lung tissues was detected by immunohistochemical staining and Western blotting. Results: A mice model of PQ-induced pulmonary fibrosis was established. Histological examination of lung tissues showed that RAPA treatment moderated the pathological changes of pulmonary fibrosis, including alveolar collapse and interstitial collagen deposition. HYP content in lung tissues increased soon after PQ intoxication but had decreased significantly by the 28th day after RAPA treatment. Immunohistochemical staining and Western blotting showed that RAPA treatment significantly down-regulated the enhanced levels of TGF-β1 and α-SMA in lung tissues caused by PQ exposure. However, RAPA treatment alone could not significantly ameliorate the lower survival rate and weight loss of treated mice. MP treatment enhanced the survival rate, but had no significant effects on attenuating PQ-induced pulmonary fibrosis or reducing the expression of TGF-β1 and α-SMA. Conclusions: This study demonstrates that RAPA treatment effectively suppresses PQ-induced alveolar collapse and collagen deposition in lung tissues through reducing the expression of TGF-β1 and α-SMA. Thus, RAPA has potential value in the treatment of PQ-induced pulmonary fibrosis.
doi:10.1631/jzus.B1400229
PMCID: PMC4288945  PMID: 25559956
Paraquat; Pulmonary fibrosis; Rapamycin; Transforming growth factor-β1; α-Smooth muscle actin; Methylprednisolone
4.  Altered MicroRNA Expression Profile in Exosomes during Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells 
PLoS ONE  2014;9(12):e114627.
The physiological role of microRNAs (miRNAs) in osteoblast differentiation remains elusive. Exosomal miRNAs isolated from human bone marrow-derived mesenchymal stem cells (BMSCs) culture were profiled using miRNA arrays containing probes for 894 human matured miRNAs. Seventy-nine miRNAs (∼8.84%) could be detected in exosomes isolated from BMSC culture supernatants when normalized to endogenous control genes RNU44. Among them, nine exosomal miRNAs were up regulated and 4 miRNAs were under regulated significantly (Relative fold>2, p<0.05) when compared with the values at 0 day with maximum changes at 1 to 7 days. Five miRNAs (miR-199b, miR-218, miR-148a, miR-135b, and miR-221) were further validated and differentially expressed in the individual exosomal samples from hBMSCs cultured at different time points. Bioinformatic analysis by DIANA-mirPath demonstrated that RNA degradation, mRNA surveillance pathway, Wnt signaling pathway, RNA transport were the most prominent pathways enriched in quantiles with differential exosomal miRNA patterns related to osteogenic differentiation. These data demonstrated exosomal miRNA is a regulator of osteoblast differentiation.
doi:10.1371/journal.pone.0114627
PMCID: PMC4263734  PMID: 25503309
5.  Autophagy-Mediated Tumor Promotion 
Cell  2013;155(6):1216-1219.
Mouse models for cancer are revealing novel cancer-promoting roles for autophagy. Autophagy promotes tumor growth by suppressing the p53 response, maintaining mitochondrial function, sustaining metabolic homeostasis and survival in stress, and preventing diversion of tumor progression to benign oncocytomas.
doi:10.1016/j.cell.2013.11.019
PMCID: PMC3987898  PMID: 24315093
6.  How Good is Automated Protein Docking? 
Proteins  2013;81(12):2159-2166.
The protein docking server ClusPro has been participating in CAPRI since its introduction in 2004. This paper evaluates the performance of ClusPro 2.0 for targets 46–58 in rounds 22–27 of CAPRI. The analysis leads to a number of important observations. First, ClusPro reliably yields acceptable or medium accuracy models for targets of moderate difficulty that have also been successfully predicted by other groups, and fails only for targets that have few acceptable models submitted. Second, the quality of automated docking by ClusPro is very close to that of the best human predictor groups, including our own submissions. This is very important, because servers have to submit results within 48 hours and the predictions should be reproducible, whereas human predictors have several weeks and can use any type of information. Third, while we refined the ClusPro results for manual submission by running computationally costly Monte Carlo minimization simulations, we observed significant improvement in accuracy only for two of the six complexes correctly predicted by ClusPro. Fourth, new developments, not seen in previous rounds of CAPRI, are that the top ranked model provided by ClusPro was acceptable or better quality for all these six targets, and that the top ranked model was also the highest quality for five of the six, confirming that ranking models based on cluster size can reliably identify the best near-native conformations.
doi:10.1002/prot.24403
PMCID: PMC3934018  PMID: 23996272
protein-protein docking; structure refinement; method development; CAPRI docking experiment; web based server; user community
7.  The DcpS inhibitor RG3039 improves motor function in SMA mice 
Human Molecular Genetics  2013;22(20):4074-4083.
Spinal muscular atrophy (SMA) is caused by mutations of the survival motor neuron 1 (SMN1) gene, retention of the survival motor neuron 2 (SMN2) gene and insufficient expression of full-length survival motor neuron (SMN) protein. Quinazolines increase SMN2 promoter activity and inhibit the ribonucleic acid scavenger enzyme DcpS. The quinazoline derivative RG3039 has advanced to early phase clinical trials. In preparation for efficacy studies in SMA patients, we investigated the effects of RG3039 in severe SMA mice. Here, we show that RG3039 distributed to central nervous system tissues where it robustly inhibited DcpS enzyme activity, but minimally activated SMN expression or the assembly of small nuclear ribonucleoproteins. Nonetheless, treated SMA mice showed a dose-dependent increase in survival, weight and motor function. This was associated with improved motor neuron somal and neuromuscular junction synaptic innervation and function and increased muscle size. RG3039 also enhanced survival of conditional SMA mice in which SMN had been genetically restored to motor neurons. As this systemically delivered drug may have therapeutic benefits that extend beyond motor neurons, it could act additively with SMN-restoring therapies delivered directly to the central nervous system such as antisense oligonucleotides or gene therapy.
doi:10.1093/hmg/ddt257
PMCID: PMC3781637  PMID: 23727836
8.  The DcpS inhibitor RG3039 improves survival, function and motor unit pathologies in two SMA mouse models 
Human Molecular Genetics  2013;22(20):4084-4101.
Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein due to the functional loss of the SMN1 gene and the inability of its paralog, SMN2, to fully compensate due to reduced exon 7 splicing efficiency. Since SMA patients have at least one copy of SMN2, drug discovery campaigns have sought to identify SMN2 inducers. C5-substituted quinazolines increase SMN2 promoter activity in cell-based assays and a derivative, RG3039, has progressed to clinical testing. It is orally bioavailable, brain-penetrant and has been shown to be an inhibitor of the mRNA decapping enzyme, DcpS. Our pharmacological characterization of RG3039, reported here, demonstrates that RG3039 can extend survival and improve function in two SMA mouse models of varying disease severity (Taiwanese 5058 Hemi and 2B/− SMA mice), and positively impacts neuromuscular pathologies. In 2B/− SMA mice, RG3039 provided a >600% survival benefit (median 18 days to >112 days) when dosing began at P4, highlighting the importance of early intervention. We determined the minimum effective dose and the associated pharmacokinetic (PK) and exposure relationship of RG3039 and DcpS inhibition ex vivo. These data support the long PK half-life with extended pharmacodynamic outcome of RG3039 in 2B/− SMA mice. In motor neurons, RG3039 significantly increased both the average number of cells with gems and average number of gems per cell, which is used as an indirect measure of SMN levels. These studies contribute to dose selection and exposure estimates for the first studies with RG3039 in human subjects.
doi:10.1093/hmg/ddt258
PMCID: PMC3781638  PMID: 23736298
9.  MTA1 Overexpression Induces Cisplatin Resistance Innasopharyngeal Carcinoma by Promoting Cancer Stem Cells Properties 
Molecules and Cells  2014;37(9):699-704.
Themetastasis-associated gene 1 (MTA1) oncogene hasbeen suggested to be involved in the regulation of cancer progression. However, there is still no direct evidence that MTA1 regulates cisplatin (CDDP) resistance, as well as cancer stem cell properties. In this study, we found that MTA1 was enriched in CNE1/CDDP cells. Knock down of MTA1 in CNE1/CDDP cells reversed CSCs properties and CDDP resistance. However, ectopic expression of MTA1 in CNE1 cells induced CSCs phenotypes and CDDP insensitivity. Interestingly, ectopic overexpression of MTA1-induced CSCs properties and CDDP resistance were reversed in CNE1 cells after inhibition of PI3K/Akt by LY294002. In addition, MTA1 expression and Akt activity in CNE1/CDDP cells was much higher than that in CNE1 cells. These results suggested that MTA1 may play a critical role in promoting CDDP resistance in NPC cells by regulatingcancer stem cell properties via thePI3K/Akt signaling pathway. Our findings suggested that MTA1 may be a potential target for overcoming CDDP resistance in NPC therapy.
doi:10.14348/molcells.2014.0029
PMCID: PMC4179139  PMID: 25245523
cancer stem cell; cisplatin-resistance; MTA1; nasopharyngeal carcinoma
10.  The microenvironmental determinants for kidney epithelial cyst morphogenesis 
European journal of cell biology  2008;87(4):251-266.
Although epithelial morphogenesis is tightly controlled by intrinsic genetic programs, the microenvironment in which epithelial cells proliferate and differentiate also contributes to the morphogenetic process. The roles of the physical microenvironment in epithelial morphogenesis, however, have not been well dissected. In this study, we assessed the impact of the microenvironment on epithelial cyst formation, which often marks the beginning or end step of morphogenesis of epithelial tissues and the pathological characteristic of some diseases. Previous studies have demonstrated that Madin-Darby canine kidney (MDCK) epithelial cells form cysts when grown in a three-dimensional (3D) extracellullar matrix (ECM) environment. We have now further demonstrated that the presence of ECM in the 3D scaffold is required for the formation of properly polarized cysts. Also, we have found that the full interface of epithelial cells with the ECM environment (in-3D) is not essential for cyst formation, since partial contact (on-3D) is sufficient to induce cystogenesis. In addition, we have defined the minimal ECM environment or the physical threshold for cystogenesis under the on-3D condition. Only above the threshold can the morphological cues from the ECM environment induce cyst formation. Moreover, cyst formation under the on-3D condition described in this study actually defines a novel and more feasible model to analyze in vitro morphogenesis. Finally, we have found that, during cystogenesis, MDCK cells generate basal microprotrusions and produce vesicle-like structures to the basal extracellular space, which are specific to and correlated with cyst formation. For the first time, we have systematically elucidated the microenvironmental determinants for epithelial cystogenesis.
doi:10.1016/j.ejcb.2007.11.004
PMCID: PMC4141498  PMID: 18191498
Cystogenesis; Epithelial morphogenesis; Polarity; Three-dimensional culture
11.  Increased Proportions of Bifidobacterium and the Lactobacillus Group and Loss of Butyrate-Producing Bacteria in Inflammatory Bowel Disease 
Journal of Clinical Microbiology  2014;52(2):398-406.
Dysbiosis in the intestinal microbiota of persons with inflammatory bowel disease (IBD) has been described, but there are still varied reports on changes in the abundance of Bifidobacterium and Lactobacillus organisms in patients with IBD. The aim of this investigation was to compare the compositions of mucosa-associated and fecal bacteria in patients with IBD and in healthy controls (HCs). Fecal and biopsy samples from 21 HCs, 21 and 15 Crohn's disease (CD) patients, and 34 and 29 ulcerative colitis (UC) patients, respectively, were analyzed by quantitative real-time PCR targeting the 16S rRNA gene. The bacterial numbers were transformed into relative percentages for statistical analysis. The proportions of bacteria were uniformly distributed along the colon regardless of the disease state. Bifidobacterium was significantly increased in the biopsy specimens of active UC patients compared to those in the HCs (4.6% versus 2.1%, P = 0.001), and the proportion of Bifidobacterium was significantly higher in the biopsy specimens than in the fecal samples in active CD patients (2.7% versus 2.0%, P = 0.012). The Lactobacillus group was significantly increased in the biopsy specimens of active CD patients compared to those in the HCs (3.4% versus 2.3%, P = 0.036). Compared to the HCs, Faecalibacterium prausnitzii was sharply decreased in both the fecal and biopsy specimens of the active CD patients (0.3% versus 14.0%, P < 0.0001 for fecal samples; 0.8% versus 11.4%, P < 0.0001 for biopsy specimens) and the active UC patients (4.3% versus 14.0%, P = 0.001 for fecal samples; 2.8% versus 11.4%, P < 0.0001 for biopsy specimens). In conclusion, Bifidobacterium and the Lactobacillus group were increased in active IBD patients and should be used more cautiously as probiotics during the active phase of IBD. Butyrate-producing bacteria might be important to gut homeostasis.
doi:10.1128/JCM.01500-13
PMCID: PMC3911339  PMID: 24478468
12.  Autophagy opposes p53-mediated tumor barrier to facilitate tumorigenesis in a model of PALB2-associated hereditary breast cancer 
Cancer discovery  2013;3(8):894-907.
Hereditary breast cancers stem from germline mutations in susceptibility genes such as BRCA1, BRCA2 and PALB2, whose products function in the DNA damage response and redox regulation. Autophagy is an intracellular waste disposal and stress mitigation mechanism important for alleviating oxidative stress and DNA damage response activation; it can either suppress or promote cancer, but its role in breast cancer is unknown. Here we show that, similar to Brca1 and Brca2, ablation of Palb2 in mouse mammary gland resulted in tumor development with long latency and the tumors harbored mutations in Trp53. Interestingly, impaired autophagy, due to monoallelic loss of the essential autophagy gene Becn1, reduced Palb2-associated mammary tumorigenesis in Trp53-wild type but not conditionally null background. These results indicate that, in the face of DNA damage and oxidative stress elicited by PALB2 loss, p53 is a barrier to cancer development, whereas autophagy facilitates cell survival and tumorigenesis.
doi:10.1158/2159-8290.CD-13-0011
PMCID: PMC3740014  PMID: 23650262
13.  Diagnostic value of stool DNA testing for multiple markers of colorectal cancer and advanced adenoma: A meta-analysis 
BACKGROUND AND OBJECTIVES:
The diagnostic value of stool DNA (sDNA) testing for colorectal neoplasms remains controversial. To compensate for the lack of large-scale unbiased population studies, a meta-analysis was performed to evaluate the diagnostic value of sDNA testing for multiple markers of colorectal cancer (CRC) and advanced adenoma.
METHODS:
The PubMed, Science Direct, Biosis Review, Cochrane Library and Embase databases were systematically searched in January 2012 without time restriction. Meta-analysis was performed using a random-effects model using sensitivity, specificity, diagnostic OR (DOR), summary ROC curves, area under the curve (AUC), and 95% CIs as effect measures. Heterogeneity was measured using the χ2 test and Q statistic; subgroup analysis was also conducted.
RESULTS:
A total of 20 studies comprising 5876 individuals were eligible. There was no heterogeneity for CRC, but adenoma and advanced adenoma harboured considerable heterogeneity influenced by risk classification and various detection markers. Stratification analysis according to risk classification showed that multiple markers had a high DOR for the high-risk subgroups of both CRC (sensitivity 0.759 [95% CI 0.711 to 0.804]; specificity 0.883 [95% CI 0.846 to 0.913]; AUC 0.906) and advanced adenoma (sensitivity 0.683 [95% CI 0.584 to 0.771]; specificity 0.918 [95% CI 0.866 to 0.954]; AUC 0.946) but not for the average-risk subgroups of either. In the methylation subgroup, sDNA testing had significantly higher DOR for CRC (sensitivity 0.753 [95% CI 0.685 to 0.812]; specificity 0.913 [95% CI 0.860 to 0.950]; AUC 0.918) and advanced adenoma (sensitivity 0.623 [95% CI 0.527 to 0.712]; specificity 0.926 [95% CI 0.882 to 0.958]; AUC 0.910) compared with the mutation subgroup. There was no significant heterogeneity among studies for subgroup analysis.
CONCLUSION:
sDNA testing for multiple markers had strong diagnostic significance for CRC and advanced adenoma in high-risk subjects. Methylation makers had more diagnostic value than mutation markers.
PMCID: PMC3956036  PMID: 23936877
Adenoma; Colorectal cancer; Diagnosis; Meta-analysis; Stool DNA test
14.  Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination 
Nature structural & molecular biology  2010;17(10):1247-1254.
Inherited mutations in human PALB2 are associated with a predisposition to breast and pancreatic cancers. The tumor-suppressing capability of PALB2 is thought to be based on its ability to enable BRCA2 function in homologous recombination. However, the biochemical properties of PALB2 are unknown. Here we show that human PALB2 binds DNA, preferentially D-loop structures, and directly interacts with the RAD51 recombinase to strongly stimulates strand invasion, a vital step of homologous recombination. Such stimulation occur by reinforcing biochemical mechanisms as PALB2 alleviates the inhibitory role of RPA and stabilizes the RAD51 filament. Moreover, PALB2 can function synergistically with a BRCA2 chimera (termed piccolo) to further promote strand invasion. Finally, we show that PALB2-deficient cells are sensitive to PARP inhibitors. Collectively, our studies provide the first biochemical insights into the homologous recombination mediator functions of PALB2 with piBRCA2 in DNA double-strand break repair.
doi:10.1038/nsmb.1915
PMCID: PMC4094107  PMID: 20871615
RAD51; PALB2; BRCA2; homologous recombination
15.  Identification and Functional Studies of a New Nrf2 Partner IQGAP1: A Critical Role in the Stability and Transactivation of Nrf2 
Antioxidants & Redox Signaling  2013;19(2):89-101.
Abstract
Aims: Nuclear factor-erythroid-related factor 2 (Nrf2) is a critical transcriptional factor that is used in regulating cellular defense against oxidative stress. This study is aimed at investigating new interacting protein partners of Nrf2 using One-strep tag pull-down coupled with LTQ Orbitrap LC/MS/MS, and at examining the impact on Nr2 signaling by the newly identified IQ motif containing GTPase activating protein 1 (IQGAP1). Results: Using the One-strep tag pull-down and LTQ Orbitrap LC/MS/MS, we identified IQGAP1 as a new Nrf2 interacting partner. Direct interactions between IQGAP1 and Nrf2 proteins were verified using in vitro glutathione S-transferase (GST) pull-down, transcription/translation assays, and in vivo utilizing Nrf2 overexpressing cells. Coexpression of Dsredmono-IQGAP1 and eGFP-Nrf2 increased the stability of eGFP-Nrf2 and enhanced the expression of Nrf2-target gene heme oxygenase-1 (HO-1). To confirm the functional role of IQGAP1 on Nrf2, knock-downed IQGAP1 using siIQGAP1 attenuated the expression of endogenous Nrf2, HO-1 proteins, and Nrf2-target genes GSTpi, GCLC, and NAD(P)H: quinone oxidoreductase 1 (NQO-1). Furthermore, the stability of Nrf2 was dramatically decreased in IQGAP1-deficient mouse embryonic fibroblast (MEF) cells. Since IQGAP1 signaling could be mediated by calcium, treating the cells with calcium showed the translocation of IQGAP1/Nrf2 complex into the nucleus, suggesting that IQGAP1 may play a critical role in Nrf2 stability. Interestingly, consistent with calcium signaling for IQGAP1, treating the cells with calcium functionally enhanced Nrf2-mediated antioxidant responsive element-transcription activity and enhanced the expression of the endogenous Nrf2-target gene HO-1. Innovation: In the aggregate, our current study identifies and functionally characterizes a new Nrf2 partner protein IQGAP1, which may contribute to Nrf2's regulation of antioxidant enzymes such as HO-1. Conclusion: IQGAP1 may play a critical role in the stability and transactivation of Nrf2. Antioxid. Redox Signal. 19, 89–101.
doi:10.1089/ars.2012.4586
PMCID: PMC3689176  PMID: 22793650
16.  Rationale, design and baseline results of the Guangxi manganese-exposed workers healthy cohort (GXMEWHC) study 
BMJ Open  2014;4(7):e005070.
Objective
To determine the relationship between biomarkers of exposure, disease and susceptibility, and early health effects and long-term diseases related to occupational manganese (Mn) exposure.
Design
Baseline survey of a longitudinal cohort study of workers in a ferromanganese refinery.
Participants
A total of 1888 individuals (1197 men, 691 women; average seniority 15.34 years) were enrolled in the Guangxi manganese-exposed workers healthy cohort (GXMEWHC) study. Participants were between 18 and 60 years of age (mean 40.31 years), had worked in the ferromanganese refinery for at least 1 year and lived in the local area.
Results
The GXMEWHC study included a baseline survey. Participants were divided into four groups according to manganese (Mn) cumulative exposure index (Mn-CEI) levels: an internal control group (Mn-CEI <1.0 mg/m3 year), a low exposure group (1.0 mg/m3 year≤Mn-CEI<2.0 mg/m3 year), a medium exposure group (2.0 mg/m3 year≤Mn-CEI<5.0 mg/m3 year) and a high exposure group (Mn-CEI≥5.0 mg/m3 year). Genome-wide association studies of quantitative trait loci and binary trait loci in 500 Mn-exposed workers were performed using Illumina Infinium HumanExome BeadChip arrays. Stored plasma, DNA, hair and urine are available for further study. Participants will be followed up every 3 years.
Conclusions
The GXMEWHC study provides abundant data for exploring the systemic health effects of occupational Mn exposure using biomarkers of exposure, disease and susceptibility.
doi:10.1136/bmjopen-2014-005070
PMCID: PMC4091505  PMID: 24993760
Occupational & Industrial Medicine; Epidemiology; Genetics
17.  Exome Sequencing Identifies DLG1 as a Novel Gene for Potential Susceptibility to Crohn's Disease in a Chinese Family Study 
PLoS ONE  2014;9(6):e99807.
Background
Genetic variants make some contributions to inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). More than 100 susceptibility loci were identified in Western IBD studies, but susceptibility gene has not been found in Chinese IBD patients till now. Sequencing of individuals with an IBD family history is a powerful approach toward our understanding of the genetics and pathogenesis of IBD. The aim of this study, which focuses on a Han Chinese CD family, is to identify high-risk variants and potentially novel loci using whole exome sequencing technique.
Methods
Exome sequence data from 4 individuals belonging to a same family were analyzed using bioinformatics methods to narrow down the variants associated with CD. The potential risk genes were further analyzed by genotyping and Sanger sequencing in family members, additional 401 healthy controls (HC), 278 sporadic CD patients, 123 UC cases, a pair of monozygotic CD twins and another Chinese CD family.
Results
From the CD family in which the father and daughter were affected, we identified a novel single nucleotide variant (SNV) c.374T>C (p.I125T) in exon 4 of discs large homolog 1 (DLG1), a gene has been reported to play mutiple roles in cell proliferation, T cell polarity and T cell receptor signaling. After genotyping among case and controls, a PLINK analysis showed the variant was of significance (P<0.05). 4 CD patients of the other Chinese family bore another non-synonymous variant c.833G>A (p.R278Q) in exon 9 of DLG1.
Conclusions
We have discovered novel genetic variants in the coding regions of DLG1 gene, the results support that DLG1 is a novel potential susceptibility gene for CD in Chinese patients.
doi:10.1371/journal.pone.0099807
PMCID: PMC4061034  PMID: 24937328
18.  CCL25/CCR9 Interactions Regulate the Function of iNKT Cells in Oxazolone-Induced Colitis in Mice 
PLoS ONE  2014;9(6):e100167.
Background
Natural killer T (NKT) cells share phenotypic and functional properties with both conventional natural killer cells and T cells. These cells might have an important role in the pathogenesis of ulcerative colitis (UC). The interaction of chemokine ligand 25 (CCL25) with chemokine receptor 9 (CCR9) is involved in gut-specific migration of leukocytes and induces regulatory T cells (Tregs) to migrate to the intestine in chronic ileitis.
Methodology/Findings
In UC patients, NKT receptor CD161, CCL25, and CCR9 expression levels were evaluated by qRT-PCR. A murine model of oxazolone-induced colitis was induced in BALB/c mice. The mRNA levels of NK1.1, CCL25 and CCR9, and pro-inflammatory cytokines in mice were evaluated. The CCR9 expression on Type I or invariant NKT (iNKT) cells, and the iNKT cells chemotaxis are observed according to flow cytometry. NKT receptor CD161, CCL25 and CCR9 expression levels were significantly increased in UC patients. And, the mRNA expression levels of NK1.1, CCL25 and CCR9 were increased in oxazolone-induced colitis in mice. The production of pro-inflammatory cytokines was significantly increased, especially interleukin 4 (IL-4), IL-10 and IL-13. We observed significantly increased CCR9 expression on iNKT cells. Furthermore, we found an increased iNKT population and enhanced chemotaxis during oxazolone-induced colitis.
Conclusions/Significance
Our study suggests that CCL25/CCR9 interactions may promote the induction and function of iNKT cells during oxazolone-induced colitis. These findings may have important implications for UC treatment and suggest a role for CCR9 inhibitors.
doi:10.1371/journal.pone.0100167
PMCID: PMC4061108  PMID: 24936795
19.  Progression of penile cutaneous horn to squamous cell carcinoma: A case report 
Oncology Letters  2014;8(3):1211-1213.
The current report presents the case of a 43-year-old male suffering from a penile cutaneous horn. A surgical excision of the lesion was performed and histopathology demonstrated hyperkeratosis, dyskeratosis and epithelial hyperplasia. The cutaneous horn progressed to squamous cell carcinoma <1.5 months following surgery and a partial penectomy was conducted. The International Index of Erectile Function 5 questionnaire was used to assess the patient and the score had decreased in the one-month postoperative follow-up compared with that of the preoperative period. These findings indicate that undergoing a partial penectomy on initial diagnosis of a penile cutaneous horn should be considered in order to conserve a greater quantity of the penile tissue and improve the postoperative quality of life.
doi:10.3892/ol.2014.2247
PMCID: PMC4114708  PMID: 25120690
penile cutaneous horn; squamous cell carcinoma; quality of life
20.  Chronic gastritis in China: a national multi-center survey 
BMC Gastroenterology  2014;14:21.
Background
Chronic gastritis is one of the most common findings at upper endoscopy in the general population, and chronic atrophic gastritis is epidemiologically associated with the occurrence of gastric cancer. However, the current status of diagnosis and treatment of chronic gastritis in China is unclear.
Methods
A multi-center national study was performed; all patients who underwent diagnostic upper endoscopy for evaluation of gastrointestinal symptoms from 33 centers were enrolled. Data including sex, age, symptoms and endoscopic findings were prospectively recorded.
Results
Totally 8892 patients were included. At endoscopy, 4389, 3760 and 1573 patients were diagnosed to have superficial gastritis, erosive gastritis, and atrophic gastritis, respectively. After pathologic examination, it is found that atrophic gastritis, intestinal metaplasia and dysplasia were prevalent, which accounted for 25.8%, 23.6% and 7.3% of this patient population. Endoscopic features were useful for predicting pathologic atrophy (PLR = 4.78), but it was not useful for predicting erosive gastritis. Mucosal-protective agents and PPI were most commonly used medications for chronic gastritis.
Conclusions
The present study suggests non-atrophic gastritis is the most common endoscopic finding in Chinese patients with upper GI symptoms. Precancerous lesions, including atrophy, intestinal metaplasia and dysplasia are prevalent in Chinese patients with chronic gastritis, and endoscopic features are useful for predicting pathologic atrophy.
doi:10.1186/1471-230X-14-21
PMCID: PMC3922313  PMID: 24502423
Chronic gastritis; Endoscopy; Epidemiology
21.  Akt Inhibitors MK-2206 and Nelfinavir overcome mTOR inhibitor resistance in DLBCL 
Purpose
The mTOR (mammalian Target of Rapamycin) pathway is constitutively activated in Diffuse Large B-Cell Lymphoma (DLBCL). mTOR inhibitors (mTORi) have activity in DLBCL, although response rates remain low. We evaluated DLBCL cell lines with differential resistance to the mTORi Rapamycin, in order to (A) identify gene-expression profile(s) (GEP) associated with resistance to Rapamycin, (B) understand mechanisms of Rapamycin resistance, and (C) identify compounds likely to synergize with mTORi.
Experimental Design
We sought to identify a GEP of mTORi resistance by stratification of eight DLBCL cell lines with respect to response to Rapamycin. Then, using pathway analysis and connectivity mapping, we sought targets likely accounting for this resistance, and compounds likely to overcome it. We then evaluated two compounds thus identified for their potential to synergize with Rapamycin in DLBCL, and confirmed mechanisms of activity with standard immunoassays.
Results
We identified a GEP capable of reliably distinguishing Rapamycin resistant from Rapamycin sensitive DLBCL cell lines. Pathway analysis identified Akt as central to the differentially expressed gene network. Connectivity mapping identified compounds targeting Akt as having a high likelihood of reversing the GEP associated with mTORi resistance. Nelfinavir and MK-2206, chosen for their Akt-inhibitory properties, yielded synergistic inhibition of cell viability in combination with Rapamycin in DLBCL cell lines, and potently inhibited phosphorylation of Akt and downstream targets of activated mTOR.
Conclusions
GEP identifies DLBCL subsets resistant to mTORi therapy. Combined targeting of mTOR and Akt suppresses activation of key components of the Akt/mTOR pathway and results in synergistic cytotoxicity. These findings are readily adaptable to clinical trials.
doi:10.1158/1078-0432.CCR-11-1407
PMCID: PMC3889476  PMID: 22338016
22.  Correction: BSP Gene Silencing Inhibits Migration, Invasion, and Bone Metastasis of MDA-MB-231BO Human Breast Cancer Cells 
PLoS ONE  2014;9(1):10.1371/annotation/d514b852-6b48-4720-a245-080daeb5eb05.
doi:10.1371/annotation/d514b852-6b48-4720-a245-080daeb5eb05
PMCID: PMC3883182
23.  High Intestinal and Systemic Levels of Interleukin-23/T-Helper 17 Pathway in Chinese Patients with Inflammatory Bowel Disease 
Mediators of Inflammation  2013;2013:425915.
Interleukin-23/T-helper 17 (IL-23/Th17) pathway plays a key role in the pathogenesis of inflammatory bowel disease (IBD), but little is known about its expression in Chinese population. In this study, we investigated the mRNA and protein levels of IL-12p40, tumor necrosis factor-like cytokine 1A (TL1A), Janus kinase 2 (JAK2), and IL-23R both locally and systemically in Chinese IBD patients. Our results indicated that the mRNA levels of IL-12p40 and TL1A were increased in ulcerative colitis (UC) patients. Furthermore, serum IL-12p40 and TL1A levels were higher in active UC patients, especially in patients with disease course less than 1.25 years or initial onset. No correlation was found between the genotype and serum levels of IL-12p40 or TL1A in UC patients. Additionally, the mRNA and protein expression of JAK2 and IL-23R were increased in UC and Crohn's disease (CD) patients. Taken together, our results provided evidence that IL-23/Th17 pathway genes may represent important biomarkers of active stage of IBD and serve as novel therapeutic targets for IBD in Chinese population.
doi:10.1155/2013/425915
PMCID: PMC3870108  PMID: 24382939
24.  Heterozygous mutations in PALB2 cause DNA replication and damage response defects 
Nature Communications  2013;4:2578.
Besides mutations in BRCA1/BRCA2, heterozygous defects in PALB2 are important in breast cancer predisposition. PALB2 heterozygosity increases the risk of malignancy about sixfold. PALB2 interacts with BRCA1 and BRCA2 to regulate homologous recombination and mediate DNA damage response. Here we show, by analysing lymphoblastoid cell lines from heterozygous female PALB2 mutation carriers, that PALB2 haploinsufficiency causes aberrant DNA replication/damage response. Mutation carrier cells show increased origin firing and shorter distance between consecutive replication forks. Carrier cell lines also show elevated ATR protein, but not phosphorylation levels, and a majority of them display aberrant Chk1-/Chk2-mediated DNA damage response. Elevated chromosome instability is observed in primary blood lymphocytes of PALB2 mutation carriers, indicating that the described mechanisms of genome destabilization operate also at the organism level. These findings provide a new mechanism for early stages of breast cancer development that may also apply to other heterozygous homologous recombination signalling pathway gene mutations in hereditary cancer predisposition.
PALB2 is a BRCA1-/BRCA2-interacting protein and heterozygous mutations in PALB2 are associated with hereditary breast cancer predisposition. Here the authors show that human lymphoblastoid cells from heterozygous PALB2 mutation carriers display abnormal DNA replication dynamics and DNA damage response.
doi:10.1038/ncomms3578
PMCID: PMC3826652  PMID: 24153426
25.  Hypophosphatemia during continuous veno-venous hemofiltration is associated with mortality in critically ill patients with acute kidney injury 
Critical Care  2013;17(5):R205.
Introduction
The primary aim of this study was to determine whether hypophosphatemia during continuous veno-venous hemofiltration (CVVH) is associated with the global outcome of critically ill patients with acute kidney injury (AKI).
Methods
760 patients diagnosed with AKI and had received CVVH therapy were retrospectively recruited. Death during the 28-day period and survival at 28 days after initiation of CVVH were used as endpoints. Demographic and clinical data including serum phosphorus levels were recorded along with clinical outcome. Hypophosphatemia was defined according to the colorimetric method as serum phosphorus levels < 0.81 mmol/L (2.5 mg/dL), and severe hypophosphatemia was defined as serum phosphorus levels < 0.32 mmol/L (1 mg/dL). The ratio of CVVH therapy days with hypophosphatemia over total CVVH therapy days was calculated to reflect the persistence of hypophosphatemia.
Results
The Cox proportional hazard survival model analysis indicated that the incidence of hypophosphatemia or even severe hypophosphatemia was not associated with 28-day mortality independently (p = 0.700). Further analysis with the sub-cohort of patients who had developed hypophosphatemia during the CVVH therapy period indicated that the mean ratio of CVVH therapy days with hypophosphatemia over total CVVH therapy days was 0.58, and the ratio independently associated with the global outcome. Compared with the patients with low ratio (< 0.58), those with high ratio (≥ 0.58) conferred a 1.451-fold increase in 28-day mortality rate (95% CI 1.103–1.910, p = 0.008).
Conclusions
Hypophosphatemia during CVVH associated with the global clinical outcome of critically ill patients with AKI. The ratio of CVVH therapy days with hypophosphatemia over total CVVH therapy days was independently associated with the 28-day mortality, and high ratio conferred higher mortality rate.
doi:10.1186/cc12900
PMCID: PMC4056808  PMID: 24050634

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