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1.  Association of the four common polymorphisms in interleukin-10 (rs1800890, rs1800896, rs1800871, and rs1800872) with non-Hodgkin’s lymphoma risk: a meta-analysis 
Interleukin-10 (IL-10) single nucleotide polymorphisms (SNPs) have been indicated to be correlated with Non-Hodgkin’s lymphoma (NHL) susceptibility. However, the results of these studies on the association remain inconsistent. This meta-analysis was conducted to derive a more accuracy estimation of the association between the common SNPs (rs1800890, rs1800896, rs1800871 and rs1800872) in IL-10 and NHL risk. Meta-analyses were performed on 21 studies with 7,749 cases and 8584 controls. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the NHL risk. Meta-analyses showed that rs1800890, rs1800871 and rs1800872 polymorphisms had no association with NHL risk. However, rs1800896 polymorphism has association with NHL risk based on the following comparison models (G vs. A: OR = 1.14, 95% CI = 1.00-1.29; AG vs. AA: OR = 1.20, 95% CI = 1.05-1.37; GG+AG vs. AA: OR = 1.22, 95% CI = 1.08-1.39). In the ethnic subgroup analysis, rs1800896 had an increased NHL risk in Caucasians based on the heterozygote model (OR = 1.21, 95% CI = 1.04-1.41) and dominant model (OR = 1.22, 95% CI = 1.00-1.48). When stratified by subtypes, rs1800890, rs1800896 and rs1800872 polymorphisms were found significant association with an increased risk of diffuse large B-cell Lymphoma (DLBCL) in different comparison models, whereas negative results were obtained for Follicular Lymphoma (FL) and chronic lymphocytic Leukemia/small lymphocytic Lymphoma (CLL/SLL) in all genetic models. Our meta-analysis suggested that the rs1800896 polymorphism had an increased risk with NHL susceptibility, where as the rs1800890, rs1800871 and rs1800872 had no association with NHL risk. Among the common subtypes of NHL, three polymorphisms (rs1800890, rs1800896 and rs1800872) had significant association with DLBCL risk.
PMCID: PMC4307416  PMID: 25663969
Non-Hodgkin’s lymphoma; interleukin-10; polymorphism; meta-analysis
2.  A Pig Model of Ischemic Mitral Regurgitation Induced by Mitral Chordae Tendinae Rupture and Implantation of an Ameroid Constrictor 
PLoS ONE  2014;9(12):e111689.
A miniature pig model of ischemic mitral regurgitation (IMR) was developed by posterior mitral chordae tendinae rupture and implantation of an ameroid constrictor. A 2.5-mm ameroid constrictor was placed around the left circumflex coronary artery (LCX) of male Tibetan miniature pigs to induce ischemia, while the posterior mitral chordae tendinae was also ruptured. X-ray coronary angiography, ECG analysis, echocardiography, and magnetic resonance imaging (MRI) were used to evaluate heart structure and function in pigs at baseline and one, two, four and eight weeks after the operation. Blood velocity of the mitral regurgitation was found to be between medium and high levels. Angiographic analyses revealed that the LCX closure was 10–20% at one week, 30–40% at two weeks and 90–100% at four weeks subsequent ameroid constrictor implantation. ECG analysis highlighted an increase in the diameter of the left atria (LA) at two weeks post-operation as well as ischemic changes in the left ventricle (LV) and LA wall at four weeks post-operation. Echocardiography and MRI further detected a gradual increase in LA and LV volumes from two weeks post-operation. LV end diastolic and systolic volumes as well as LA end diastolic and systolic volume were also significantly higher in pig hearts post-operation when compared to baseline. Pathological changes were observed in the heart, which included scar tissue in the ischemic central area of the LV. Transmission electron microscopy highlighted the presence of contraction bands and edema surrounding the ischemia area, including inflammatory cell infiltration within the ischemic area. We have developed a pig model of IMR using the posterior mitral chordae tendineae rupture technique and implantation of an ameroid constrictor. The pathological features of this pig IMR model were found to mimic the natural history and progression of IMR in patients.
doi:10.1371/journal.pone.0111689
PMCID: PMC4257529  PMID: 25479001
3.  Grafts Enriched with Subamnion-Cord-Lining Mesenchymal Stem Cell Angiogenic Spheroids Induce Post-Ischemic Myocardial Revascularization and Preserve Cardiac Function in Failing Rat Hearts 
Stem Cells and Development  2013;22(23):3087-3099.
A crucial question in post-ischemic cell therapy refers to the ideal method of cell delivery to the heart. We hypothesized that epicardial implantation of subamnion-cord-lining mesenchymal stem cells (CL-MSC) angiogenic spheroids embedded within fibrin grafts (SASG) facilitates donor cell survival and enhances cardiac function in failing rat hearts. Furthermore, we compared the efficacy of this approach applied through two delivery methods. Spheroids made of 1.5×104 human CL-MSC coated with 2×103 human umbilical vein endothelial cells were self-assembled in hanging drops. SASG were constructed by embedding 150 spheroids in fibrin matrix. Except for untreated rats (MI, n=8), grafts were implanted 2 weeks after myocardial infarction upon confirmation of ensued heart failure through thoracotomy: SASG (n=8) and fibrin graft (FG, n=8); or video-assisted thoracoscopic surgery (VATS): SASG-VATS (n=8) and FG-VATS (n=7). In vivo CL-MSC survival was comparable between both SASG-treated groups throughout the study. SASG and SASG-VATS animals had decreased left ventricular end-diastolic pressure relative to untreated animals, and increased fractional shortening compared to MI and FG controls, 4 weeks after treatment. A 14.1% and 6.2% enhancement in ejection fraction from week 2 to 6 after injury was observed in SASG/SASG-VATS, paralleled by improvement in cardiac output. Treated hearts had smaller scar size, and more blood vessels than MI, while donor CL-MSC contributed to arteriogenesis within the graft and infarct areas. Taken together, our data suggest that SASG treatment has the potential to restore failing hearts by preserving cardiac function and inducing myocardial revascularization, while attenuating cardiac fibrosis. Furthermore, we introduce a method for minimally invasive in situ graft assembly.
doi:10.1089/scd.2013.0119
PMCID: PMC3856952  PMID: 23869939
4.  11β-hydroxysteroid dehydrogenase types 1 and 2 in postnatal development of rat testis: gene expression, localization and regulation by luteinizing hormone and androgens 
Asian Journal of Andrology  2014;16(6):811-816.
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and type 2 (11β-HSD2) are expressed in rat testis, where they regulate the local concentrations of glucocorticoids. Here, we investigated the expression and localization of 11β-HSD in rat testis during postnatal development, and the regulation of these genes by luteinizing hormone (LH) and androgens. mRNA and protein levels were analyzed by quantitative real-time-polymerase chain reaction and western blotting, respectively, in testes collected from rats at postnatal day (PND) 7, 14, 21, 35, and 90, and from rats treated with LH, 7α-methyl-19-nortestosterone (MENT) and testosterone at PND 21 and PND 90. Immunohistochemical staining was used to identify the localization of the 11β-HSD in rat testis at PND 7, 14, and 90. We found that 11β-HSD1 expression was restricted to the interstitial areas, and that its levels increased during rat testis development. In contrast, whereas 11β-HSD2 was expressed in both the interstitial areas and seminiferous tubules at PND 7, it was present only in the interstitial areas at PND 90, and its levels declined during testicular development. Moreover, 11β-HSD1 mRNA was induced by LH in both the PND 21 and 90 testes and by MENT at PND 21, whereas 11β-HSD2 mRNA was induced by testosterone and MENT in the PND 21 testis and by LH in the PND 90 testis. In conclusion, our study indicates that the 11β-HSD1 and 11β-HSD2 genes have distinct patterns of spatiotemporal expression and hormonal regulation during postnatal development of the rat testis.
doi:10.4103/1008-682X.132471
PMCID: PMC4236321  PMID: 25038180
11β-hydroxysteroid dehydrogenase type 1; 11β-hydroxysteroid dehydrogenase type 2; development; Leydig cell; testis
5.  Lentiviral Small Hairpin RNA Knockdown of Macrophage Inflammatory Protein-1γ Ameliorates Experimentally Induced Osteoarthritis in Mice 
Human Gene Therapy  2013;24(10):871-882.
Abstract
Immune cells are involved in the pathogenesis of osteoarthritis (OA). CD4+ T cells were activated during the onset of OA and induced macrophage inflammatory protein (MIP)-1γ expression and subsequent osteoclast formation. We evaluated the effects of local knockdown of MIP-1γ in a mouse OA model induced by anterior cruciate ligament transection. The mouse macrophage cell lines and osteoclast-like cells generated from immature hematopoietic monocyte/macrophage progenitors of murine bone marrow were cocultured with either receptor activator of NFκB ligand (RANKL) or CD4+ T cells. The levels of MIP-1γ and RANKL in cells and mice were examined by enzyme-linked immunosorbent assay (ELISA). The osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase and cathepsin K staining. OA was induced in one hind-leg knee joint of B6 mice. Lentiviral vector encoding MIP-1γ small hairpin RNA (shRNA) and control vector were individually injected intra-articularly into the knee joints, which were histologically assessed for manifestations of OA. The expression of MIP-1γ and matrix metalloproteinase (MMP)-13 and the infiltration of CD4+ T cells, macrophages, and osteoclastogenesis in tissues were examined using immunohistochemistry. CD4+ T cells were involved in OA by inducing MIP-1γ expression in osteoclast progenitors and the subsequent osteoclast formation. Neutralizing MIP-1γ with a specific antibody abolishes RANKL-stimulated and CD4+ T-cell-stimulated osteoclast formation. MIP-1γ levels were significantly higher in synovium and the chondro-osseous junction of joints 90 days postsurgery. The number of infiltrated CD4+ T cells and macrophages and IL-1β expression were reduced in the synovial tissues of mice treated with MIP-1γ shRNA. Histopathological examinations revealed that mice treated with MIP-1γ shRNA had less severe OA than control mice had, as well as decreased osteoclast formation and MMP-13 expression. Locally inhibiting MIP-1γ expression may ameliorate disease progression and provide a new OA therapy.
Shen and colleagues reveal that CD4+ T cells are involved in osteoarthritis via induction of MIP-1γ in osteoclast progenitors, which leads to osteoclast formation. They demonstrate that shRNA-mediated knockdown of MIP-1γ leads to decreased osteoclast formation and reduced osteoarthritis in mice.
doi:10.1089/hum.2012.189
PMCID: PMC3787402  PMID: 24016310
6.  Sero-Survey of Polio Antibodies during Wild Poliovirus Outbreak in Southern Xinjiang Uygur Autonomous Region, China 
PLoS ONE  2014;9(7):e80069.
Background
After being polio free for more than 10 years, an outbreak following importation of wild poliovirus (WPV) was confirmed in Xinjiang Uygur Autonomous Region, China, in 2011.
Methods
A cross-sectional study was conducted prior to supplementary immunization activities (SIAs), immediately after the confirmation of the WPV outbreak. In selected prefectures, participants aged ≤60 years old who visited hospitals at county-level or above to have their blood drawn for reasons not related to the study, were invited to participate in our study. Antibody titers ≥8 were considered positive.
Results
Among the 2,611 participants enrolled, 2,253 (86.3%), 2,283 (87.4%), and 1,989 (76.2%) were seropositive to P1, P2 and P3 respectively, and 1744 (66.8%) participants were seropositive to all the three serotypes. Lower antibody seropositivities and geometric mean titers were observed in children <1 year of age and in adults aged 15–39 years.
Conclusion
Serosurveys to estimate population immunity in districts at high risk of polio importation might be useful to gauge underlying population immunity gaps to polio and possibly to guide preparedness and response planning. Consideration should be given to older children and adults during polio risk assessment planning and outbreak response.
doi:10.1371/journal.pone.0080069
PMCID: PMC4081020  PMID: 24991811
7.  Optimization of the quenching method for metabolomics analysis of Lactobacillus bulgaricus *  
This study proposed a quenching protocol for metabolite analysis of Lactobacillus delbrueckii subsp. bulgaricus. Microbial cells were quenched with 60% methanol/water, 80% methanol/glycerol, or 80% methanol/water. The effect of the quenching process was assessed by the optical density (OD)-based method, flow cytometry, and gas chromatography-mass spectrometry (GC-MS). The principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were employed for metabolite identification. The results indicated that quenching with 80% methanol/water solution led to less damage to the L. bulgaricus cells, characterized by the lower relative fraction of prodium iodide (PI)-labeled cells and the higher OD recovery ratio. Through GC-MS analysis, higher levels of intracellular metabolites (including focal glutamic acid, aspartic acid, alanine, and AMP) and a lower leakage rate were detected in the sample quenched with 80% methanol/water compared with the others. In conclusion, we suggested a higher concentration of cold methanol quenching for L. bulgaricus metabolomics due to its decreasing metabolite leakage.
doi:10.1631/jzus.B1300149
PMCID: PMC3989152  PMID: 24711354
Metabolomics; Quenching method; Lactobacillus bulgaricus; Leakage
8.  Synergistic Effect of Zuo Jin Wan on DDP-Induced Apoptosis in Human Gastric Cancer SGC-7901/DDP Cells 
A traditional Chinese medicine (TCM) formula, Zuo Jin Wan (ZJW), has been found as an anticancer drug in human cancer. In this study, we investigated the synergistic effect of ZJW extracts on DDP-induced apoptosis in human gastric cancer SGC-7901/DDP cells. Our results demonstrated that ZJW extracts could increase the sensitivity of SGC-7901/DDP cells to DDP by increasing the concentration of DDP in cytoplasm and enhance the proapoptosis of DDP by upregulating the JNK and Bax expression, downregulating the Bcl-2 expression, increasing the accumulation of Cytochrome C in cytoplasm, and promoting the activities of caspase-3 and caspase-9. In vivo, ZJW extracts enhanced the inhibiting effect of DDP on tumor growth in SGC-7901/DDP xenograft model and upregulated the expression of p-JNK and Bax but downregulated the Bcl-2 expression in xenograft tumors. In conclusion, in vitro and in vivo, ZJW extracts could enhance the proapoptotic effect of DDP by promoting the activation of JNK and the expression of Bcl-2, inhibiting the Bax expression, followed by increasing the release of Cytochrome C from mitochondria to cytoplasm, and finally activating the caspase cade reaction. Our results implied that ZJW might serve as a synergistic drug with chemotherapeutic drugs DDP in the treatment of gastric cancer.
doi:10.1155/2014/724764
PMCID: PMC3958763  PMID: 24723962
9.  Urinary Methylmalonic Acid as an Indicator of Early Vitamin B12 Deficiency and Its Role in Polyneuropathy in Type 2 Diabetes 
Journal of Diabetes Research  2014;2014:921616.
The rising incidence of diabetes and its negative impact on quality of life highlights the urgent need to develop biomarkers of early nerve damage. Measurement of total vitamin B12 has some limitations. We want to determine the levels of urinary methylmalonic acid and its relationships with serum vitamin B12 and polyneuropathy. The 176 Chinese patients with Type 2 diabetes mellitus were divided into 3 groups according to the levels of vitamin B12. A gas chromatography mass spectrometric technique was used to determine blood methylmalonic acid and urinary methylmalonic acid. The diagnosis of distal diabetic polyneuropathy was based on the determination of bilateral limb sensory and motor nerve conduction velocity and amplitude with electromyogram. Multiple regression analysis revealed that urinary methylmalonic acid/creatinine, blood methylmalonic acid, and so forth were variables that influenced diabetic polyneuropathy significantly. Nerve sensory conduction velocity and nerve amplitude in the group of urinary methylmalonic acid/creatinine >3.5 mmol/mol decreased significantly. Superficial peroneal nerve sensory and motor conduction velocity and ulnar nerve compound motor active potential amplitude were inversely correlated with urinary methylmalonic acid/creatinine. Urinary methylmalonic acid correlates with serum vitamin B12 levels in person with diabetes and is a sensitive marker of early polyneuropathy.
doi:10.1155/2014/921616
PMCID: PMC3955587  PMID: 24719898
10.  Zhankuic Acid A Isolated from Taiwanofungus camphoratus Is a Novel Selective TLR4/MD-2 Antagonist with Anti-Inflammatory Properties 
TLR4, a membrane receptor that functions in complex with its accessory protein myeloid differentiation factor-2 (MD-2), is a therapeutic target for bacterial infections. Taiwanofungus camphoratus is highly valued as a medicinal mushroom for cancer, hypertension, and inflammation in traditional medicine. Zhankuic acid A (ZAA) is the major pharmacologically active compound of T. camphoratus. The mechanism of action of T. camphoratus or ZAA has not been fully elucidated. We analyzed the structure of human TLR4/MD-2 complex with ZAA by X-score and HotLig modeling approaches. Two Abs against MD-2 were used to verify the MD-2/ZAA interaction. The inflammation and survival of the mice pretreated with ZAA and injected with LPS were monitored. The modeling structure shows that ZAA binds the MD-2 hydrophobic pocket exclusively via specific molecular recognition; the contact interface is dominated by hydrophobic interactions. Binding of ZAA to MD-2 reduced Ab recognition to native MD-2, similar to the effect of LPS binding. Furthermore, ZAA significantly ameliorated LPS-induced endotoxemia and Salmonella-induced diarrhea in mice. Our results suggest that ZAA, which can compete with LPS for binding to MD-2 as a TLR4/MD-2 antagonist, may be a potential therapeutic agent for gram-negative bacterial infections.
doi:10.4049/jimmunol.1301931
PMCID: PMC3948111  PMID: 24532584
11.  Genome-Wide Analysis of the MADS-Box Gene Family in Brachypodium distachyon 
PLoS ONE  2014;9(1):e84781.
MADS-box genes are important transcription factors for plant development, especially floral organogenesis. Brachypodium distachyon is a model for biofuel plants and temperate grasses such as wheat and barley, but a comprehensive analysis of MADS-box family proteins in Brachypodium is still missing. We report here a genome-wide analysis of the MADS-box gene family in Brachypodium distachyon. We identified 57 MADS-box genes and classified them into 32 MIKCc-type, 7 MIKC*-type, 9 Mα, 7 Mβ and 2 Mγ MADS-box genes according to their phylogenetic relationships to the Arabidopsis and rice MADS-box genes. Detailed gene structure and motif distribution were then studied. Investigation of their chromosomal localizations revealed that Brachypodium MADS-box genes distributed evenly across five chromosomes. In addition, five pairs of type II MADS-box genes were found on synteny blocks derived from whole genome duplication blocks. We then performed a systematic expression analysis of Brachypodium MADS-box genes in various tissues, particular floral organs. Further detection under salt, drought, and low-temperature conditions showed that some MADS-box genes may also be involved in abiotic stress responses, including type I genes. Comparative studies of MADS-box genes among Brachypodium, rice and Arabidopsis showed that Brachypodium had fewer gene duplication events. Taken together, this work provides useful data for further functional studies of MADS-box genes in Brachypodium distachyon.
doi:10.1371/journal.pone.0084781
PMCID: PMC3890268  PMID: 24454749
12.  Adenovirus-Mediated Prothymosin α Gene Transfer Inhibits the Development of Atherosclerosis in Apoe-Deficient Mice 
Prothymosin α (ProT) is involved in regulating expression of the oxidative stress-protective genes and it also exerts immunomodulatory activities. In this study, we investigated the therapeutic effects of ProT gene transfer on atherosclerosis in endothelial cells and in ApoE-deficient mice. Adenoviruses encoding mouse ProT (AdProT) were used for the management of atherosclerosis. In vitro, the effects of ProT on antioxidant gene expressions and the protection effect against oxidant-mediated injury in endothelial cells were examined. In vivo, AdProT were administered intraventricularly into the heart of ApoE-/- mice. Histopathological and immunohistochemical assessments of the aortic tissues were performed. Expressions of HO-1 and antioxidant genes in the aortic tissues were also determined. Our results demonstrated that ProT gene transfer increased antioxidant gene expressions, eNOS expression and NO release, as well as reduced the reactive oxygen species production in endothelial cells. Intraventricular administration of AdProT reduced the lesion formation, increased expressions of HO-1 and SOD genes, and reduced infiltrating macrophages in the aorta of ApoE-/- mice. This study suggests that ProT gene transfer may have the therapeutic potential for the management of atherosclerosis via inducing antioxidant gene expressions, eNOS expression and NO release, reducing ROS production and macrophage infiltration in endothelium.
doi:10.7150/ijbs.8634
PMCID: PMC3979988  PMID: 24719553
atherosclerosis; gene transfer; antioxidant gene expressions; prothymosin α.
13.  Intravenous microemulsion of docetaxel containing an anti-tumor synergistic ingredient (Brucea javanica oil): formulation and pharmacokinetics 
The purpose of this study was to develop a docetaxel microemulsion containing an anti-tumor synergistic ingredient (Brucea javanica oil) and to investigate the characteristics of the microemulsion. Brucea javanica oil contains oleic acid and linoleic acids that have been shown by animal and human studies to inhibit tumor formation. The microemulsion containing Brucea javanica oil, medium-chain triglyceride, soybean lecithin, Solutol®HS 15, PEG 400, and water was developed for docetaxel intravenous administration. A formulation with higher drug content, lower viscosity, and smaller particle size was developed. The droplet size distribution of the dispersed phase of the optimized microemulsion was 13.5 nm, determined using a dynamic light scattering technique. The small droplet size enabled the microemulsion droplets to escape from uptake and phagocytosis by the reticuloendothelial system and increased the circulation time of the drug. The zeta potential was −41.3 mV. The optimized microemulsion was pale yellow, transparent, and non-opalescent in appearance. The value of the combination index was 0.58, showing that there was a synergistic effect when docetaxel was combined with Brucea javanica oil. After a single intravenous infusion dose (10 mg/kg) in male Sprague Dawley rats, the area under the curve of the microemulsion was higher and the half-time was longer compared with that of docetaxel solution alone, and showed superior pharmacokinetic characteristics. These results indicate that this preparation of docetaxel in emulsion is likely to provide an excellent prospect for clinical tumor treatment.
doi:10.2147/IJN.S47956
PMCID: PMC3810894  PMID: 24179332
microemulsion; docetaxel; synergistic ingredient; formulation; pharmacokinetic
14.  CD8+ T Cell-Induced Expression of Tissue Inhibitor of Metalloproteinses-1 Exacerbated Osteoarthritis 
Despites the fact that T cells are involved in the pathogenesis of osteoarthritis (OA) little is known about the roles of CD8+ T cells in this disease. We investigated the effects of CD8+ T cells and the expression of tissue inhibitor of metalloproteinases 1 (TIMP-1) on joint pathology. Using anterior cruciate ligament-transection (ACLT), OA was induced in mice. The knee joints were histologically assessed for manifestations of OA. The CD8+ T cells from splenocytes and synovium were flow-cytometrically and immunochemically evaluated, respectively. Local expression of TIMP-1, matrix metalloproteinase (MMP)-13, and VEGF were examined. Cartilage degeneration was slower in CD8+ T cell knockout mice than in control mice. CD8+ T cells were activated once OA was initiated and expanded during OA progression. More CD8+ T cells from splenocytes expressed TIMP-1 in ACLT-group mice than in Sham-group mice. The number of TIMP-1-expressing CD8+ T cells in OA mice correlated with the disease severity. TIMP-1 expression in cartilage was co-localized with that of MMP-13 and VEGF. TIMP-1 protein was detected in synovium in which angiogenesis occurred. During the pathogenesis of OA, the expression of TIMP-1, VEGF and MMP-13 accompanying with CD8+ T cells activation were increased. Furthermore, inhibiting the expression of TIMP-1 in joints could retard the progression of OA.
doi:10.3390/ijms141019951
PMCID: PMC3821596  PMID: 24108368
CD8+ T cells; osteoarthritis; TIMP-1; VEGF; MMP-13
15.  Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies 
Abnet, Christian C. | Wang, Zhaoming | Song, Xin | Hu, Nan | Zhou, Fu-You | Freedman, Neal D. | Li, Xue-Min | Yu, Kai | Shu, Xiao-Ou | Yuan, Jian-Min | Zheng, Wei | Dawsey, Sanford M. | Liao, Linda M. | Lee, Maxwell P. | Ding, Ti | Qiao, You-Lin | Gao, Yu-Tang | Koh, Woon-Puay | Xiang, Yong-Bing | Tang, Ze-Zhong | Fan, Jin-Hu | Chung, Charles C. | Wang, Chaoyu | Wheeler, William | Yeager, Meredith | Yuenger, Jeff | Hutchinson, Amy | Jacobs, Kevin B. | Giffen, Carol A. | Burdett, Laurie | Fraumeni, Joseph F. | Tucker, Margaret A. | Chow, Wong-Ho | Zhao, Xue-Ke | Li, Jiang-Man | Li, Ai-Li | Sun, Liang-Dan | Wei, Wu | Li, Ji-Lin | Zhang, Peng | Li, Hong-Lei | Cui, Wen-Yan | Wang, Wei-Peng | Liu, Zhi-Cai | Yang, Xia | Fu, Wen-Jing | Cui, Ji-Li | Lin, Hong-Li | Zhu, Wen-Liang | Liu, Min | Chen, Xi | Chen, Jie | Guo, Li | Han, Jing-Jing | Zhou, Sheng-Li | Huang, Jia | Wu, Yue | Yuan, Chao | Huang, Jing | Ji, Ai-Fang | Kul, Jian-Wei | Fan, Zhong-Min | Wang, Jian-Po | Zhang, Dong-Yun | Zhang, Lian-Qun | Zhang, Wei | Chen, Yuan-Fang | Ren, Jing-Li | Li, Xiu-Min | Dong, Jin-Cheng | Xing, Guo-Lan | Guo, Zhi-Gang | Yang, Jian-Xue | Mao, Yi-Ming | Yuan, Yuan | Guo, Er-Tao | Zhang, Wei | Hou, Zhi-Chao | Liu, Jing | Li, Yan | Tang, Sa | Chang, Jia | Peng, Xiu-Qin | Han, Min | Yin, Wan-Li | Liu, Ya-Li | Hu, Yan-Long | Liu, Yu | Yang, Liu-Qin | Zhu, Fu-Guo | Yang, Xiu-Feng | Feng, Xiao-Shan | Wang, Zhou | Li, Yin | Gao, She-Gan | Liu, Hai-Lin | Yuan, Ling | Jin, Yan | Zhang, Yan-Rui | Sheyhidin, Ilyar | Li, Feng | Chen, Bao-Ping | Ren, Shu-Wei | Liu, Bin | Li, Dan | Zhang, Gao-Fu | Yue, Wen-Bin | Feng, Chang-Wei | Qige, Qirenwang | Zhao, Jian-Ting | Yang, Wen-Jun | Lei, Guang-Yan | Chen, Long-Qi | Li, En-Min | Xu, Li-Yan | Wu, Zhi-Yong | Bao, Zhi-Qin | Chen, Ji-Li | Li, Xian-Chang | Zhuang, Xiang | Zhou, Ying-Fa | Zuo, Xian-Bo | Dong, Zi-Ming | Wang, Lu-Wen | Fan, Xue-Pin | Wang, Jin | Zhou, Qi | Ma, Guo-Shun | Zhang, Qin-Xian | Liu, Hai | Jian, Xin-Ying | Lian, Sin-Yong | Wang, Jin-Sheng | Chang, Fu-Bao | Lu, Chang-Dong | Miao, Jian-Jun | Chen, Zhi-Guo | Wang, Ran | Guo, Ming | Fan, Zeng-Lin | Tao, Ping | Liu, Tai-Jing | Wei, Jin-Chang | Kong, Qing-Peng | Fan, Lei | Wang, Xian-Zeng | Gao, Fu-Sheng | Wang, Tian-Yun | Xie, Dong | Wang, Li | Chen, Shu-Qing | Yang, Wan-Cai | Hong, Jun-Yan | Wang, Liang | Qiu, Song-Liang | Goldstein, Alisa M. | Yuan, Zhi-Qing | Chanock, Stephen J. | Zhang, Xue-Jun | Taylor, Philip R. | Wang, Li-Dong
Human Molecular Genetics  2012;21(9):2132-2141.
Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10−8, and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19–1.40) and P= 7.63 × 10−10. An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.
doi:10.1093/hmg/dds029
PMCID: PMC3315211  PMID: 22323360
16.  Phylogeographic Evidence for a Link of Species Divergence of Ephedra in the Qinghai-Tibetan Plateau and Adjacent Regions to the Miocene Asian Aridification 
PLoS ONE  2013;8(2):e56243.
The Qinghai-Tibetan Plateau (QTP) has become one of the hotspots for phylogeographical studies due to its high species diversity. However, most previous studies have focused on the effects of the Quaternary glaciations on phylogeographical structures and the locations of glacial refugia, and little is known about the effects of the aridization of interior Asia on plant population structure and speciation. Here the chloroplast DNA (cpDNA) trnT-trnF and trnS-trnfM sequences were used to investigate the differentiation and phylogeographical history of 14 Ephedra species from the QTP and northern China, based on a sampling of 107 populations. The phylogeographical analysis, together with phylogenetic reconstruction based on combined four cpDNA fragments (rbcL, rpl16, rps4, and trnS-trnfM), supports three main lineages (eastern QTP, southern QTP, and northern China) of these Ephedra species. Divergence of each lineage could be dated to the Middle or Late Miocene, and was very likely linked to the uplift of the QTP and the Asian aridification, given the high drought and/or cold tolerance of Ephedra. Most of the Ephedra species had low intraspecific variation and lacked a strong phylogeographical structure, which could be partially attributed to clonal reproduction and a relatively recent origin. In addition, ten of the detected 25 cpDNA haplotypes are shared among species, suggesting that a wide sampling of species is helpful to investigate the origin of observed haplotypes and make reliable phylogeographical inference. Moreover, the systematic positions of some Ephedra species are discussed.
doi:10.1371/journal.pone.0056243
PMCID: PMC3571962  PMID: 23418542
17.  Inhibition of BDNF in Multiple Myeloma Blocks Osteoclastogenesis via Down-Regulated Stroma-Derived RANKL Expression Both In Vitro and In Vivo 
PLoS ONE  2012;7(10):e46287.
Brain-derived neurotrophic factor (BDNF) was recently identified as a factor produced by multiple myeloma (MM) cells, which may contribute to bone resorption and disease progression in MM, though the molecular mechanism of this process is not well understood. The purpose of this study was to test the effect of BDNF on bone disease and growth of MM cells both in vitro and in vivo. Co- and triple-culture systems were implemented. The in vitro results demonstrate that BDNF augmented receptor activator of nuclear factor kappa B ligand (RANKL) expression in human bone marrow stromal cells, thus contributing to osteoclast formation. To further clarify the effect of BDNF on myeloma bone disease in vivo, ARH-77 cells were stably transfected with an antisense construct to BDNF (AS-ARH) or empty vector (EV-ARH) to test their capacity to induce MM bone disease in SCID–rab mice. Mice treated with AS-ARH cells were preserved, exhibited no radiologically identifiable lytic lesions and, unlike the controls treated with EV-ARH cells, lived longer and showed reduced tumor burden. Consistently, bones harboring AS-ARH cells showed marked reductions of RANKL expression and osteoclast density compared to the controls harboring EV-ARH cells. These results provide further support for the potential osteoclastogenic effects of BDNF, which may mediate stromal–MM cell interactions to upregulate RANKL secretion, in myeloma bone diseases.
doi:10.1371/journal.pone.0046287
PMCID: PMC3471864  PMID: 23077504
18.  Differential Expression of Anthocyanin Biosynthetic Genes and Transcription Factor PcMYB10 in Pears (Pyrus communis L.) 
PLoS ONE  2012;7(9):e46070.
Anthocyanin biosynthesis in various plants is affected by environmental conditions and controlled by the transcription level of the corresponding genes. In pears (Pyrus communis cv. ‘Wujiuxiang’), anthocyanin biosynthesis is significantly induced during low temperature storage compared with that at room temperature. We further examined the transcriptional levels of anthocyanin biosynthetic genes in ‘Wujiuxiang’ pears during developmental ripening and temperature-induced storage. The expression of genes that encode flavanone 3-hydroxylase, dihydroflavonol 4-reductase, anthocyanidin synthase, UDP-glucose: flavonoid 3-O-glucosyltransferase, and R2R3 MYB transcription factor (PcMYB10) was strongly positively correlated with anthocyanin accumulation in ‘Wujiuxiang’ pears in response to both developmental and cold-temperature induction. Hierarchical clustering analysis revealed the expression patterns of the set of target genes, of which PcMYB10 and most anthocyanin biosynthetic genes were related to the same cluster. The present work may help explore the molecular mechanism that regulates anthocyanin biosynthesis and its response to abiotic stress at the transcriptional level in plants.
doi:10.1371/journal.pone.0046070
PMCID: PMC3460990  PMID: 23029391
19.  Discovery of N-(3,5-bis(1-pyrrolidylmethyl)-4-hydroxybenzyl)-4-methoxybenzenesulfamide (sulcardine) as a novel anti-arrhythmic agent 
Acta Pharmacologica Sinica  2012;33(9):1176-1186.
Aim:
To investigate the anti-arrhythmic effects of sulfamide analogues of changrolin and to characterize the sulfate of compound 6f (sulcardine sulfate, Sul) as a novel anti-arrhythmic agent.
Methods:
The anti-arrhythmic effects of compounds were studied against aconitine-induced arrhythmias in rats and ouabain-induced arrhythmias in guinea pigs. The effects of Sul on transmembrane action potentials were investigated in isolated rabbit sinoatrial nodes and guinea-pig papillary muscles using intracellular recording. With a whole-cell recording technique, the effects of Sul on sodium current, calcium current, and potassium currents were examined in isolated single guinea-pig ventricular myocytes.
Results:
In aconitine-induced arrhythmias of rats, sulfamide analogues of changrolin (4, 5, and 6a–6p) exhibited various anti-arrhythmic activities. The sulfate of compound 6f (Sul) increased the amount of aconitine required to induce arrhythmias in each treated animal. The ED50 value of Sul in rats was 196 mg/kg. In ouabain-induced arrhythmias of guinea pigs, 25, 50, and 100 mg/kg doses of Sul increased the dose of ouabain required to induce VP, VT, and VF in a dose-dependent manner. In papillary preparations, Sul produced a concentration-dependent decrease in APA and Vmax, prolonged APD90 and ERP, whereas RP was unaffected. In the spontaneously beating sinus nodes, Sul reduced APA and Vmax in a concentration-dependent manner. The whole-cell recording studies revealed that Sul produced a reversible reduction in INa (IC50=26.9 μmol/L) and ICa,L(IC50=69.2 μmol/L), whereas the inward rectifier (IK1) and the delayed rectifier potassium currents (IK) were unaffected.
Conclusion:
As a multi-ion channel blocker, Sul may have potent efficacy in anti-atrial and ventricular arrhythmias.
doi:10.1038/aps.2012.119
PMCID: PMC4003109  PMID: 22922342
sulcardine; sulcardine sulfate; changrolin; heart; arrhythmias; aconitine; ouabain; sodium current; L-type calcium current
20.  Interplay between the Westerlies and Asian monsoon recorded in Lake Qinghai sediments since 32 ka 
Scientific Reports  2012;2:619.
Two atmospheric circulation systems, the mid-latitude Westerlies and the Asian summer monsoon (ASM), play key roles in northern-hemisphere climatic changes. However, the variability of the Westerlies in Asia and their relationship to the ASM remain unclear. Here, we present the longest and highest-resolution drill core from Lake Qinghai on the northeastern Tibetan Plateau (TP), which uniquely records the variability of both the Westerlies and the ASM since 32 ka, reflecting the interplay of these two systems. These records document the anti-phase relationship of the Westerlies and the ASM for both glacial-interglacial and glacial millennial timescales. During the last glaciation, the influence of the Westerlies dominated; prominent dust-rich intervals, correlated with Heinrich events, reflect intensified Westerlies linked to northern high-latitude climate. During the Holocene, the dominant ASM circulation, punctuated by weak events, indicates linkages of the ASM to orbital forcing, North Atlantic abrupt events, and perhaps solar activity changes.
doi:10.1038/srep00619
PMCID: PMC3431539  PMID: 22943005
21.  Great Genetic Differentiation among Populations of Meconopsis integrifolia and Its Implication for Plant Speciation in the Qinghai-Tibetan Plateau 
PLoS ONE  2012;7(5):e37196.
The complex tectonic events and climatic oscillations in the Qinghai-Tibetan Plateau (QTP), the largest and highest plateau in the world, are thought to have had great effects on the evolutionary history of the native plants. Of great interest is to investigate plant population genetic divergence in the QTP and its correlation with the geologic and climatic changes. We conducted a range-wide phylogeographical analysis of M. integrifolia based on the chloroplast DNA (cpDNA) trnL-trnF and trnfM-trnS regions, and defined 26 haplotypes that were phylogenetically divided into six clades dated to the late Tertiary. The six clades correspond, respectively, to highly differentiated population groups that do not overlap in geographic distribution, implying that the mountain ranges acting as corridors or barriers greatly affected the evolutionary history of the QTP plants. The older clade of M. integrifolia only occurs in the southwest of the species' range, whereas the distributions of younger clades extend northeastward in the eastern QTP, suggesting that climatic divergence resulting from the uplift of the QTP triggered the initial divergence of M. integrifolia native to the plateau. Also, the nrDNA ITS region was used to clarify the unexpected phylogenetic relationships of cpDNA haplotypes between M. integrifolia and M. betonicifolia. The topological incongruence between the two phylogenies suggests an ancestral hybridization between the two species. Our study indicates that geographic isolation and hybridization are two important mechanisms responsible for the population differentiation and speciation of Meconopsis, a species-rich genus with complex polyploids.
doi:10.1371/journal.pone.0037196
PMCID: PMC3349641  PMID: 22590654
22.  Galectin-1 Binds to Influenza Virus and Ameliorates Influenza Virus Pathogenesis ▿  
Journal of Virology  2011;85(19):10010-10020.
Innate immune response is important for viral clearance during influenza virus infection. Galectin-1, which belongs to S-type lectins, contains a conserved carbohydrate recognition domain that recognizes galactose-containing oligosaccharides. Since the envelope proteins of influenza virus are highly glycosylated, we studied the role of galectin-1 in influenza virus infection in vitro and in mice. We found that galectin-1 was upregulated in the lungs of mice during influenza virus infection. There was a positive correlation between galectin-1 levels and viral loads during the acute phase of viral infection. Cells treated with recombinant human galectin-1 generated lower viral yields after influenza virus infection. Galectin-1 could directly bind to the envelope glycoproteins of influenza A/WSN/33 virus and inhibit its hemagglutination activity and infectivity. It also bound to different subtypes of influenza A virus with micromolar dissociation constant (Kd) values and protected cells against influenza virus-induced cell death. We used nanoparticle, surface plasmon resonance analysis and transmission electron microscopy to further demonstrate the direct binding of galectin-1 to influenza virus. More importantly, we show for the first time that intranasal treatment of galectin-1 could enhance survival of mice against lethal challenge with influenza virus by reducing viral load, inflammation, and apoptosis in the lung. Furthermore, galectin-1 knockout mice were more susceptible to influenza virus infection than wild-type mice. Collectively, our results indicate that galectin-1 has anti-influenza virus activity by binding to viral surface and inhibiting its infectivity. Thus, galectin-1 may be further explored as a novel therapeutic agent for influenza.
doi:10.1128/JVI.00301-11
PMCID: PMC3196456  PMID: 21795357
23.  Relative expression of TAp73 and ΔNp73 isoforms 
Aging (Albany NY)  2012;4(3):202-205.
The transcription factor p73 belongs to the p53 family of tumour suppressors and similar to other family members, transcribed as different isoforms with opposing pro- and anti-apoptotic functions. Unlike p53, p73 mutations are extremely rare in cancers. Instead, the pro-apoptotic activities of transcriptionally active p73 isoforms are commonly inhibited by over-expression of the dominant negative p73 isoforms. Therefore the relative ratio of different p73 isoforms is critical for the cellular response to a chemotherapeutic agent. Here, we analysed the expression of N-terminal p73 isoforms in cell lines and mouse tissues. Our data showed that the transcriptionally competent TAp73 isoform is abundantly expressed in cancer cell lines compared to the dominant negative ΔNp73 isoform. Interestingly, we detected higher levels of ΔNp73 in some mouse tissues, suggesting that ΔNp73 may have a physiological role in these tissues.
PMCID: PMC3348480  PMID: 22388545
p73; alternative splicing; expression; cancer
24.  Serum or Target Deprivation Induced Neuronal Death Cause Oxidative Neuronal Accumulation of Zn2+ and Loss of NAD+ 
Trophic deprivation mediated neuronal death is important during development, acute brain or nerve trauma, and neurodegeneration. Serum deprivation (SD) approximates trophic deprivation in vitro, and an in vivo model is neuronal death in the mouse dorsal lateral geniculate nucleus (LGNd) after ablation of the visual cortex (VCA). Oxidant-induced intracellular Zn2+ release, ([Zn2+]i), from metallothionein-3 (MT-III), mitochondria, or “protein Zn2+” was implicated in trophic deprivation neurotoxicity. We previously showed that neurotoxicity of extracellular Zn2+ required entry, elevation in [Zn2+]i, reduction of NAD+ and ATP levels causing inhibition of glycolysis and cellular metabolism. Exogenous NAD+ and sirtuin inhibition attenuated Zn2+ neurotoxicity. Here we show that: 1) Zn2+ is released intracellularly after oxidant and SD injuries, and sensitivity to these injuries is proportional to neuronal Zn2+ content; 2) NAD+ loss is involved; restoration of NAD+ using exogenous NAD+, pyruvate, or nicotinamide attenuated these injuries, and potentiation of NAD+ loss potentiated injury; 3) Neurons from genetically modified mouse strains which reduce intracellular Zn2+ content (MT-III knockout), reduce NAD+ catabolism (PARP-1 knockout), or increase expression of an NAD+ synthetic enzyme (Wlds) each had attenuated SD and oxidant neurotoxicities; 4) Sirtuin inhibitors attenuated, and sirtuin activators potentiated these neurotoxicities; 5) VCA induces Zn2+ staining and death only in ipsilateral LGNd neurons, and a 1ppm Zn2+ diet attenuated injury; 6) Finally, NAD+ synthesis and levels are involved because LGNd neuronal death after VCA was dramatically reduced in Wlds animals, and by intraperitoneal pyruvate or nicotinamide. Zn2+ toxicity is involved in serum and trophic deprivation induced neuronal death.
doi:10.1111/j.1460-9568.2010.07372.x
PMCID: PMC2946389  PMID: 20722716
visual cortex ablation; mouse; pyruvate; sirtuin; dorsal lateral geniculate nucleus
25.  Effects of Fasting During Ramadan Month on Cognitive Function in Muslim Athletes 
Asian Journal of Sports Medicine  2011;2(3):145-153.
Purpose
Our study aimed to profile the effect of fasting during the Ramadan month on cognitive function in a group of healthy Muslim athletes.
Methods
Eighteen male athletes underwent computerized neuropsychological testing during (fasting) and after (non-fasting) Ramadan. Diet was standardized, and tests were performed at 0900h and 1600h to characterize potential time-of-day (TOD) interactions. Psychomotor function (processing speed), vigilance (visual attention), visual learning and memory, working memory (executive function), verbal learning and memory were examined. Capillary glucose, body temperature, urine specific gravity, and sleep volume were also recorded.
Results
Fasting effects were observed for psychomotor function (Cohen's d=1.3, P=0.01) and vigilance (d=0.6, P=0.004), with improved performance at 0900h during fasting; verbal learning and memory was poorer at 1600h (d=-0.8, P=0.03). A TOD effect was present for psychomotor function (d=-0.4, P<0.001), visual learning (d=-0.5, P=0.04), verbal learning and memory (d=-1.3, P=0.001), with poorer performances at 1600h. There was no significant fasting effect on visual learning and working memory.
Conclusions
Our results show that the effect of fasting on cognition is heterogeneous and domain-specific. Performance in functions requiring sustained rapid responses was better in the morning, declining in the late afternoon, whereas performance in non-speed dependent accuracy measures was more resilient.
PMCID: PMC3289210  PMID: 22375233
Psychomotor Function; Cognition; Ramadan Fasting; Memory

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