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1.  Lean-non-alcoholic fatty liver disease increases risk for metabolic disorders in a normal weight Chinese population 
World Journal of Gastroenterology : WJG  2014;20(47):17932-17940.
AIM: To study the prevalence and clinical biochemical, blood cell and metabolic features of lean-non-alcoholic fatty liver disease (lean-NAFLD) and its association with other diseases.
METHODS: Demographic, biochemical and blood examinations were conducted in all the subjects in this study. We classified the subjects into four groups according to their weight and NAFLD status: lean-control, lean-NAFLD [body mass index (BMI) < 24 kg/m2], overweight-obese control and overweight-obese NAFLD. One-way analysis of variance (ANOVA) was used to compare the means of continuous variables (age, BMI, blood pressure, glucose, lipid, insulin, liver enzymes and blood cell counts) and the χ2 test was used to compare the differences in frequency of categorical variables (sex, education, physical activity, smoking, alcohol consumption and prevalence of hypertension, hyperlipidemia, diabetes, metabolic syndrome central obesity and obesity). Both univariate and multivariate logistic regression models were adopted to calculate odds ratios (ORs) and predict hyperlipidemia, hypertension, diabetes and metabolic syndrome when we respectively set all controls, lean-control and overweight-obese-control as references. In multivariate logistic regression models, we adjusted potential confounding factors, including age, sex, smoking, alcohol consumption and physical activity.
RESULTS: The prevalence of NAFLD was very high in China. NAFLD patients were older, had a higher BMI, waist circumference, blood pressure, fasting blood glucose, insulin, blood lipid, liver enzymes and uric acid than the controls. Although lean-NAFLD patients had lower BMI and waist circumstance, they had significantly higher visceral adiposity index than overweight-obese controls. Lean-NAFLD patients had comparable triglyceride, cholesterin and low-density lipoprotein cholesterin to overweight-obese NAFLD patients. In blood cell examination, both lean and overweight-obese NAFLD was companied by higher white blood cell count, red blood cell count, hemoglobin and hematocrit value. All NAFLD patients were at risk of hyperlipidemia, hypertension, diabetes and metabolic syndrome (MetS). Lean-NAFLD was more strongly associated with diabetes (OR = 2.47, 95%CI: 1.14-5.35), hypertension (OR = 1.72, 95%CI: 1.00-2.96) and MetS (OR = 3.19, 95%CI: 1.17-4.05) than overweight-obese-NAFLD (only OR for MetS was meaningful: OR = 1.89, 95%CI: 1.29-2.77). NAFLD patients were more likely to have central obesity (OR = 1.97, 95%CI: 1.38-2.80), especially in lean groups (OR = 2.17, 95%CI: 1.17-4.05).
CONCLUSION: Lean-NAFLD has unique results in demographic, biochemical and blood examinations, and adds significant risk for diabetes, hypertension and MetS in lean individuals.
PMCID: PMC4273143  PMID: 25548491
Lean-non-alcoholic fatty liver disease; Metabolic disorder; Diabetes; Risk; Chinese
2.  Herpes B virus gD interaction with its human receptor – an in silico analysis approach 
The glycoprotein D (gD) is essential for Herpes B virus (BV) entry into mammalian cells. Nectin-1, an HSV-1 gD receptor, is found to be the receptor which mediated BV induced cell-cell fusion, while HVEM does not mediate fusion by BV glycoprotein. However, the specific sequence and structural requirements of the BV gD for the recognition of and binding to Nectin-1 are unknown. Moreover, the 3D structures of BV gD and the BV gD-receptor complex have not been determined. In this study, we propose a reliable model of the interaction of the BV gD with receptor using bioinformatics tools.
The three-dimensional structures of two BV gD-receptor complexes were constructed using homology modelling and docking strategy. Based on the models of these complexes, the BV gD receptor interaction patterns were calculated. The results showed that the interface between the BV gD and nectin-1 molecule is not geometrically complementary. The computed molecular interactions indicated that two terminal extensions were the main region of BV gD that binds to nectin-1 and that hydrophobic contacts between the two molecules play key roles in their recognition and binding. The constructed BV gD-HVEM complex model showed that this complex had a lower shape complementarity value and a smaller interface area compared with the HSV-1 gD-HVEM complex, and the number of intermolecular interactions between BV gD-HVEM were fewer than that of HSV-1 gD-HVEM complex. These results could explain why HVEM does not function as a receptor for BV gD.
In this study, we present structural model for the BV gD in a complex with its receptor. Some features predicted by this model can explain previously reported experimental data. This complex model may lead to a better understanding of the function of BV gD and its interaction with receptor and will improve our understanding of the activation of the BV fusion and entry process.
PMCID: PMC4106229  PMID: 24902525
Herpes B virus; Glycoprotein D; Receptor; Interaction; Complex
3.  Synthesis of l-Ascorbic Acid Lactone Derivatives 
A small focused library which comprised of l-AA lactone derivatives was built with a facile method. This reported method was optimized by modifying the acidity of the solvent. As a result, 12 l-AA lactones were synthesized. Among these lactones, lactones 8–12 were new compounds. The cytotoxicity of these synthetic compounds were investigated.
PMCID: PMC4050306  PMID: 24955300
l-Ascorbic acid lactone; Cytotoxicity; Focused library
4.  Synthesis of l-Ascorbic Acid Lactone Derivatives 
A small focused library which comprised of l-AA lactone derivatives was built with a facile method. This reported method was optimized by modifying the acidity of the solvent. As a result, 12 l-AA lactones were synthesized. Among these lactones, lactones 8–12 were new compounds. The cytotoxicity of these synthetic compounds were investigated.
PMCID: PMC4050306  PMID: 24955300
l-Ascorbic acid lactone; Cytotoxicity; Focused library
5.  Overexpression of GRB2 is correlated with lymph node metastasis and poor prognosis in esophageal squamous cell carcinoma 
The adapter protein growth factor receptor-bound 2 (GRB2) is essential for various basic cellular functions by mediating the regulation of receptor tyrosine kinase (RTK) signaling, however, little is known about GRB2 expression in esophageal squamous cell carcinoma (ESCC). We sought to characterize GRB2 expression and its relationship with clinicopathological parameters and prognostic significance in ESCC patients. Here, it was presented that GRB2 was overexpressed in cytoplasm in 58.1% (100/172) of ESCC cases by immunohistochemistry. Survival analysis demonstrated overexpression of GRB2 protein was significantly related to poor prognosis of ESCC patients (P = 0.021). Furthermore, overexpression of GRB2 was significantly associated with the lymph node metastases. In addition, subgroup analysis according to lymph node metastasis revealed a shorter disease-free survival (DFS) in the ESCC patients with GRB2 overexpression than the patients with GRB2 low-expression (Means for DFS months: 33.8 versus 52.1). Finally, the significant difference between overexpression of GRB2 and poor survival rates exhibited in univariate analysis (P = 0.022) and multivariate Cox analysis (close to significance, P = 0.065), demonstrated that GRB2 was an independent factor in prognosis of ESCC patients. In conclusion, GRB2 expression status could be as a positive biomarker of ESCC progression and lymph node metastasis.
PMCID: PMC4097250  PMID: 25031732
GRB2 expression; survival; lymph node metastasis; immunohistochemistry; esophageal squamous cell carcinoma
6.  Recoding RNA editing of antizyme inhibitor 1 predisposes to hepatocellular carcinoma 
Nature medicine  2013;19(2):209-216.
Better understanding of human hepatocellular carcinoma (HCC) pathogenesis at the molecular level will facilitate the discovery of tumor initiating events. Herein, transcriptome sequencing revealed that adenosine (A)-to-inosine (I) RNA editing of antizyme inhibitor 1 (AZIN1) displays a high modification rate in HCC specimens. A-to-I editing of AZIN1 transcripts is specifically regulated by adenosine deaminase acting on RNA-1 (ADAR1). The serine (S) → glycine (G) substitution at residue 367, located in β-strand 15 (β15), predicted a conformational change, induced a cytoplasmic-to-nuclear translocation, and conferred “gain-of-function” phenotypes manifested by augmented tumor initiating potential and more aggressive behavior. Compared with wild-type AZIN1 protein, the edited form possesses stronger affinity to antizyme, and the resultant higher protein stability promotes cell proliferation via the neutralization of antizyme-mediated degradation of ornithine decarboxylase (ODC) and cyclin D1 (CCND1). Collectively, A-to-I RNA editing of AZIN1 may be a potential driver in the pathogenesis of human cancers, particularly HCC.
PMCID: PMC3783260  PMID: 23291631
A-to-I; RNA editing; AZIN1; ADAR1; antizyme; ODC; CCND1; HCC
7.  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.
PMCID: PMC3315211  PMID: 22323360
8.  Exploring of drug leads from diversity-oriented Michael-acceptor library derived from natural products 
A potential strategy for drug lead identification and in-active natural products re-discovery is elaborated. Starting from fifteen structurally diverse natural products, a focused library featured by Michael acceptors is constructed with IBX mediated oxidation. Biological assay on five tumor cell lines indicates that four Michael acceptors, 8a, 11a, 12a, 14a, are with improved cytotoxicity (3–10 folds more potent than the parent compounds), which merit further investigations. Further thiol-sensitive assay of the active hit 8a revealed that it was an irreversible Michael acceptor. The results suggest that the strategy is not only effective and relatively high discovery rate (28%), but also resource saving.
Graphical abstract
Electronic Supplementary Material
Supplementary material is available for this article at 10.1007/s13659-012-0071-7 and is accessible for authorized users.
PMCID: PMC4131632
drug leads identification; in-active natural products re-discovery; Michael acceptors; anti-tumor activity
9.  Euglobal-IIIa, a novel acylphloroglucinol-sesquiterpene derivative from Eucalyptus robusta: absolute structure and cytotoxicity 
Euglobal-IIIa (1), a novel acylphloroglucinol-sesquiterpene derivative, and a known analogue, have been isolated from leaves of Eucalyptus robusta. The structures was elucidated by extensive spectroscopic data and by comparison with data reported in literature, while the absolute configuration of 1 was determined by the X-ray diffraction analysis. Compound 1 exhibited comparable cytotoxicity with that of cisplatin against five human cancer cell lines HL-60, SMMC-7721, A-549, MCF-7, and SW480 with IC50 values of 15.7, 15.5, 17.6, 14.3, and 21.8 µM, respectively.
Electronic Supplementary Material
Supplementary material is available for this article at 10.1007/s13659-011-0021-9 and is accessible for authorized users.
PMCID: PMC4131649
Eucalyptus robusta; acylphloroglucinol-sesquiterpene; absolute structure; cytotoxicity
10.  Chemical constituents from the aerial parts of Musella lasiocarpa 
Phytochemical investigation of the aerial parts of the monotypic plant, Musella lasiocarpa, led to the isolation of four rare bicyclic diarylheptanoids, musellarins B-E (2–5), two new phenylphenalenones, 2-methoxy-9-(3′,4′-dihydroxyphenyl)-1Hphenalen-1-one (9), 2-methoxy-9-(3′-methoxy-4′-hydroxyphenyl)-1H-phenalen-1-one (10), a new acenaphtylene derivative, trans-(1S,2S)-3-(4′-methoxyphenyl)-acenaphthene-1,2-diol (13), and two new sucrose esters, 1,2′,3′,4′,6′-O-pentaacetyl-3-O-trans-pcoumaroylsucrose (16), 1,2′,3′,4′,6′-O-pentaacetyl-3-O-cis-p-coumaroylsucrose (17), together with nine known compounds. In addition, (4E,6E)-1-(3′,4′-dihydroxyphenyl)-7-(4″-hydroxyphenyl)-hepta-4,6-dien-3-one (15) was isolated for the first time from a natural source. The structures of new compounds were elucidated by analysis of their spectroscopic data. Compounds 2, 6, 8–10, 12, and 14 were cytotoxic toward several of the human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480). Of these, the new compound 9 was the most potent one, with IC50 values of 5.8, 10.3, 6.3, 3.3, and 2.3 µM, respectively.
Electronic Supplementary Material
Supplementary material is available for this article at 10.1007/s13659-011-0007-7 and is accessible for authorized users.
PMCID: PMC4131711
monotypic; diarylheptanoid; phenylphenalenone; acenaphtylene; sucrose ester; Musella lasiocarpa
11.  Hypoxia augments the calcium-activated chloride current carried by anoctamin-1 in cardiac vascular endothelial cells of neonatal mice 
British Journal of Pharmacology  2014;171(15):3680-3692.
The molecular identity of calcium-activated chloride channels (CaCCs) in vascular endothelial cells remains unknown. This study sought to identify whether anoctamin-1 (Ano1, also known as TMEM16A) functions as a CaCC and whether hypoxia alters the biophysical properties of Ano1 in mouse cardiac vascular endothelial cells (CVECs).
Western blot, quantitative real-time PCR, confocal imaging analysis and patch-clamp analysis combined with pharmacological approaches were used to determine whether Ano1 was expressed and functioned as CaCC in CVECs.
Ano1 was expressed in CVECs. The biophysical properties of the current generated in the CVECs, including the Ca2+ and voltage dependence, outward rectification, anion selectivity and the pharmacological profile, are similar to those described for CaCCs. The density of ICl(Ca) detected in CVECs was significantly inhibited by T16Ainh-A01, an Ano1 inhibitor, and a pore-targeting, specific anti-Ano1 antibody, and was markedly decreased in Ano1 gene knockdown CVECs. The density of ICl(Ca) was significantly potentiated in CVECs exposed to hypoxia, and this hypoxia-induced increase in the density of ICl(Ca) was inhibited by T16Ainh-A01 or anti-Ano1 antibody. Hypoxia also increased the current density of ICl(Ca) in Ano1 gene knockdown CVECs.
Ano1 formed CaCC in CVECs of neonatal mice. Hypoxia enhances Ano1-mediated ICl(Ca) density via increasing its expression, altering the ratio of its splicing variants, sensitivity to membrane voltage and to Ca2+. Ano1 may play a role in the pathophysiological processes during ischaemia in heart, and therefore, Ano1 might be a potential therapeutic target to prevent ischaemic damage.
PMCID: PMC4128065  PMID: 24758567
calcium-activated chloride channels; cardiac vascular endothelial cells; anoctamin; hypoxia
12.  Protective effects of thalidomide on pulmonary injuries in a rat model of paraquat intoxication 
This study was designed to evaluate the protective effects of thalidomide on paraquat (PQ)-induced lung injuries in a rat model and to explore the underlying mechanisms.
Rats were exposed to 50 mg/kg PQ by oral gavage, and treated with thalidomide through oral administration at 60 mg/kg once a day, 6 days/week for 2 weeks. Serum levels of IL-6, TNF-alpha, TGFbeta1 and COL1A1 were detected at different time points after paraquat exposure. At the end of the study, lung tissues were collected for pathological inspection as well as analyses of water content and expression levels of IL-6, TNF-alpha, TGFbeta1 and COL1A1 mRNA.
The results showed that thalidomide treatment could significantly alleviate PQ-induced pathological changes in lung tissue and severity of lung edema. Thalidomide treatment after PQ exposure resulted in significantly reduced serum levels of IL-6, TNF-alpha, TGF-beta1 and COL1A1, as compared to PQ group. PCR analysis demonstrated that expression levels of IL-6, TNF-alpha, TGF-beta1 and COL1A1 in lung tissue were significantly increased after PQ exposure but reduced by thalidomide, which were confirmed by immunohistochemistry staining.
Our results indicated that inflammatory factors played important roles in PQ-induced lung injuries and thalidomide could protect rats from PQ-induced lung injuries by inhibiting the upregulation of inflammatory factors.
PMCID: PMC4517355  PMID: 26221080
Paraquat; Lung injury; Thalidomide; Protective effects
13.  Hypoxia-inducible miR-182 enhances HIF1α signaling via targeting PHD2 and FIH1 in prostate cancer 
Scientific Reports  2015;5:12495.
Activation of hypoxia-inducible factor 1α (HIF1α) controls the transcription of genes governing angiogenesis under hypoxic condition during tumorigenesis. Here we show that hypoxia-responsive miR-182 is regulated by HIF1α at transcriptional level. Prolyl hydroxylase domain enzymes (PHD) and factor inhibiting HIF-1 (FIH1), negative regulators of HIF1 signaling, are direct targets of miR-182. Overexpression of miR-182 in prostate cancer cells led to a reduction of PHD2 and FIH1 expression and an increase in HIF1α level either under normoxic or hypoxic condition. Consistently, inhibition of miR-182 could increase PHD2 and FIH1 levels, thereby reducing the hypoxia-induced HIF1α expression. Matrigel plug assay showed that angiogenesis was increased by miR-182 overexpression, and vice versa. miR-182 overexpression in PC-3 prostate cancer xenografts decreased PHD2 and FIH1 expression, elevated HIF1α protein levels, and increased tumor size. Lastly, we revealed that the levels of both miR-182 and HIF1α were elevated, while the expression PHD2 and FIH1 was downregulated in a mouse model of prostate cancer. Together, our results suggest that the interplay between miR-182 and HIF1α could result in a sustained activation of HIF1α pathway, which might facilitate tumor cell adaption to hypoxic stress during prostate tumor progression.
PMCID: PMC4513346  PMID: 26205124
14.  Apparent plasticity in functional traits determining competitive ability and spatial distribution: a case from desert 
Scientific Reports  2015;5:12174.
Species competitive abilities and their distributions are closely related to functional traits such as biomass allocation patterns. When we consider how nutrient supply affects competitive abilities, quantifying the apparent and true plasticity in functional traits is important because the allometric relationships among traits are universal in plants. We propose to integrate the notion of allometry and the classical reaction norm into a composite theoretical framework that quantifies the apparent and true plasticity. Combining the framework with a meta-analysis, a series of field surveys and a competition experiment, we aimed to determine the causes of the dune/interdune distribution patterns of two Haloxylon species in the Gurbantonggut Desert. We found that (1) the biomass allocation patterns of both Haloxylon species in responses to environmental conditions were apparent rather than true plasticity and (2) the allometric allocation patterns affected the plants’ competition for soil nutrient supply. A key implication of our results is that the apparent plasticity in functional traits of plants determines their response to environmental change. Without identifying the apparent and true plasticity, we would substantially overestimate the magnitude, duration and even the direction of plant responses in functional traits to climate change.
PMCID: PMC4507175  PMID: 26190745
15.  MTA1 promotes proliferation and invasion in human gastric cancer cells 
OncoTargets and therapy  2015;8:1785-1794.
Although metastasis-associated protein 1 (MTA1) has been widely linked to tumor metastasis, the relevant mechanisms remain to be elucidated, especially in gastric cancer. The aim of this study was to examine whether the MTA1 gene is associated with the process of proliferation and invasion by regulating several molecular targets in gastric cancer. MTA1 expression in 61 gastric cancer tissue and adjacent noncancerous tissues was analyzed by immunohistochemistry. The prognostic value of MTA1 for overall survival and disease-free survival was determined by Kaplan–Meier estimates, and the significance of differences between curves was evaluated by the log-rank test. Furthermore, overexpression of MTA1 in SGC7901 and BGC823 cells promoted cell cycle progression, cell adhesion, and cell invasion. Our study found that MTA1 is overexpressed in gastric cancers, which contributes to malignant cell growth by facilitating cell cycle progression through upregulation of cyclin D1 and accelerates the migration and invasion of human gastric cancer cells by regulating expression of fibronectin and MMP2/MMP9. Taken together, MTA1 was involved in the pathogenesis of gastric cancer and might be a candidate therapeutic target in gastric cancer.
PMCID: PMC4516181
cell cycle; cell adhesion; migration
16.  A small molecular agent YL529 inhibits VEGF-D-induced lymphangiogenesis and metastasis in preclinical tumor models in addition to its known antitumor activities 
BMC Cancer  2015;15:525.
The lymph node metastasis is a key early step of the tumor metastatic process. VEGFD-mediated tumor lymphangiogenesis plays a key role, since down-regulation of p-VEGFR-3 could block the lymph node metastasis. YL529 has been reported to possess potent anti-angiogenesis and antitumor activities; however, its roles in tumor-associated lymphangiogenesis and lymphatic metastasis remain unclear.
We investigated the effect of YL529 on tumor-associated lymphangiogenesis and lymph node metastasis using in vitro lymph node metastasis models and in vivo subcutaneous tumor models in C57 BL/6 mice.
We found that YL529 inhibited VEGF-D-induced survival, proliferation and tube-formation of Human Lymphatic Endothelial Cells. Furthermore, in established in vitro and in vivo lymph node metastasis models using VEGF-D-LL/2 cells, YL529 significantly inhibited the tumor-associated lymphangiogenesis and metastasis. At molecular level, YL529 down-regulated p-VEGFR-3, p-JNK and Bax while up-regulated Bcl-2.
YL529 provided the therapeutic benefits by both direct effects on tumor cells and inhibiting lymphangiogenesis and metastasis via the VEGFR-3 signaling pathway, which may have significant direct clinical implications.
PMCID: PMC4506598  PMID: 26187637
YL529; Lymphangiogenesis; Metastasis; VEGF-D; VEGFR-3
17.  Uric Acid Produces an Inflammatory Response through Activation of NF-κB in the Hypothalamus: Implications for the Pathogenesis of Metabolic Disorders 
Scientific Reports  2015;5:12144.
Epidemiological studies have shown that an elevated uric acid (UA) level predicts the development of metabolic syndrome and diabetes; however, there is no direct evidence of this, and the underlying mechanism remains unclear. Here, we showed that a high-UA diet triggered the expression of pro-inflammatory cytokines, activated the NF-κB pathway, and increased gliosis in the hypothalamus. Intracerebroventricular injection of UA induced hypothalamic inflammation and reactive gliosis, whereas these effects were markedly ameliorated by the inhibition of NF-κB. Moreover, magnetic resonance imaging confirmed that hyperuricemia in rodents and humans was associated with gliosis in the mediobasal hypothalamus. Importantly, the rats administered UA exhibited dyslipidemia and glucose intolerance, which were probably mediated by hypothalamic inflammation and hypothalamic neuroendocrine alterations. These results suggest that UA can cause hypothalamic inflammation via NF-κB signaling. Our findings provide a potential therapeutic strategy for UA-induced metabolic disorders.
PMCID: PMC4503982  PMID: 26179594
18.  Ethanol extract of propolis protects macrophages from oxidized low density lipoprotein-induced apoptosis by inhibiting CD36 expression and endoplasmic reticulum stress-C/EBP homologous protein pathway 
Ethanol extract of propolis (EEP), rich in flavones, has been known for various biological activities including antioxidant, antiinflammatory and antibiotic activities. Our previous studies have shown that EEP protects endothelial cells from oxidized low-density lipoprotein (ox-LDL)-induced apoptosis and inhibits atherosclerotic lesion development. In this present study, we explored the protective effect of EEP on ox-LDL-induced cytotoxicity in macrophages and specifically the endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP) pathway-mediated apoptosis.
EEP was prepared and the total flavonoids content of EEP was determined by the colorimetric method of Chinese Standard (GB/T 20574-2006). The effects of EEP on lipid accumulation, cytotoxicity and apoptosis in RAW264.7 cells induced by ox-LDL or tunicamycin (TM, an ER stress inducer) were assayed using oil red O staining, MTT assay, flow cytometric analysis and so on. Immunofluorescence, Western blot and real time-PCR analysis were then used to further investigate the molecular mechanisms by which EEP protects macrophages from ox-LDL-induced apoptosis. 4-phenylbutyric acid (PBA), an ER stress inhibitor, was used as a positive control.
EEP (7.5, 15 and 30 mg/L) not only attenuated ox-LDL-induced lipid accumulation in RAW264.7 macrophages in a dose-dependent manner but also inhibited the decreased cell viability and the increased lactate dehydrogenase (LDH) leakage, caspase-3 activation and apoptosis induced by ox-LDL or tunicamycin (TM, a classical ER stress inducer), which were similar to 4-phenylbutyric acid (PBA, an inhibitor of ER stress) treatment. In addition, like PBA, EEP significantly suppressed the ox-LDL- or TM-induced activation of ER stress signaling pathway including the phosphorylation of double-stranded RNA-activated protein kinase-like ER kinase (PERK) and eukaryotic translation initiation factor 2α (eIF2α) as well as upregulation of glucose regulated protein 78 (GRP78) and the pro-apoptotic protein CHOP. Furthermore, EEP significantly suppressed ox-LDL intake by macrophages and the upregulation of CD36 induced by ox-LDL.
These data indicate that EEP may protect macrophages from ox-LDL-induced apoptosis and the mechanism at least partially involves its ability to suppress the CD36-mediated ox-LDL intake and subsequent activation of ER stress-CHOP signalling pathway.
PMCID: PMC4501110  PMID: 26169264
Ethanol extract of propolis; Endoplasmic reticulum stress; C/EBP homologous protein; Oxidized low density lipoprotein; Macrophage; Apoptosis
19.  Large-scale Direct Targeting for Drug Repositioning and Discovery 
Scientific Reports  2015;5:11970.
A system-level identification of drug-target direct interactions is vital to drug repositioning and discovery. However, the biological means on a large scale remains challenging and expensive even nowadays. The available computational models mainly focus on predicting indirect interactions or direct interactions on a small scale. To address these problems, in this work, a novel algorithm termed weighted ensemble similarity (WES) has been developed to identify drug direct targets based on a large-scale of 98,327 drug-target relationships. WES includes: (1) identifying the key ligand structural features that are highly-related to the pharmacological properties in a framework of ensemble; (2) determining a drug’s affiliation of a target by evaluation of the overall similarity (ensemble) rather than a single ligand judgment; and (3) integrating the standardized ensemble similarities (Z score) by Bayesian network and multi-variate kernel approach to make predictions. All these lead WES to predict drug direct targets with external and experimental test accuracies of 70% and 71%, respectively. This shows that the WES method provides a potential in silico model for drug repositioning and discovery.
PMCID: PMC4496667  PMID: 26155766
20.  Identification of Glycoproteins Containing Specific Glycans Using a Lectin-Chemical Method 
Analytical chemistry  2015;87(9):4683-4687.
Glycosylation is one of the most common protein modifications. Each glycoprotein can be glycosylated at multiple glycosites, and each glycosites can be modified by different glycans. Due to this heterogeneity of glycosylation, it has proven difficult to study the structure–function relationship of specific glycans and their affected glycoproteins. Here, we report a novel method for rapid and quantitative identification of glycoproteins containing specific glycans. Lectin affinity isolations are followed by chemical immobilization of the captured glycopeptides, allowing the identification of glycoproteins containing specific glycans by subsequent mass spectrometry. The application of the method should be useful to facilitate our understanding of how changes in glycan associate with diseases, and to discover novel glycoproteins with certain glycans that could serve as biomarkers or therapeutic targets.
PMCID: PMC4496425  PMID: 25837443
21.  BBS4 and BBS5 show functional redundancy in the BBSome to regulate the degradative sorting of ciliary sensory receptors 
Scientific Reports  2015;5:11855.
Cilia harbor sensory receptors for various signaling cascades critical for vertebrate development. However, the mechanisms underlying the ciliary homeostasis of sensory receptors remain elusive. Here, we demonstrate that BBS-4 and BBS-5, two distinct BBSome components, show unexpected functional redundancy in the context of cilia in C. elegans. BBS-4 directly interacts with BBS-5 and the interaction can be disrupted by a conserved mutation identified in human BBS4. Surprisingly, we found that BBS-4 and BBS-5 act redundantly in the BBSome to regulate the ciliary removal, rather than the ciliary entry or retrograde IFT transport, of various sensory receptors. Further analyses indicate that co-depletion of BBS-4 and BBS-5 disrupts the lysosome-targeted degradative sorting of ciliary sensory receptors. Moreover, mammalian BBS4 and BBS5 also interact directly and coordinate the ciliary removal of polycystin 2. Hence, we reveal a novel and highly conserved role for the BBSome in fine-tuning ciliary signaling by regulating the ciliary removal of sensory receptors for lysosomal degradation.
PMCID: PMC4493597  PMID: 26150102
22.  VHH Phage-Based Competitive Real-Time Immuno-Polymerase Chain Reaction for Ultrasensitive Detection of Ochratoxin A in Cereal 
Analytical Chemistry  2014;86(15):7471-7477.
Phage display-mediated immuno-polymerase chain reaction (PD-IPCR) is an ultrasensitive detection technology that combines the advantages of immuno-PCR and phage display. The phage particle, which displayed antibody fragments including single-chain fragment variable (scFv), variable domain of heavy-chain antibodies (VHH), and antigen-binding fragment (Fab) on the surface can be directly used in IPCR, supplying both the detection antibody and deoxyribonucleic acid (DNA) template. In this work, we used ochratoxin A (OTA) as a model system to study the capacity of PD-IPCR in the detection of toxic small molecular weight compounds, especially mycotoxins. An alpaca-derived VHH library was constructed and subjected to four cycles of panning. In total, 16 clones with four unique sequences were selected by competitive binding with OTA. The clone VHH-28 resulted in the lowest 50% inhibitory concentration of 0.31 ng/mL in the phage enzyme-linked immunosorbent assay (ELISA) and was selected to develop the VHH phage-based real-time immuno-PCR (RT-IPCR). The detection limit of the VHH phage-based RT-IPCR was 3.7 pg/L, with a linear range of 0.01–1000 pg/mL. This method was compared with conventional ELISA, and validation results indicated the reliability of VHH phage-based RT-IPCR in the detection of OTA in cereal samples. This study provides a new idea for the ultrasensitive detection of mycotoxins and other toxic small molecular weight compounds.
PMCID: PMC4306448  PMID: 24992514
23.  A Novel Mittag-Leffler Kernel Based Hybrid Fault Diagnosis Method for Wheeled Robot Driving System 
The wheeled robots have been successfully applied in many aspects, such as industrial handling vehicles, and wheeled service robots. To improve the safety and reliability of wheeled robots, this paper presents a novel hybrid fault diagnosis framework based on Mittag-Leffler kernel (ML-kernel) support vector machine (SVM) and Dempster-Shafer (D-S) fusion. Using sensor data sampled under different running conditions, the proposed approach initially establishes multiple principal component analysis (PCA) models for fault feature extraction. The fault feature vectors are then applied to train the probabilistic SVM (PSVM) classifiers that arrive at a preliminary fault diagnosis. To improve the accuracy of preliminary results, a novel ML-kernel based PSVM classifier is proposed in this paper, and the positive definiteness of the ML-kernel is proved as well. The basic probability assignments (BPAs) are defined based on the preliminary fault diagnosis results and their confidence values. Eventually, the final fault diagnosis result is archived by the fusion of the BPAs. Experimental results show that the proposed framework not only is capable of detecting and identifying the faults in the robot driving system, but also has better performance in stability and diagnosis accuracy compared with the traditional methods.
PMCID: PMC4504124
24.  Multidrug Resistance-Associated Protein 2 (MRP2) Mediated Transport of Oxaliplatin-Derived Platinum in Membrane Vesicles 
PLoS ONE  2015;10(7):e0130727.
The platinum-based anticancer drug oxaliplatin is important clinically in cancer treatment. However, the role of multidrug resistance-associated protein 2 (MRP2) in controlling oxaliplatin membrane transport, in vivo handling, toxicity and therapeutic responses is unclear. In the current study, preparations of MRP2-expressing and control membrane vesicles, containing inside-out orientated vesicles, were used to directly characterise the membrane transport of oxaliplatin-derived platinum measured by inductively coupled plasma mass spectrometry. Oxaliplatin inhibited the ATP-dependent accumulation of the model MRP2 fluorescent probe, 5(6)-carboxy-2,'7'-dichlorofluorescein, in MRP2-expressing membrane vesicles. MRP2-expressing membrane vesicles accumulated up to 19-fold more platinum during their incubation with oxaliplatin and ATP as compared to control membrane vesicles and in the absence of ATP. The rate of ATP-dependent MRP2-mediated active transport of oxaliplatin-derived platinum increased non-linearly with increasing oxaliplatin exposure concentration, approaching a plateau value (Vmax) of 2680 pmol Pt/mg protein/10 minutes (95%CI, 2010 to 3360 pmol Pt/mg protein/10 minutes), with the half-maximal platinum accumulation rate (Km) at an oxaliplatin exposure concentration of 301 μM (95% CI, 163 to 438 μM), in accordance with Michaelis-Menten kinetics (r2 = 0.954). MRP2 inhibitors (myricetin and MK571) reduced the ATP-dependent accumulation of oxaliplatin-derived platinum in MRP2-expressing membrane vesicles in a concentration-dependent manner. To identify whether oxaliplatin, or perhaps a degradation product, was the likely substrate for this active transport, HPLC studies were undertaken showing that oxaliplatin degraded slowly in membrane vesicle incubation buffer containing chloride ions and glutathione, with approximately 95% remaining intact after a 10 minute incubation time and a degradation half-life of 2.24 hours (95%CI, 2.08 to 2.43 hours). In conclusion, MRP2 mediates the ATP-dependent active membrane transport of oxaliplatin-derived platinum. Intact oxaliplatin and its anionic monochloro oxalate ring-opened intermediate appear likely candidates as substrates for MRP2-mediated transport.
PMCID: PMC4488857  PMID: 26131551
25.  Toll-like receptor 4 signaling contributes to paclitaxel-induced peripheral neuropathy 
This paper tests the contribution of the toll-like receptors (TLRs), TLR4 in particular, in the initiation and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy (CIPN). TLR4 and its immediate down-stream signaling molecules MyD88 and TRIF were increased in dorsal root ganglion (DRG) by western blot by day 7 of paclitaxel treatment. The behavioral phenotype, the increase of both TLR4 and MyD88 was blocked by co-treatment with the TLR4 antagonist LPS-RS during chemotherapy. A similar, but less robust behavioral effect was observed using intrathecal treatment of MyD88 homodimerization inhibitory peptide. DRG levels of TLR4 and MyD88 reduced over the next two weeks, whereas these levels remained increased in spinal cord through day 21 following chemotherapy. Immunohistochemical analysis revealed TLR4 expression in both CGRP- and IB4-positive small DRG neurons. MyD88 was only found in CGRP-positive neurons and TRIF was found both in CGRP- and IB4-positive small DRG neurons as well as in medium and large size DRG neurons. In spinal cord TLR4 was only found co-localized to astrocytes but not with either microglia or neurons. Intrathecal treatment with the TLR4 antagonist lipopolysaccharide-RS (LPS-RS) transiently reversed pre-established CIPN mechanical hypersensitivity. These results strongly implicate TLR4 signaling in DRG and spinal cord in the induction and maintenance of paclitaxel related CIPN.
PMCID: PMC4083500  PMID: 24755282
Neuropathy; DRG; spinal cord; TLR4; MyD88; TRIF; LPS-RS

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