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1.  Rapid and Sustainable Detoxication of Airborne Pollutants by Broccoli Sprout Beverage: Results of a Randomized Clinical Trial in China 
Broccoli sprouts are a convenient and rich source of the glucosinolate, glucoraphanin, which can generate the chemopreventive agent, sulforaphane, an inducer of glutathione S-transferases (GSTs) and other cytoprotective enzymes. A broccoli sprout-derived beverage providing daily doses of 600 μmol glucoraphanin and 40 μmol sulforaphane was evaluated for magnitude and duration of pharmacodynamic action in a 12-week randomized clinical trial. Two hundred and ninety-one study participants were recruited from the rural He-He Township, Qidong, in the Yangtze River delta region of China, an area characterized by exposures to substantial levels of airborne pollutants. Exposure to air pollution has been associated with lung cancer and cardiopulmonary diseases. Urinary excretion of the mercapturic acids of the pollutants, benzene, acrolein, and crotonaldehyde, were measured before and during the intervention using liquid chromatography tandem mass spectrometry. Rapid and sustained, statistically significant (p ≤ 0.01) increases in the levels of excretion of the glutathione-derived conjugates of benzene (61%), acrolein (23%), but not crotonaldehyde were found in those receiving broccoli sprout beverage compared with placebo. Excretion of the benzene-derived mercapturic acid was higher in participants who were GSTT1-positive compared to the null genotype, irrespective of study arm assignment. Measures of sulforaphane metabolites in urine indicated that bioavailability did not decline over the 12-week daily dosing period. Thus, intervention with broccoli sprouts enhances the detoxication of some airborne pollutants and may provide a frugal means to attenuate their associated long-term health risks.
PMCID: PMC4125483  PMID: 24913818
Air pollution; broccoli; sulforaphane; benzene; chemoprevention
2.  Dynamic Electrochemical Membranes for Continuous Affinity Protein Separation 
Advanced functional materials  2014;24(27):4317-4323.
A membrane system with nm-scale thick electrodes is able to selectively bind genetically modified proteins and pump them across the membrane with sequential voltage pulses. The electrodes are located at the first 20nm of pore entrances to specifically capture targeted proteins and block non-specific protein transport through the pores during the binding cycle. During the release cycle, concentration of imidazole is controlled to keep the pore blocked while releasing proteins at the bottom edge of the electrode. A separation factor for GFP:BSA of 16 was achieved with observed GFP electrophoretic mobility of 2.54×10-6cm2v-1S-1. This non-optimized system with a membrane area of 0.75 cm2 has the same throughput as 1ml of commercially available chromatography columns showing viability as a continuous process. This system will enable continuous separation of expressed proteins directly from fermentation broths dramatically simplifying the separation process as well as reducing biopharmaceutical production costs.
PMCID: PMC4220452  PMID: 25383076
Nanoporous electrode; continuous separation; electrophoresis; dynamic membrane; Biomimetics
3.  Management of iatrogenic colorectal perforation: From surgery to endoscopy 
Iatrogenic colon perforation is one the most pernicious complications for patients undergoing endoscopic screening or therapy. It is a serious but rare complication of colonoscopy. However, with the expansion of the indications for endoscopic therapies for gastrointestinal diseases, the frequency of colorectal perforation has increased. The management of iatrogenic colorectal perforation is still a challenge for many endoscopists. The methods for treating this complication vary, including conservative treatment, surgical treatment, laparoscopy and endoscopy. In this review, we highlight the etiology, recognition and treatment of colorectal iatrogenic perforation. Specifically, we shed light on the endoscopic management of this rare complication.
PMCID: PMC4501973  PMID: 26191347
Iatrogenic perforation; Colorectum; Surgery; Laparoscopy; Endoscopy
4.  Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome 
Neuropsychopharmacology  2014;39(8):1955-1967.
Fragile X syndrome, caused by the mutation of the Fmr1 gene, is characterized by deficits of attention and learning ability. In the hippocampus of Fmr1 knockout mice (KO), long-term depression is enhanced whereas long-term potentiation (LTP) including late-phase LTP (L-LTP) is reduced or unaffected. Here we examined L-LTP in the anterior cingulate cortex (ACC) in Fmr1 KO mice by using a 64-electrode array recording system. In wild-type mice, theta-burst stimulation induced L-LTP that does not occur in all active electrodes/channels within the cingulate circuit and is typically detected in ∼75% of active channels. Furthermore, L-LTP recruited new responses from previous inactive channels. Both L-LTP and the recruitment of inactive responses were blocked in the ACC slices of Fmr1 KO mice. Bath application of metabotropic glutamate receptor 5 (mGluR5) antagonist or glycogen synthase kinase-3 (GSK3) inhibitors rescued the L-LTP and network recruitment. Our results demonstrate that loss of FMRP will greatly impair L-LTP and recruitment of cortical network in the ACC that can be rescued by pharmacological inhibition of mGluR5 or GSK3. This study is the first report of the network properties of L-LTP in the ACC, and provides basic mechanisms for future treatment of cortex-related cognitive defects in fragile X patients.
PMCID: PMC4059905  PMID: 24553731
5.  Seropositivity for Avian Influenza H6 Virus among Humans, China 
Emerging Infectious Diseases  2015;21(7):1267-1269.
PMCID: PMC4480397  PMID: 26079934
avian influenza; H6N2; viruses; occupationally exposed populations; human infection; agricultural workers' diseases; poultry; China; seropositivity
6.  Association of Serum Gamma-Glutamyl Transferase and Ferritin with the Metabolic Syndrome 
Journal of Diabetes Research  2015;2015:741731.
Aim. To investigate the relationship among GGT, ferritin, and the risk of metabolic syndrome. Methods. A total of 1024 eligible individuals of the Chinese Yi ethnic group were enrolled in this cross-sectional study. The presence of metabolic syndrome was determined using the revised NCEP-ATP III and CDS criteria. Odds ratios for the metabolic syndrome and its components for different groups based on the levels of GGT and ferritin were calculated using multiple logistic regressions. Results. Serum GGT and ferritin concentrations were significantly higher in subjects with metabolic syndrome compared to those without metabolic syndrome in both genders (p < 0.05). Serum GGT was positively correlated with ferritin (p < 0.05). The risk of the metabolic syndrome was significantly higher in female subjects who had elevated GGT and ferritin levels (p < 0.05). Furthermore, the increased risk of having each of the metabolic syndrome components (overweight or obesity, hypertriglyceridemia, hypertension, hyperglycemia, and insulin resistance) was also observed in those subjects after adjustment for possible confounders (p < 0.05). Conclusions. These data indicate that GGT and ferritin synergistically correlate with the risk of the metabolic syndrome, suggesting that they could potentially be used as predictive biomarkers for the metabolic syndrome.
PMCID: PMC4491402  PMID: 26185768
7.  Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead 
Goodson, William H. | Lowe, Leroy | Carpenter, David O. | Gilbertson, Michael | Manaf Ali, Abdul | Lopez de Cerain Salsamendi, Adela | Lasfar, Ahmed | Carnero, Amancio | Azqueta, Amaya | Amedei, Amedeo | Charles, Amelia K. | Collins, Andrew R. | Ward, Andrew | Salzberg, Anna C. | Colacci, Annamaria | Olsen, Ann-Karin | Berg, Arthur | Barclay, Barry J. | Zhou, Binhua P. | Blanco-Aparicio, Carmen | Baglole, Carolyn J. | Dong, Chenfang | Mondello, Chiara | Hsu, Chia-Wen | Naus, Christian C. | Yedjou, Clement | Curran, Colleen S. | Laird, Dale W. | Koch, Daniel C. | Carlin, Danielle J. | Felsher, Dean W. | Roy, Debasish | Brown, Dustin G. | Ratovitski, Edward | Ryan, Elizabeth P. | Corsini, Emanuela | Rojas, Emilio | Moon, Eun-Yi | Laconi, Ezio | Marongiu, Fabio | Al-Mulla, Fahd | Chiaradonna, Ferdinando | Darroudi, Firouz | Martin, Francis L. | Van Schooten, Frederik J. | Goldberg, Gary S. | Wagemaker, Gerard | Nangami, Gladys | Calaf, Gloria M. | Williams, Graeme | Wolf, Gregory T. | Koppen, Gudrun | Brunborg, Gunnar | Kim Lyerly, H. | Krishnan, Harini | Ab Hamid, Hasiah | Yasaei, Hemad | Sone, Hideko | Kondoh, Hiroshi | Salem, Hosni K. | Hsu, Hsue-Yin | Park, Hyun Ho | Koturbash, Igor | Miousse, Isabelle R. | Scovassi, A.Ivana | Klaunig, James E. | Vondráček, Jan | Raju, Jayadev | Roman, Jesse | Wise, John Pierce | Whitfield, Jonathan R. | Woodrick, Jordan | Christopher, Joseph A. | Ochieng, Josiah | Martinez-Leal, Juan Fernando | Weisz, Judith | Kravchenko, Julia | Sun, Jun | Prudhomme, Kalan R. | Narayanan, Kannan Badri | Cohen-Solal, Karine A. | Moorwood, Kim | Gonzalez, Laetitia | Soucek, Laura | Jian, Le | D’Abronzo, Leandro S. | Lin, Liang-Tzung | Li, Lin | Gulliver, Linda | McCawley, Lisa J. | Memeo, Lorenzo | Vermeulen, Louis | Leyns, Luc | Zhang, Luoping | Valverde, Mahara | Khatami, Mahin | Romano, Maria Fiammetta | Chapellier, Marion | Williams, Marc A. | Wade, Mark | Manjili, Masoud H. | Lleonart, Matilde | Xia, Menghang | Gonzalez, Michael J. | Karamouzis, Michalis V. | Kirsch-Volders, Micheline | Vaccari, Monica | Kuemmerle, Nancy B. | Singh, Neetu | Cruickshanks, Nichola | Kleinstreuer, Nicole | van Larebeke, Nik | Ahmed, Nuzhat | Ogunkua, Olugbemiga | Krishnakumar, P.K. | Vadgama, Pankaj | Marignani, Paola A. | Ghosh, Paramita M. | Ostrosky-Wegman, Patricia | Thompson, Patricia | Dent, Paul | Heneberg, Petr | Darbre, Philippa | Sing Leung, Po | Nangia-Makker, Pratima | Cheng, Qiang (Shawn) | Robey, R.Brooks | Al-Temaimi, Rabeah | Roy, Rabindra | Andrade-Vieira, Rafaela | Sinha, Ranjeet K. | Mehta, Rekha | Vento, Renza | Di Fiore, Riccardo | Ponce-Cusi, Richard | Dornetshuber-Fleiss, Rita | Nahta, Rita | Castellino, Robert C. | Palorini, Roberta | Abd Hamid, Roslida | Langie, Sabine A.S. | Eltom, Sakina | Brooks, Samira A. | Ryeom, Sandra | Wise, Sandra S. | Bay, Sarah N. | Harris, Shelley A. | Papagerakis, Silvana | Romano, Simona | Pavanello, Sofia | Eriksson, Staffan | Forte, Stefano | Casey, Stephanie C. | Luanpitpong, Sudjit | Lee, Tae-Jin | Otsuki, Takemi | Chen, Tao | Massfelder, Thierry | Sanderson, Thomas | Guarnieri, Tiziana | Hultman, Tove | Dormoy, Valérian | Odero-Marah, Valerie | Sabbisetti, Venkata | Maguer-Satta, Veronique | Rathmell, W.Kimryn | Engström, Wilhelm | Decker, William K. | Bisson, William H. | Rojanasakul, Yon | Luqmani, Yunus | Chen, Zhenbang | Hu, Zhiwei
Carcinogenesis  2015;36(Suppl 1):S254-S296.
Low-dose exposures to common environmental chemicals that are deemed safe individually may be combining to instigate carcinogenesis, thereby contributing to the incidence of cancer. This risk may be overlooked by current regulatory practices and needs to be vigorously investigated.
Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
PMCID: PMC4480130  PMID: 26106142
8.  Elucidating the Reaction Pathways in the Synthesis of Organolead Trihalide Perovskite for High-Performance Solar Cells 
Scientific Reports  2015;5:10557.
The past two years have witnessed unprecedentedly rapid development of organic–inorganic halide perovskite–based solar cells. The solution–processability and high efficiency make this technology extraordinarily attractive. The intensive investigations have accumulated rich experiences in the perovskite fabrication; while the mechanism of the chemical synthesis still remains unresolved. Here, we set up the chemical equation of the synthesis and elucidate the reactions from both thermodynamic and kinetic perspectives. Our study shows that gaseous products thermodynamically favour the reaction, while the activation energy and “collision” probability synergistically determine the reaction rate. These understandings enable us to finely tune the crystal size for high-quality perovskite film, leading to a record fill factor among similar device structures in the literature. This investigation provides a general strategy to explore the mechanism of perovskite synthesis and benefits the fabrication of high–efficiency perovskite photoactive layer.
PMCID: PMC4447066  PMID: 26020476
9.  Native Contact Density and Nonnative Hydrophobic Effects in the Folding of Bacterial Immunity Proteins 
PLoS Computational Biology  2015;11(5):e1004260.
The bacterial colicin-immunity proteins Im7 and Im9 fold by different mechanisms. Experimentally, at pH 7.0 and 10°C, Im7 folds in a three-state manner via an intermediate but Im9 folding is two-state-like. Accordingly, Im7 exhibits a chevron rollover, whereas the chevron arm for Im9 folding is linear. Here we address the biophysical basis of their different behaviors by using native-centric models with and without additional transferrable, sequence-dependent energies. The Im7 chevron rollover is not captured by either a pure native-centric model or a model augmented by nonnative hydrophobic interactions with a uniform strength irrespective of residue type. By contrast, a more realistic nonnative interaction scheme that accounts for the difference in hydrophobicity among residues leads simultaneously to a chevron rollover for Im7 and an essentially linear folding chevron arm for Im9. Hydrophobic residues identified by published experiments to be involved in nonnative interactions during Im7 folding are found to participate in the strongest nonnative contacts in this model. Thus our observations support the experimental perspective that the Im7 folding intermediate is largely underpinned by nonnative interactions involving large hydrophobics. Our simulation suggests further that nonnative effects in Im7 are facilitated by a lower local native contact density relative to that of Im9. In a one-dimensional diffusion picture of Im7 folding with a coordinate- and stability-dependent diffusion coefficient, a significant chevron rollover is consistent with a diffusion coefficient that depends strongly on native stability at the conformational position of the folding intermediate.
Author Summary
In order to fold correctly, a globular protein must avoid being trapped in wrong, i.e., nonnative conformations. Thus a biophysical account of how attractive nonnative interactions are bypassed by some amino acid sequences but not others is key to deciphering protein structure and function. We examine two closely related bacterial immunity proteins, Im7 and Im9, that are experimentally known to fold very differently: Whereas Im9 folds directly, Im7 folds through a mispacked conformational intermediate. A simple model we developed accounts for their intriguingly different folding kinetics in terms of a balance between the density of native-promoting contacts and the hydrophobicity of local amino acid sequences. This emergent principle is extensible to other biomolecular recognition processes.
PMCID: PMC4446218  PMID: 26016652
10.  Size-Dependent MRI Relaxivity and Dual Imaging with Eu0.2Gd0.8PO4·H2O Nanoparticles 
Langmuir  2014;30(20):5873-5879.
Three different sizes of Eu0.2Gd0.8PO4·H2O nanoparticles have been prepared to investigate the particle size influence on water proton relaxivity. Longitudinal relaxivity (r1) values increase for smaller particles, reaching as high as r1 = 6.13 mM–1 s–1 for a sample of 40 ± 4 nm particles, which, with a ratio of transverse/longitudinal relaxivity, r2/r1 = 1.27, are shown to be effective positive contrast agents. The correlation between relaxivity and the surface-to-volume ratio implies that access to surface Gd3+ sites is the principal factor affecting relaxivity. On the other hand, although ionic molar relaxivity decreases for larger particles, the relaxivity per particle can be significantly greater. Gadolinium-based nanoparticles doped with fluorescent lanthanide elements have attracted attention for their dual-imaging abilities, combining magnetic resonance imaging (MRI) and fluorescence imaging agents. In both in vitro experiments with HeLa cells and in vivo experiments with C. elegans, strong red fluorescence is observed from Eu0.2Gd0.8PO4·H2O with high resolution, demonstrating the parallel use of the particles as fluorescence imaging agents.
PMCID: PMC4039354  PMID: 24825171
11.  Timing and Spatial Distribution of Loess in Xinjiang, NW China 
PLoS ONE  2015;10(5):e0125492.
Central Asia is one of the most significant loess regions on Earth, with an important role in understanding Quaternary climate and environmental change. However, in contrast to the widely investigated loess deposits in the Chinese Loess Plateau, the Central Asian loess–paleosol sequences are still insufficiently known and poorly understood. Through field investigation and review of the previous literature, the authors have investigated the distribution, thickness and age of the Xinjiang loess, and analyzed factors that control these parameters in the Xinjiang in northwest China, Central Asia. The loess sediments cover river terraces, low uplands, the margins of deserts and the slopes of the Tianshan Mountains and Kunlun Mountains and are also present in the Ili Basin. The thickness of the Xinjiang loess deposits varies from several meters to 670 m. The variation trend of the sand fraction (>63 μm) grain-size contour can indicate the local major wind directions, so we conclude that the NW and NE winds are the main wind directions in the North and South Xinjiang, and the westerly wind mainly transport dust into the Ili basin. We consider persistent drying, adequate regional wind energy and well-developed river terraces to be the main factors controlling the distribution, thickness and formation age of the Xinjiang loess. The well-outcropped loess sections have mainly developed since the middle Pleistocene in Xinjiang, reflecting the appearance of the persistent drying and the present air circulation system. However, the oldest loess deposits are as old as the beginning of the Pliocene in the Tarim Basin, which suggests that earlier aridification occurred in the Tarim Basin rather than in the Ili Basin and the Junggar Basin.
PMCID: PMC4430276  PMID: 25970617
12.  Tubulin structure-based drug design for the development of novel 4β-sulfur-substituted podophyllum tubulin inhibitors with anti-tumor activity 
Scientific Reports  2015;5:10172.
The well-characterized anti-tubulin agent, podophyllotoxin (PTOX), with the 4′-position methoxyl group, targets the colchicines domain located between α- and β-tubulin. Two guanosine triphosphate (GTP) analogs of the tubulin-binding region were synthesized from PTOX, where a hydroxyl group was substituted with a carbon-sulfur bond. These compounds, 4-MP-PTOX and 4-TG-PTOX, reduce the dosage and greatly improve the therapeutic effect for microtubule damage in cancer cells. Here we characterize the anti-tubulin properties of these compounds. We found the stronger inhibition of tubulin polymerization (the concentration of 50% growth inhibition, GI50 < 2 μM) for compounds 4-TG-PTOX and 4-MP-PTOX, which were better than that of PTOX or colchicine. The cytotoxicity of two designed compounds on tumor cells was also significantly enhanced by comparing to those of PTOX and colchicines. The ΔH value of 4-MP-PTOX and 4-TG-PTOX binding to tubulin by isothermal titration calorimetry (ITC) was found to be −7.4 and −5.3 kcal·mol−1, respectively. The wide range of enthalpy values across the series may reflect entropy/enthalpy compensation effects. Fragments 6-mercaptopurine (MP) and 6-thioguanine (TG) likely enhance the affinity of 4-MP-PTOX and 4-TG-PTOX binding to tubulin by increasing the number of binding sites. The correctness of rational drug design was strictly demonstrated by a bioactivity test.
PMCID: PMC4426677  PMID: 25959922
13.  Integrated microRNA, mRNA, and protein expression profiling reveals microRNA regulatory networks in rat kidney treated with a carcinogenic dose of aristolochic acid 
BMC Genomics  2015;16(1):365.
Aristolochic Acid (AA), a natural component of Aristolochia plants that is found in a variety of herbal remedies and health supplements, is classified as a Group 1 carcinogen by the International Agency for Research on Cancer. Given that microRNAs (miRNAs) are involved in cancer initiation and progression and their role remains unknown in AA-induced carcinogenesis, we examined genome-wide AA-induced dysregulation of miRNAs as well as the regulation of miRNAs on their target gene expression in rat kidney.
We treated rats with 10 mg/kg AA and vehicle control for 12 weeks and eight kidney samples (4 for the treatment and 4 for the control) were used for examining miRNA and mRNA expression by deep sequencing, and protein expression by proteomics. AA treatment resulted in significant differential expression of miRNAs, mRNAs and proteins as measured by both principal component analysis (PCA) and hierarchical clustering analysis (HCA). Specially, 63 miRNAs (adjusted p value < 0.05 and fold change > 1.5), 6,794 mRNAs (adjusted p value < 0.05 and fold change > 2.0), and 800 proteins (fold change > 2.0) were significantly altered by AA treatment. The expression of 6 selected miRNAs was validated by quantitative real-time PCR analysis. Ingenuity Pathways Analysis (IPA) showed that cancer is the top network and disease associated with those dysregulated miRNAs. To further investigate the influence of miRNAs on kidney mRNA and protein expression, we combined proteomic and transcriptomic data in conjunction with miRNA target selection as confirmed and reported in miRTarBase. In addition to translational repression and transcriptional destabilization, we also found that miRNAs and their target genes were expressed in the same direction at levels of transcription (169) or translation (227). Furthermore, we identified that up-regulation of 13 oncogenic miRNAs was associated with translational activation of 45 out of 54 cancer-related targets.
Our findings suggest that dysregulated miRNA expression plays an important role in AA-induced carcinogenesis in rat kidney, and that the integrated approach of multiple profiling provides a new insight into a post-transcriptional regulation of miRNAs on their target repression and activation in a genome-wide scale.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1516-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4456708  PMID: 25952319
Aristolochic acid; Carcinogenesis; Kidney tumor; microRNA; Proteomics; Deep-Sequencing; RNA array; Target prediction; Rat
14.  Analgesic effects of lappaconitine in leukemia bone pain in a mouse model 
PeerJ  2015;3:e936.
Bone pain is a common and severe symptom in cancer patients. The present study employed a mouse model of leukemia bone pain by injection K562 cells into tibia of mouse to evaluate the analgesic effects of lappacontine. Our results showed that the lappaconitine treatment at day 15, 17 and 19 could effectively reduce the spontaneous pain scoring values, restore reduced degree in the inclined-plate test induced by injection of K562 cells, as well as restore paw mechanical withdrawal threshold and paw withdrawal thermal latency induced by injection of K562 cells to the normal levels. Additionally, the molecular mechanisms of lappaconitine’s analgesic effects may be related to affect the expression levels of endogenous opioid system genes (POMC, PENK and MOR), as well as apoptosis-related genes (Xiap, Smac, Bim, NF-κB and p53). Our present results indicated that lappaconitine may become a new analgesic agent for leukemia bone pain management.
PMCID: PMC4435501  PMID: 26019998
Lappaconitine; Leukemia; Bone pain; Analgesia
15.  MicroRNA-31 contributes to colorectal cancer development by targeting factor inhibiting HIF-1α (FIH-1) 
Cancer Biology & Therapy  2014;15(5):516-523.
The molecular mechanisms underlying colorectal cancer (CRC) tumorigenesis remain incompletely understood, partially contributing to the mortality of CRC. Advances in identification of novel mechanisms are therefore in an urgent need to fill the gap of our knowledge in CRC development. Here, we performed both in vitro and in vivo experiments along with in silico analysis to identify a new regulatory circuit that stimulated CRC tumorigenesis. In this report, we, for the first time, analyzed the correlation of FIH-1 level with clinicopathological features of CRC. The finding that FIH-1 was not only significantly decreased in tumor tissue as compared with the adjacent normal tissue but also was significantly correlated with tumor T stage status, indicated the role of FIH-1 as a tumor suppressor in CRC development. Moreover, we found the expression of miR-31, a short non-coding RNA which played a critical role in CRC development, was negatively correlated with FIH-1 expression in CRC samples and cell lines. Together with the result from luciferase report assay, it was demonstrated that miR-31 could directly regulate FIH-1 expression in CRC. This miR-31/FIH-1 nexus was further shown to control cell proliferation, migration and invasion in vitro and to control tumor growth in vivo. Additionally, correlation of the miR-31 expression with clinicopathologic features in CRC samples was examined in support of the driving role of newly identified miR-31/FIH-1 nexus in CRC tumorigenesis. These findings highlight the critical role of miR-31/FIH-1 nexus in CRC and reveal the contribution of miR-31 to CRC development by targeting FIH-1.
PMCID: PMC4026074  PMID: 24521875
FIH-1; miRNA-31; regulatory circuit; colorectal cancer; tumorigenesis
16.  High expression of AFAP1-AS1 is associated with poor survival and short-term recurrence in pancreatic ductal adenocarcinoma 
Pancreatic ductal adenocarcinoma (PDAC) is still a lethal malignancy. Long noncoding RNAs (lncRNAs) have been shown to play a critical role in cancer development and progression. Here we identified overexpression of the lncRNA AFAP1-AS1 in PDAC patients and evaluated its prognostic and functional relevance.
The global lncRNA expression profile in PDAC was measured by lncRNA microarray. Expression of AFAP1-AS1 was evaluated by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) in 90 PDAC tissue samples and adjacent normal tissues. The impact of AFAP1-AS1 expression on cell proliferation, migration, and invasion were evaluated in vitro using knockdown and ectopic expression strategies.
Microarray analysis revealed that up-regulation of AFAP1-AS1 expression in PDAC tissues compared with normal adjacent tissues, which was confirmed by RT-qPCR in 69/90 cases (76.7%). Its overexpression was associated with lymph node metastasis, perineural invasion, and poor survival. When using AFAP1-AS1 as a prognostic marker, the areas under ROC curves were 0.8669 and 0.9370 for predicting tumor progression within 6 months and 1 year, respectively. In vitro functional experiments involving knockdown of AFAP1-AS1 resulted in attenuated PDAC cell proliferation, migration, and invasion. Ectopic expression of AFAP1-AS1 promoted cell proliferation, migration, and invasion.
AFAP1-AS1 is a potential novel prognostic marker to predict the clinical outcome of PDAC patients after surgery and may be a rational target for therapy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0490-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4458022  PMID: 25925763
Pancreatic ductal adenocarcinoma; AFAP1-AS1; Long noncoding RNAs
17.  An automatically contamination-avoiding technique for intracorporeal esophagojejunostomy using a transorally inserted anvil during laparoscopic total gastrectomy for gastric cancer 
Intracorporeal Roux-en-Y esophagojejunostomy during laparoscopic total gastrectomy for gastric cancer remains a challenging manipulation due to the uncontrolled direction of the jejunal side or unintended embedded tissues, although several methods have been introduced. In this study, we simplified the procedure based on a surgical string fixing technique using a transorally inserted anvil (OrVil™; Covidien Ltd., Mansfield, MA, USA).
From March 2012 to September 2013, 14 consecutive patients underwent simplified intracorporeal Roux-en-Y esophagojejunostomy using OrVil™ during laparoscopic total gastrectomy for gastric cancer at our hospital. Clinicopathologic characteristics and surgical outcomes of these patients were retrospectively analyzed.
All of the procedures were successful completed with no complication or conversion to open surgery. The mean overall operative time was 193.8 ± 41.8 min, whereas the mean reconstruction time was 32.6 ± 4.6 min. The mean estimated blood loss was 105.7 ± 65.4 ml. The mean diameter of anastomosis measured by upper gastrointestinal contrast X-ray test at 1 month after operation was 2.3 cm. During a median follow-up period of 12 months, neither local recurrence nor anastomosis-related morbidity was observed.
Our preliminary results suggested that this automatically contamination-avoiding technique based on a surgical-string-fixing strategy using OrVil™ during laparoscopic total gastrectomy for gastric cancer might be feasible and safe and provide a simple solution for intracorporeal Roux-en-Y esophagojejunostomy.
PMCID: PMC4411702  PMID: 25926082
Gastric cancer; Laparoscopy; Esophagojejunostomy; Gastrectomy
18.  Hydroxysafflor yellow A inhibits lipopolysaccharide-induced proliferation and migration of vascular smooth muscle cells via Toll-like receptor-4 pathway 
Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) is closely associated with early vascular hyperplasic lesions. Toll-like receptor (TLR)-4 is a pathogen pattern recognition receptor expressed on VSMCs, and can be activated by lipopolysaccharide. Activated TLR-4 plays a promoting role in VSMCs proliferation and migration through the downstream signaling pathways including Rac1/Akt. Hydroxysafflor yellow A (HSYA) is the main component of the safflower yellow pigments, which has long been used for the treatment of cardiovascular diseases in traditional Chinese medicine. However, the effect of HSYA on VSMC proliferation and migration remains unknown. In the present study, we showed that HYSA could inhibit LPS-induced VSMCs proliferation and migration, accompanied by the downregulated levels of several key pro-inflammatory cytokines, including TNF-α, IL-6, and IL-8. We further showed that HYSA inhibited LPS-induced upregulation of TLR-4 expression as well as the activation of Rac1/Akt pathway, suggesting that HSYA inhibits LPS-induced VSMCs proliferation and migration, partly at least, via inhibition of TLR-4/Rac1/Akt pathway. Accordingly, HSYA may be used as a promising agent for prevention and treatment of vascular hyperplasic disorders.
PMCID: PMC4483943  PMID: 26131104
Hydroxysafflor yellow A; vascular smooth muscle cell; lipopolysaccharide; proliferation; migration
19.  Knowledge, Attitudes and Practice of Desalinated Water among Professionals in Health and Water Departments in Shengsi, China: A Qualitative Study 
PLoS ONE  2015;10(4):e0118360.
Desalination has been considered as an essential way to solve water stress all over the world. Most of previous studies focused on its environmental impacts, energy consumption and desalination technologies rather than human health. However, the safety of desalinated water remains unclear. This study was undertaken to investigate the knowledge, attitude and practice (KAP) of the residents in an island county in eastern China to desalinated water. Seventeen people working in medical and water industries were recruited, and focus group discussion and in-depth interview were conducted among them. Our results showed that the majority of people interviewed knew the definition and local supply pattern of desalinated water, while some of them showed some concern about the safety and nutrition of desalinated water. Current drinking water standard has no specific item for desalination, so we strongly suggest issuing a standard for desalinated water.
PMCID: PMC4395245  PMID: 25874459
20.  Screening for frailty phenotype with objectively-measured physical activity in a west Japanese suburban community: evidence from the Sasaguri Genkimon Study 
BMC Geriatrics  2015;15:36.
The low physical activity domain of the frailty phenotype has been assessed with various self-reported questionnaires, which are prone to possible recall bias and a lack of diagnostic accuracy. The primary purpose of this study was to define the low physical activity domain of the frailty phenotype using accelerometer-based measurement and to evaluate the internal construct validity among older community-dwellers. Secondly, we examined potential correlates of frailty in this population.
We conducted a cross-sectional study of 1,527 community-dwelling older men and women aged 65 and over. Data were drawn from the baseline survey of the Sasaguri Genkimon Study, a cohort study carried out in a west Japanese suburban community. Frailty phenotypes were defined by the following five components: unintentional weight loss, low grip strength, exhaustion, slow gait speed, and low physical activity. Of these criteria, physical activity was objectively measured with a tri-axial accelerometer. To confirm our measure’s internal validity, we performed a latent class analysis (LCA) to assess whether the five components could aggregate statistically into a syndrome. We examined the correlates of frailty using multiple stepwise logistic regression models.
The estimated prevalence of frailty was 9.3% (95% confidence intervals, CI, 8.4-11.2); 43.9% were pre-frail (95% CI, 41.5-46.4). The percentage of low physical activity was 19.5%. Objectively-assessed physical activity and other components aggregated statistically into a syndrome. Overall, increased age, poorer self-perceived health, depressive and anxiety symptoms, not consuming alcohol, no engagement in social activities, and cognitive impairment were associated with increased odds of frailty status, independent of co-morbidities.
This study confirmed the internal construct validity of the frailty phenotype that defined the low energy expenditure domain with the objective measurement of physical activity. Accelerometry may potentially standardize the measurement of low physical activity and improve the diagnostic accuracy of the frailty phenotype criteria in primary care setting. The potential role of factors associated with frailty merits further studies to explore their clinical application.
Electronic supplementary material
The online version of this article (doi:10.1186/s12877-015-0037-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4391124  PMID: 25887474
Frail older people; Aging; Prevalence; Accelerometer; Community health
21.  Enhanced Antimalarial Activity by a Novel Artemether-Lumefantrine Lipid Emulsion for Parenteral Administration 
Antimicrobial Agents and Chemotherapy  2014;58(10):5658-5665.
Artemether and lumefantrine (also known as benflumetol) are difficult to formulate for parenteral administration because of their low aqueous solubility. Cremophor EL as an emulsion excipient has been shown to cause serious side effects. This study reports a method of preparation and the therapeutic efficacies of novel lipid emulsion (LE) delivery systems with artemether, lumefantrine, or artemether in combination with lumefantrine, for parenteral administration. Their physical and chemical stabilities were also evaluated. Furthermore, the in vivo antimalarial activities of the lipid emulsions developed were tested in Plasmodium berghei-infected mice. Artemether, lumefantrine, or artemether in combination with lumefantrine was encapsulated in an oil phase, and the in vivo performance was assessed by comparison with artesunate for injection. It was found that the lumefantrine lipid emulsion (LUM-LE) and artemether-lumefantrine lipid emulsion (ARM-LUM-LE-3) (1:6) began to decrease the parasitemia levels after only 3 days, and the parasitemia inhibition was 90% at doses of 0.32 and 0.27 mg/kg, respectively, with immediate antimalarial effects greater than those of the positive-control group and constant antimalarial effects over 30 days. LUM-LE and ARM-LUM-LE-3 demonstrated the best performance in terms of chemical and physical stabilities and antiplasmodial efficacy, with a mean particle size of 150 nm, and they have many favorable properties for parenteral administration, such as biocompatibility, physical stability, and ease of preparation.
PMCID: PMC4187974  PMID: 24982079
22.  Selection of Reference Genes for MicroRNA Quantitative Expression Analysis in Chinese Perch, Siniperca chuatsi 
Real-time quantitative reverse transcription PCR (RT-qPCR) is one of the most effective and sensitive techniques in gene expression assay, for which selection of reference genes is a prerequisite. In teleost species, such as Chinese perch, the expression profiling of miRNAs as reference genes for RT-qPCR has not been intensively studied. In the present study, the expression profiles of six miRNAs (miR-101a, miR-146a, miR-22a, miR-23a, miR-26a and let-7a) and one small nuclear RNA (U6) were assayed with RT-qPCR in different adult tissues, developmental stages and growth conditions of Chinese perch, Siniperca chuatsi. The analyses revealed that embryonic developmental stage is an important variability factor in the expression stability of miRNAs. All six miRNAs exhibited better expression consistency than U6 in most of the conditions examined, and therefore, they may be more suitable as a reference gene for miRNA quantification. When different tissues and developmental stages were considered, miR-22a demonstrated the most consistent expression pattern, and the best combination of reference genes was miR-22a and miR-23a. Our study offers useful data for selecting miRNAs as reference genes for RT-qPCR analysis of miRNAs in teleost fishes under different conditions.
PMCID: PMC4425082  PMID: 25874758
miRNA; real-time PCR; reference genes; relative quantification; Siniperca chuatsi
23.  Gold-Coated Fe3O4 Nanoroses with Five Unique Functions for Cancer Cell Targeting, Imaging and Therapy 
Advanced functional materials  2014;24(12):1772-1780.
The development of nanomaterials that combine diagnostic and therapeutic functions within a single nanoplatform is extremely important for molecular medicine. Molecular imaging with simultaneous diagnosis and therapy will provide the multimodality needed for accurate diagnosis and targeted therapy. Here, we demonstrate gold-coated iron oxide (Fe3O4@Au) nanoroses with five distinct functions, which integrate aptamer-based targeting, magnetic resonance imaging (MRI), optical imaging, photothermal therapy and chemotherapy into one single probe. The inner Fe3O4 core functions as an MRI agent, while the photothermal effect is achieved through near-infrared absorption by the gold shell, causing a rapid rise in temperature and also resulting in a facilitated release of the anticancer drug doxorubicin carried by the nanoroses. Where the doxorubicin is released is monitored by its fluorescent. Aptamers immobilized on the surfaces of the nanoroses enable efficient and selective drug delivery, imaging and photothermal effect with high specificity. The five-function-embedded nanoroses show great advantages in multimodality.
PMCID: PMC4266531  PMID: 25530745
nanorose; chemotherapy; photothermal therapy; cancer cells; imaging
24.  Effect of B Vitamin (Folate, B6, and B12) Supplementation on Osteoporotic Fracture and Bone Turnover Markers: A Meta-Analysis 
B vitamins (including folate, B6, and B12) supplementation can effectively and easily modify high plasma homocysteine (Hcy). However, the role of Hcy in the pathogenesis of osteoporotic fracture and bone turnover is still controversial. This meta-analysis aimed to assess the impact of B vitamin supplementation on occurrence of any osteoporotic fracture and bone turnover by pooling the results of previous studies.
Relevant randomized controlled trials (RCTs) were searched in databases. Data integration and analysis were done by using Review Manager 5.3 (the Cochrane Collaboration). The risk ratio (RR) and corresponding 95% confidence intervals (CI) of fracture (intervention vs. control) were estimated. Changes in bone turnover indicators (continuous data), weighted mean difference (WMD), and corresponding 95% (CI) were pooled for estimation.
Based on the results of 4 RCTs, this meta-analysis failed to identify a risk-reducing effect of daily supplementation of B vitamins on osteoporotic fracture in patients with vascular disease and with relatively normal plasma Hcy. In addition, we also did not find any positive effects of B vitamin supplementation on bone turnover.
B vitamin supplementation might not be effective in preventing fracture and improving bone turnover. However, the possible benefits in selective populations, such as populations with very high plasma Hcy and from regions without B vitamin fortification should be explored in the future.
PMCID: PMC4384513  PMID: 25805360
Fractures, Bone; Homocysteine; Meta-Analysis as Topic; Vitamin B Complex
25.  Self-assembled Hybrid Nanoparticles for Targeted Co-delivery of Two Drugs into Cancer Cells 
A therapeutic aptamer-lipid-poly(lactide-co-glycolic acid) hybrid nanoparticle-based drug delivery system was prepared and characterized. The hybrid can co-deliver two different drugs with distinct solubility characteristics and different anticancer mechanisms to target cancer cells with high specificity and efficiency.
PMCID: PMC3973031  PMID: 24516863

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