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1.  Effects of Nitrogen Addition on Nitrogen Resorption in Temperate Shrublands in Northern China 
PLoS ONE  2015;10(6):e0130434.
Nutrient resorption from senescing leaves is a key mechanism of nutrient conservation for plants. The nutrient resorption efficiency is highly dependent on leaf nutrient status, species identity and soil nutrient availability. Nitrogen is a limiting nutrient in most ecosystems, it is widely reported that nitrogen resorption efficiency (NRE) was highly dependent on the soil nitrogen availability and vary with N deposition. The effects of nitrogen deposition on NRE and nitrogen concentration in green and senescing leaves have been well established for forests and grasslands; in contrast, little is known on how plants in shrublands respond to nitrogen deposition across the world. In this study, we conducted a two-year nitrogen addition manipulation experiment to explore the responses of nitrogen concentration in green and senescing leaves, and NRE of seven dominant species, namely, Vitex negundo, Wikstroemia chamaedaphne, Carex rigescens and Cleistogenes chinensis from the Vitex negundo community, and Spirea trilobata, Armeniaca sibirica, V. negundo, C. rigescens and Spodiopogon sibiricus from the Spirea trilobata community, to nitrogen deposition in two typical shrub communities of Mt. Dongling in northern China. Results showed that NRE varied remarkably among different life forms, which was lowest in shrubs, highest in grasses, and intermediate in forbs, implying that shrubs may be most capable of obtaining nitrogen from soil, grasses may conserve more nitrogen by absorption from senescing leaves, whereas forbs may adopt both mechanisms to compete for limited nitrogen supply from the habitats. As the N addition rate increases, N concentration in senescing leaves ([N]s) increased consistent from all species from both communities, that in green leaves ([N]g) increased for all species from the Vitex negundo community, while no significant responses were found for all species from the Spirea trilobata community; NRE decreased for all species except A. sibirica from the Vitex community and W. chamaedaphn from the Spirea community. Given the substantial interspecific variations in nutrient concentration, resorption and the potentially changing community composition, and the increased soil nutrient availability due to fertilization may indirectly impact nutrient cycling in this region.
PMCID: PMC4472726  PMID: 26086737
2.  IL-29/IL-28A suppress HSV-1 infection of human NT2-N neurons 
Journal of neurovirology  2011;17(3):212-219.
The newly identified cytokines, IL-28/IL-29 (also termed type III IFNs), are able to inhibit a number of viruses. Here, we examined the antiviral effects of IL-29/IL-28A against herpes simplex virus type 1 (HSV-1) in human NT2-N neurons and CHP212 neuronal cells. Both IL-29 and IL-28A could efficiently inhibit HSV-1 replication in neuronal cells, as evidenced by the reduced expression of HSV-1 DNA and proteins. This inhibitory effect of IL-29 and IL-28A against HSV-1 could be partially blocked by antibody to IL-10Rβ, one of the key receptors for IL-29 and IL-28A. To explore the underlying antiviral mechanisms employed by IL-29/IL-28A, we showed that IL-29/IL-28A could selectively induce the expression of several Toll-like receptors (TLRs) as well as activate TLR-mediated antiviral pathway, including IFN regulatory factor 7, IFN-α, and the key IFN-α stimulated antiviral genes.
PMCID: PMC4444784  PMID: 21499846
IFN; HSV-1; TLR; Neuron; IRF-7
3.  An extensive DeBakey type IIIb aortic dissection with massive right pleural effusion presenting as abdominal pain and acute anemia: particular case report 
We describe the case of a 79-year-old male presented with sudden onset of abdominal pain and mild breathlessness, and complicated acute progressive anemia with haemoglobin which declined from 120 g/L to 70 g/L within five days. An urgent computed tomography angiography showed acute thoracic aortic dissection, DeBakey type IIIb, a dissecting aneurysm in the proximal descending thoracic aorta starting immediately after the origin of the left subclavian artery and extending distally below the renal arteries with evidence of rupture into the right pleural cavity for massive pleural effusion. Plasma D-dimer, brain natriuretic peptide and C reactive protein level were elevated. Our case showed that D-dimer can be used as a ‘rule-out’ test in patients with suspected aortic dissection. A raised BNP may exert a protective role through anti-inflammatory endothelial actions in the systemic circulation.
PMCID: PMC4460177  PMID: 26089858
Acute aortic dissection; Anemia; D-dimer; The elderly
4.  PSCA s2294008 C>T and rs2976392 G>A polymorphisms contribute to cancer susceptibility: evidence from published studies 
Genes & Cancer  2015;6(5-6):254-264.
PSCA gene plays an important role in cell adhesion, proliferation and survival. Increasing studies have focused on the association of PSCA gene rs2294008 C>T and rs2976392 G>A with cancer risk. However, the conclusions were inconsistent. Therefore, we performed a meta-analysis to elucidate whether there is a true association, or artifact. We systematically searched eligible studies from MEDLINE, EMBASE and CBM database. Odds ratios and 95% confidence intervals were used to evaluate the strength of the association. The final analysis included 32 studies consisting of 30028 cases and 38765 controls for the rs2294008 C>T polymorphism, and 14 studies with 8190 cases and 7176 controls for the rs2976392 G>A polymorphism. Consequently, the PSCA rs2294008 C>T polymorphism was significantly associated with increased overall cancer risk. Further stratifications indicated the increased risk was more pronounced for gastric (diffused type and non-gastric cardia adenocarcinoma) and bladder cancer. A similar association was observed for the rs2976392 G>A polymorphism. This meta-analysis demonstrated that both of the PSCA rs2294008 C>T and rs2976392 G>A polymorphisms are associated with increased cancer risk, especially for gastric cancer and bladder cancer. Further large-scale studies with different ethnicities and subtypes of gastric cancer are required to confirm the results from this meta-analysis.
PMCID: PMC4482246  PMID: 26124924
PSCA; GWAS; polymorphism; susceptibility; meta-analysis
5.  A New and Practical Synthetic Method for the Synthesis of 6-O-Methyl-scutellarein: One Metabolite of Scutellarin in Vivo 
Scutellarin (1) has been used for the treatment of angina pectoris, cerebral infarction and coronary heart disease with a large market share in China. Pharmacokinetic studies on scutellarin showed that scutellarin (1) is readily converted into its metabolites in vivo. In this paper, a new and practical synthetic method for the synthesis of 6-O-methyl-scutellarein (3) (one metabolite of scutellarin in vivo) is reported. The benzyl bromide was firstly used to selectively replace the acetyl group at C-7 in 7, and was then used to protect the hydroxy groups at C-4' in 10, 6-O-methyl-scutellarein (3) is obtained in high yield through these methods.
PMCID: PMC4425036  PMID: 25854429
6-O-methyl-scutellarein; scutellarin; scutellarein; metabolite; synthesis
6.  G-protein-coupled receptors regulate autophagy by ZBTB16-mediated ubiquitination and proteasomal degradation of Atg14L 
eLife  null;4:e06734.
Autophagy is an important intracellular catabolic mechanism involved in the removal of misfolded proteins. Atg14L, the mammalian ortholog of Atg14 in yeast and a critical regulator of autophagy, mediates the production PtdIns3P to initiate the formation of autophagosomes. However, it is not clear how Atg14L is regulated. In this study, we demonstrate that ubiquitination and degradation of Atg14L is controlled by ZBTB16-Cullin3-Roc1 E3 ubiquitin ligase complex. Furthermore, we show that a wide range of G-protein-coupled receptor (GPCR) ligands and agonists regulate the levels of Atg14L through ZBTB16. In addition, we show that the activation of autophagy by pharmacological inhibition of GPCR reduces the accumulation of misfolded proteins and protects against behavior dysfunction in a mouse model of Huntington's disease. Our study demonstrates a common molecular mechanism by which the activation of GPCRs leads to the suppression of autophagy and a pharmacological strategy to activate autophagy in the CNS for the treatment of neurodegenerative diseases.
eLife digest
Proteins need to be folded into specific three-dimensional shapes for them to work properly. However, the folding process does not always work perfectly, and proteins are sometimes misfolded. If left to accumulate, these misfolded proteins can damage cells, and most long-term human neurodegenerative diseases, such as Huntington's disease, Parkinson's disease, and Alzheimer's disease, are caused by the build-up of misfolded proteins in the brain.
Autophagy helps to clean up misfolded proteins (and other damaged cell components) by first wrapping them in membrane vesicles. The membrane-wrapped vesicles—known as autophagosomes—then move to fuse with lysosomes, a different kind of membrane compartment in the cell, which breaks down misfolded proteins and recycles the degradation products. In mammalian cells, a protein called Atg14L is critical in the process of autophagosome formation.
The levels of autophagosome formation are regulated by signals that originate from outside the cell. However, it is not clear if and how cells respond to external signals to control the levels of autophagy by regulating the amount of Atg14L. The G-protein-coupled receptors (GPCRs) are the largest class of membrane proteins that our cells have that are involved in sensing and responding to external signals. The activation of GPCRs has been shown to lead to diverse physiological responses. Zhang et al. now show that when any of a wide range of different signaling molecules bind to the GPCRs, the receptors activate a protein called ZBTB16 that leads to the degradation of Atg14L to inhibit autophagy.
Furthermore, Zhang et al. found that blocking the activity of the GPCRs with a drug can activate autophagy and reduce the amount of misfolded proteins in the cell. In mice that have a version of a gene that causes Huntington's disease, this inhibition also protects against the symptoms of the disease. The challenge now is to identify appropriate GPCRs that can be safely manipulated to control the levels of autophagy in the brain in order to reduce the levels of the misfolded proteins that cause neurodegeneration.
PMCID: PMC4421748  PMID: 25821988
autophagy; ubiquitination; GPCR; mouse
7.  Efficacy of Chinese Eye Exercises on Reducing Accommodative Lag in School-Aged Children: A Randomized Controlled Trial 
PLoS ONE  2015;10(3):e0117552.
To evaluate the efficacy of Chinese eye exercises on reducing accommodative lag in children by a randomized, double-blinded controlled trial.
A total of 190 children aged 10 to 14 years with emmetropia to moderate myopia were included. They were randomly allocated to three groups: standard Chinese eye exercises group (trained for eye exercises by doctors of traditional Chinese medicine); sham point eye exercises group (instructed to massage on non-acupoints); and eyes closed group (asked to close their eyes without massage). Primary outcome was change in accommodative lag immediately after intervention. Secondary outcomes included changes in corrected near and distant visual acuity, and visual discomfort score.
Children in the standard Chinese eye exercises group had significantly greater alleviation of accommodative lag (-0.10D) than those in sham point eye exercises group (-0.03D) and eyes closed group (0.07D) (P = 0.04). The proportion of children with alleviation of accommodative lag was significantly higher in the standard Chinese eye exercises group (54.0%) than in the sham point eye exercises group (32.8%) and the eyes closed group (34.9%) (P = 0.03). No significant differences were found in secondary outcomes.
Chinese eye exercises as performed daily in primary and middle schools in China have statistically but probably clinically insignificant effect in reducing accommodative lag of school-aged children in the short-term. Considering the higher amounts of near work load of Chinese children, the efficacy of eye exercises may be insufficient in preventing myopia progression in the long-term.
Trial Registration NCT01756287
PMCID: PMC4350838  PMID: 25742161
8.  Antagonistic Mechanism of Iturin A and Plipastatin A from Bacillus amyloliquefaciens S76-3 from Wheat Spikes against Fusarium graminearum 
PLoS ONE  2015;10(2):e0116871.
Controlling toxigenic Fusarium graminearum (FG) is challenging. A bacterial strain (S76-3, identified as Bacillus amyloliquefaciens) that was isolated from diseased wheat spikes in the field displayed strong antifungal activity against FG. Reverse-phase high performance liquid chromatography and electrospray ionization mass spectrometry analyses revealed that S76-3 produced three classes of cyclic lipopeptides including iturin, plipastatin and surfactin. Each class consisted of several different molecules. The iturin and plipastatin fractions strongly inhibited FG; the surfactin fractions did not. The most abundant compound that had antagonistic activity from the iturin fraction was iturin A (m/z 1043.35); the most abundant active compound from the plipastatin fraction was plipastatin A (m/z 1463.90). These compounds were analyzed with collision-induced dissociation mass spectrometry. The two purified compounds displayed strong fungicidal activity, completely killing conidial spores at the minimal inhibitory concentration range of 50 µg/ml (iturin A) and 100 µg/ml (plipastatin A). Optical and fluorescence microscopy analyses revealed severe morphological changes in conidia and substantial distortions in FG hyphae treated with iturin A or plipastatin A. Iturin A caused leakage and/or inactivation of FG cellular contents and plipastatin A caused vacuolation. Time-lapse imaging of dynamic antagonistic processes illustrated that iturin A caused distortion and conglobation along hyphae and inhibited branch formation and growth, while plipastatin A caused conglobation in young hyphae and branch tips. Transmission electron microscopy analyses demonstrated that the cell walls of conidia and hyphae of iturin A and plipastatin A treated FG had large gaps and that their plasma membranes were severely damaged and separated from cell walls.
PMCID: PMC4331432  PMID: 25689464
9.  A New PAMPA Model Proposed on the Basis of a Synthetic Phospholipid Membrane 
PLoS ONE  2015;10(2):e0116502.
The purpose of this work was to investigate the synthetic phospholipid dependence of permeability measured by parallel artificial membrane permeability assay (PAMPA) method. Three phospholipids with hydrophobic groups of different lengths and phosphorylcholine as the hydrophilic group were concisely synthesized. Ten model drug molecules were selected because of their distinct human fraction absorbed (%FA) values and various pKa characteristics. In vitro drug permeation experiments were designed to determine the effect of the incubation time (4–20 h), pH gradient (4.6–9.32) and carbon chain length (8, 10, 12) on the drug permeability through the synthetic phospholipid membrane in the PAMPA system. The results showed that intensive and significant synthetic phospholipids dependence of permeability influenced by the length of lipid’s hydrophobic carbon chain. The effective permeability constant (Pe) of each drug increased rapidly with time, then decreased slightly after reaching the maximum; the pH gradient changed the drug permeability according to the pH-partition hypothesis for drugs with diverse pKa values; and longer hydrophobic chains in the synthetic phospholipid membrane improved the drug permeability, as observed for all test drugs at almost all incubation time points. This newly proposed PAMPA model considered the synthetic phospholipid membrane and showed good Pe-%FA correlation for the passive transport of drugs, making it a helpful supplementary method for PAMPA systems.
PMCID: PMC4315410  PMID: 25647086
10.  Combined Cancer Photothermal-Chemotherapy Based on Doxorubicin/Gold Nanorod-Loaded Polymersomes 
Theranostics  2015;5(4):345-356.
Gold nanorods (GNRs) are well known in photothermal therapy based on near-infrared (NIR) laser absorption of the longitudinal plasmon band. Herein, we developed an effective stimulus system -- GNRs and doxorubicin co-loaded polymersomes (P-GNRs-DOX) -- to facilitate co-therapy of photothermal and chemotherapy. DOX can be triggered to release once the polymersomes are corrupted under local hyperthermic condition of GNRs induced by NIR laser irradiation. Also, the cytotoxicity of GNRs caused by the residual cetyltrimethylacmmonium bromide (CTAB) was reduced by shielding the polymersomes. The GNRs-loaded polymersomes (P-GNRs) can be efficiently taken up by the tumor cells. The distribution of the nanomaterial was imaged by IR-820 and quantitatively analyzed by ICP-AES. We studied the ablation of tumor cells in vitro and in vivo, and found that co-therapy offers significantly improved therapeutic efficacy (tumors were eliminated without regrowth.) compared with chemotherapy or photothermal therapy alone. By TUNEL immunofluorescent staining of tumors after NIR laser irradiation, we found that the co-therapy showed more apoptotic tumor cells than the other groups. Furthermore, the toxicity study by pathologic examination of the heart tissues demonstrated a lower systematic toxicity of P-GNRs-DOX than free DOX. Thus, the chemo-photothermal treatment based on polymersomes loaded with DOX and GNRs is a useful strategy for maximizing the therapeutic efficacy and minimizing the dosage-related side effects in the treatment of solid tumors.
PMCID: PMC4329499  PMID: 25699095
polymersomes; gold nanorod; NIR; photothermal therapy; chemotherapy.
11.  The K-segments of wheat dehydrin WZY2 are essential for its protective functions under temperature stress 
Dehydrins (DHNs), group 2 of late embryogenesis abundant (LEA) proteins, are up-regulated in most plants during cold, drought, heat, or salinity stress. All DHNs contain at least one K-segment, which is believed to play a significant role in DHN function by forming an amphipathic helix. In previous studies, wzy2, an YSK2-type DHN gene, was isolated from the Zhengyin 1 cultivar of Triticum aestivum under cold and drought stress treatment conditions. Four WZY2 truncated derivatives were constructed to knock out the K-, Y- or S-segment, which potentially affect the function of the protein. In vivo assays of Escherichia coli viability enhancement, in vitro lactate dehydrogenase (LDH) activity protection and ex vivo protein aggregation prevention assays revealed that WZY2 acted as a protectant and improved stress tolerance during temperature variation. The results also showed that unlike the truncated derivative without K-segments, the derivative containing two K-segments had remarkable effects that were similar to those of full-length WZY2, indicating that the K-segment is the major functional component of WZY2. Moreover, compared with the other segments, the first K-segment might be the most critical contributor to WZY2 functionality. In general, this work highlights the behavior of DHNs in relieving cold stress ex vivo and the contribution of the K-segment to DHN function.
PMCID: PMC4467595  PMID: 26124763
dehydrin; K-segment; protectant; temperature stress; cell viability; lactate dehydrogenase; protein aggregation
12.  Association of Genetic Polymorphisms with Warfarin Dose Requirements in Chinese Patients 
Objective: Warfarin is a commonly used anticoagulant with a narrow therapeutic range and large interindividual differences in dosing requirements. Previously, studies have identified that the interindividual variability was influenced by varieties of factors, including age, body size, vitamin K intake, interacting medications, as well as genetic variants. We aimed to investigate the effect of single-nucleotide polymorphisms (SNPs) on the interindividual variability of warfarin dose requirements in Chinese patients. Methods: The study population consisted of 300 patients with a stable maintenance dose of warfarin. We examined SNPs in eight genes involving in the biotransformation and mode of action of warfarin (i.e., CYP4F2, CYP2C19, APOE, CALU, EPHX1, PROC, CYP2C9, and GGCX) using the SNaPshot assay. Results: The mean daily warfarin dose in patients carrying CYP2C19 rs3814637CC, CYP2C9 rs1057910AA, and GGCX rs699664AA genotype was 3.39, 3.34, and 3.51 mg/day, respectively, which was higher than those carrying CYP2C19 rs3814637TT, CYP2C9 rs1057910CC, and rs699664GG genotype (2.00, 0.81, and 3.09 mg/day, respectively). Conclusion: These findings indicate that individuals carrying the CYP2C19 rs3814637CC or CYP2C9 rs1057910AA or GGCX rs699664AA genotype needed higher warfarin doses in the Chinese population.
PMCID: PMC3865618  PMID: 23941071
13.  CD24 expression predicts poor prognosis for patients with cutaneous malignant melanoma 
Cutaneous malignant melanoma represents the major cause of mortality among skin cancers. Metastasis-associated protein CD24 is a small, heavily glycosylated cell surface protein that is overexpressed in various human malignancies. The present study was designed to determine the roles of CD24 in cutaneous malignant melanoma. The levels of CD24 mRNA and protein in cutaneous malignant melanoma tissues were detected by RT-PCR, Western blot and IHC. In patient samples, the levels of CD24 mRNA and protein were higher in cancer tissues than that in normal tissues. CD24 expression decreased the survival time of the patients with melanoma. Taken together, these results suggest that CD24 may be used as a new drug target for cutaneous malignant melanoma.
PMCID: PMC4276209  PMID: 25550951
CD24; melanoma; prognosis
14.  The Glasgow Prognostic Score Predicts Poor Survival in Cisplatin-Based Treated Patients with Metastatic Nasopharyngeal Carcinoma 
PLoS ONE  2014;9(11):e112581.
Several inflammation-based prognostic scoring systems, including Glasgow Prognostic Score (GPS), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) have been reported to predict survival in many malignancies, whereas their role in metastatic nasopharyngeal carcinoma (NPC) remains unclear. The aim of this study is to evaluate the clinical value of these prognostic scoring systems in a cohort of cisplatin-based treated patients with metastatic NPC.
Two hundred and eleven patients with histologically proven metastatic NPC treated with first-line cisplatin-based chemotherapy were retrospectively evaluated. Demographics, disease-related characteristics and relevant laboratory data before treatment were recorded. GPS, NLR and PLR were calculated as described previously. Response to first-line therapy and survival data were also collected. Survival was analyzed in Cox regressions and stability of the models was examined by bootstrap resampling. The area under the receiver operating characteristics curve (AUC) was calculated to compare the discriminatory ability of each scoring system.
Among the above three inflammation-based prognostic scoring systems, GPS (P<0.001) and NLR (P = 0.019) were independently associated with overall survival, which showed to be stable in a bootstrap resampling study. The GPS consistently showed a higher AUC value at 6-month (0.805), 12-month (0.705), and 24-month (0.705) in comparison with NLR and PLR. Further analysis of the association of GPS with progression-free survival showed GPS was also associated independently with progression-free survival (P<0.001).
Our study demonstrated that the GPS may be of prognostic value in metastatic NPC patients treated with cisplatin-based palliative chemotherapy and facilitate individualized treatment. However a prospective study to validate this prognostic model is still needed.
PMCID: PMC4230992  PMID: 25393117
15.  Expression of serotonin receptors in human lower esophageal sphincter 
Serotonin (5-HT) is a neurotransmitter and vasoactive amine that is involved in the regulation of a large number of physiological functions. The wide variety of 5-HT-mediated functions is due to the existence of different classes of serotonergic receptors in the mammalian gastrointestinal tract and nervous system. The aim of this study was to explore the expression of multiple types of 5-HT receptor (5-HT1AR, 5-HT2AR, 5-HT3AR, 5-HT4R, 5-HT5AR, 5-HT6R and 5-HT7R) in sling and clasp fibers from the human lower esophageal sphincter (LES). Muscle strips of sling and clasp fibers from the LES were obtained from patients undergoing esophagogastrectomy, and circular muscle strips from the esophagus and stomach were used as controls. Reverse transcription-polymerase chain reaction (RT-PCR), quantitative PCR and western blotting were used to investigate the expression of the various 5-HT receptor types. Messenger RNA for all seven 5-HT receptor types was identified in the sling and clasp fibers of the LES. At the mRNA level, the expression levels were highest for 5-HT3AR and 5-HT4R, and lowest for 5-HT5AR, 5-HT6R and 5-HT7R. At the protein level, the expression levels were highest for 5-HT3AR and 5-HT4R, followed by 5-HT1AR and 5-HT2AR; 5-HT7R was also detected at a low level. The expression of 5-HT5AR and 5-HT6R proteins was not confirmed. The results indicate that a variety of 5-HT receptor types can be detected in the human LES and probably contribute to LES function.
PMCID: PMC4247306  PMID: 25452775
serotonin receptors; human; lower esophageal sphincter; sling fibers; clasp fibers
16.  HREM Analysis of Graphite-Encapsulated Metallic Nanoparticles for Possible Medical Applications 
Ultramicroscopy  2013;134:167-174.
High resolution electron microscopy has been applied to study the structure of metallic nanoparticles. These have sparked considerable interest as contrast agents in the field of biological imaging, including in magnetic resonance imaging (MRI) and computed tomography (CT). Here, we describe a method of synthesizing sub-10nm superparamagnetic metal and alloy nanoparticles by reduction of metallic salts. Annealing at 900°C in a methane/hydrogen environment forms a thin graphitic-carbon shell which is expected to improve stability, biocompatibility, and functionalization. Subsequent high resolution electron microscopy verifies graphitization and allows for crystallographic analysis. Most particles consist of single crystals in the phase predicted for the bulk material at the annealing temperature. Electron energy loss spectroscopy, energy dispersive X-ray spectroscopy and lattice constant measurements show large variation in composition for alloy nanoparticles from a single synthesis. The magnetization relaxation time (T2) measurements demonstrate that Fe and AuFe nanoparticles compete with commercially available iron oxide MRI contrast agents. X-ray attenuation measurements of an AuFe alloy nanoparticle solution gave a relative radiodensity of 280 Hounsfield Units, demonstrating promise as a dual-purpose contrast agent in CT and MRI. Long term stability in an atmospheric environment was also tested, with no signs of corrosion or oxidation after several years of storage.
PMCID: PMC3769614  PMID: 23809196
Metallic nanoparticles; HREM; Computed tomography; Magnetic resonance imaging
17.  Prepubertal Exposure to Genistein Alleviates Di-(2-ethylhexyl) Phthalate Induced Testicular Oxidative Stress in Adult Rats 
BioMed Research International  2014;2014:598630.
Di-(2-ethylhexyl) phthalate (DEHP) is the most widely used plastizer in the world and can suppress testosterone production via activation of oxidative stress. Genistein (GEN) is one of the isoflavones ingredients exhibiting weak estrogenic and potentially antioxidative effects. However, study on reproductive effects following prepubertal multiple endocrine disrupters exposure has been lacking. In this study, DEHP and GEN were administrated to prepubertal male Sprague-Dawley rats by gavage from postnatal day 22 (PND22) to PND35 with vehicle control, GEN at 50 mg/kg body weight (bw)/day (G), DEHP at 50, 150, 450 mg/kg bw/day (D50, D150, D450) and their mixture (G + D50, G + D150, G + D450). On PND90, general morphometry (body weight, AGD, organ weight, and organ coefficient), testicular redox state, and testicular histology were studied. Our results indicated that DEHP could significantly decrease sex organs weight, organ coefficient, and testicular antioxidative ability, which largely depended on the dose of DEHP. However, coadministration of GEN could partially alleviate DEHP-induced reproductive injuries via enhancement of testicular antioxidative enzymes activities, which indicates that GEN has protective effects on DEHP-induced male reproductive system damage after prepubertal exposure and GEN may have promising future in its curative antioxidative role for reproductive disorders caused by other environmental endocrine disruptors.
PMCID: PMC4228721  PMID: 25530965
18.  Anticancer drug-loaded multifunctional nanoparticles to enhance the chemotherapeutic efficacy in lung cancer metastasis 
Inhalation of chemotherapeutic drugs directly into the lungs augments the drug exposure to lung cancers. The inhalation of free drugs however results in over exposure and causes severe adverse effect to normal cells. In the present study, epidermal growth factor (EGF)-modified gelatin nanoparticles (EGNP) was developed to administer doxorubicin (DOX) to lung cancers.
The EGNP released DOX in a sustained manner and effectively internalized in EGFR overexpressing A549 and H226 lung cancer cells via a receptor-mediated endocytosis. In vitro cytotoxicity assay showed that EGNP effectively inhibited the growth of A549 and H226 cells in a dose-dependent manner. In vivo biocompatibility study showed that both GNP and EGNP did not activate the inflammatory response and had a low propensity to cause immune response. Additionally, EGNP maintained a high therapeutic concentration in lungs throughout up to 24 h comparing to that of free drug and GNP, implying the effect of ligand-targeted tumor delivery. Mice treated with EGNP remarkably suppressed the tumor growth (~90% tumor inhibition) with 100% mice survival rate. Furthermore, inhalation of EGNP resulted in elevated levels of cleaved caspase-3 (apoptotic marker), while MMP-9 level significantly reduced comparing to that of control group.
Overall, results suggest that EGF surface-modified nanocarriers could be delivered to lungs via inhalation and controlled delivery of drugs in the lungs will greatly improve the therapeutic options in lung cancer therapy. This ligand-targeted nanoparticulate system could be promising for the lung cancer treatment.
PMCID: PMC4190288  PMID: 25266303
Doxorubicin; EGF; EGFR; Gelatin nanoparticles; Lung cancer; Inhalation; Ligand targeting; Controlled release
19.  Mitochondrial Gene Expression Profiles and Metabolic Pathways in the Amygdala Associated with Exaggerated Fear in an Animal Model of PTSD 
The metabolic mechanisms underlying the development of exaggerated fear in post-traumatic stress disorder (PTSD) are not well defined. In the present study, alteration in the expression of genes associated with mitochondrial function in the amygdala of an animal model of PTSD was determined. Amygdala tissue samples were excised from 10 non-stressed control rats and 10 stressed rats, 14 days post-stress treatment. Total RNA was isolated, cDNA was synthesized, and gene expression levels were determined using a cDNA microarray. During the development of the exaggerated fear associated with PTSD, 48 genes were found to be significantly upregulated and 37 were significantly downregulated in the amygdala complex based on stringent criteria (p < 0.01). Ingenuity pathway analysis revealed up- or downregulation in the amygdala complex of four signaling networks – one associated with inflammatory and apoptotic pathways, one with immune mediators and metabolism, one with transcriptional factors, and one with chromatin remodeling. Thus, informatics of a neuronal gene array allowed us to determine the expression profile of mitochondrial genes in the amygdala complex of an animal model of PTSD. The result is a further understanding of the metabolic and neuronal signaling mechanisms associated with delayed and exaggerated fear.
PMCID: PMC4172054  PMID: 25295026
PTSD; amygdala; mitochondrial genes; stress; fear; Bcl-2; microarray
20.  Inhibition of EZH2 reverses chemotherapeutic drug TMZ chemosensitivity in glioblastoma 
Glioblastoma remains among the most devastating cancers with a median survival of less than 15 months and virtually no survival beyond five years. Currently, the treatment of glioma includes surgery, radiation therapy, chemotherapy, and comprehensive treatment. Intrinsic or acquired resistance to TMZ, is one of the greatest obstacles in successful GB treatment, and is thought to be influenced by a variety of mechanisms. The EZH2 gene, which is expressed in various solid tumors, can regulate gene transcription and promote the generation and progression of tumors. Our aim was to investigate the relationship between EZH2 and multidrug-resistance of human glioblastoma cells. In this study, we established TMZ-resistant U251 and U87 clones (U251/TMZ and U87/TMZ cells), which expressed high level of EZH2. Using RNA interference, we demonstrated that the downregulation of Ezh2 expression in U251/TMZ and U87/TMZ cells resulted in apoptosis and a cell cycle arrest in the G1/S phase. Furthermore, the reduced expression of Ezh2 altered the MDR, MRP and BCRP mRNA and protein levels. These findings suggest that EZH2 plays an important part in the development of multidrug resistance and may represent a novel therapeutic target for multidrug-resistant glioblastoma.
PMCID: PMC4230130  PMID: 25400745
Glioblastoma; EZH2; multidrug-resistance; therapeutic target
21.  Differential Expression of Brain Cannabinoid Receptors between Repeatedly Stressed Males and Females may Play a Role in Age and Gender-Related Difference in Traumatic Brain Injury: Implications from Animal Studies 
Inconsistent gender differences in the outcome of TBI have been reported. The mechanism is unknown. In a recent male animal study, repeated stress followed by TBI had synergistic effects on brain gene expression and caused greater behavioral deficits. Because females are more likely to develop anxiety after stress and because anxiety is mediated by cannabinoid receptors (CBRs) (CB1 and CB2), there is a need to compare CB1 and CB2 expression in stressed males and females. CB1 and CB2 mRNA expression was determined in the amygdala, hippocampus, prefrontal cortex (PFC), and hypothalamus of adolescent male and female rats after 3 days of repeated tail-shock stress using qPCR. PFC CB1 and CB2 protein levels were determined using Western blot techniques. Both gender and stress had significant effects on brain CB1 mRNA expression levels. Overall, females showed significantly higher CB1 and CB2 mRNA levels in all brain regions than males (p < 0.01). Repeated stress reduced CB1 mRNA levels in the amygdala, hippocampus, and PFC (p < 0.01, each). A gender × stress interaction was found in CB1 mRNA level in the hippocampus (p < 0.05), hypothalamus (p < 0.01), and PFC (p < 0.01). Within-sex one-way ANOVA analysis showed decreased CB1 mRNA in the hippocampus, hypothalamus, and PFC of stressed females (p < 0.01, each) but increased CB1 mRNA levels in the hypothalamus of stressed males (p < 01). There was a gender and stress interaction in prefrontal CB1 receptor protein levels (p < 0.05), which were decreased in stressed females only (p < 0.05). Prefrontal CB2 protein levels were decreased in both male and female animals after repeated stress (p < 0.05, each). High basal levels of CBR expression in young naïve females could protect against TBI damage whereas stress-induced CBR deficits could predict a poor outcome of TBI in repeatedly stressed females. Further animal studies could help evaluate this possibility.
PMCID: PMC4147999  PMID: 25221540
stress; anxiety; brain cannabinoid receptors; sex dimorphism; TBI outcome
22.  Acute acalculous cholecystitis immediately after gastric operation: Case report and literatures review 
World Journal of Gastroenterology : WJG  2014;20(30):10642-10650.
Acute acalculous cholecystitis (AAC) is a rare complication of gastric surgery. The most commonly accepted concepts regarding its pathogenesis are bile stasis, sepsis and ischemia, but it has not been well described how to identify and manage this disease in the early stage. We report three cases of AAC in elderly patients immediately after gastric surgery, which were treated with three different strategies. One patient died 42 d after emergency cholecystectomy, and the other two finally recovered through timely cholecystostomy and percutaneous transhepatic gallbladder drainage, respectively. These cases informed us of the value of early diagnosis and proper treatment for perioperative AAC after gastric surgery. We further reviewed reported cases of AAC immediately after gastric operation, which may expand our knowledge of this disease.
PMCID: PMC4130878  PMID: 25132787
Acute acalculous cholecystitis; Postoperative complication; Gastric surgery
23.  Lactobacillus casei reduces susceptibility to type 2 diabetes via microbiota-mediated body chloride ion influx 
Scientific Reports  2014;4:5654.
Gut microbiota mediated low-grade inflammation is involved in the onset of type 2 diabetes (T2DM). In this study, we used a high fat sucrose (HFS) diet-induced pre-insulin resistance and a low dose-STZ HFS rat models to study the effect and mechanism of Lactobacillus casei Zhang in protecting against T2DM onset. Hyperglycemia was favorably suppressed by L. casei Zhang treatment. Moreover, the hyperglycemia was connected with type 1 immune response, high plasma bile acids and urine chloride ion loss. This chloride ion loss was significantly prevented by L. casei via upregulating of chloride ion-dependent genes (ClC1-7, GlyRα1, SLC26A3, SLC26A6, GABAAα1, Bestrophin-3 and CFTR). A shift in the caecal microflora, particularly the reduction of bile acid 7α-dehydroxylating bacteria, and fecal bile acid profiles also occurred. These change coincided with organ chloride influx. Thus, we postulate that the prevention of T2DM onset by L. casei Zhang may be via a microbiota-based bile acid-chloride exchange mechanism.
PMCID: PMC4135721  PMID: 25133590
24.  The association of PTPN22 rs2476601 polymorphism and CTLA-4 rs231775 polymorphism with LADA risks: a systematic review and meta-analysis 
Acta Diabetologica  2014;51(5):691-703.
Although the polymorphisms of PTPN22 and the variants of CTLA-4 have been reported to be the susceptibility genes, which increased risk of latent autoimmune diabetes in adults (LADA), the results remained inconclusive. The aim of this meta-analysis was to evaluate the association between the polymorphisms of two genes and LADA. We performed a systematic review by identifying relevant studies and applied meta-analysis to pool gene effects. Data from ten studies published between 2001 and 2013 were pooled for two polymorphisms: rs2476601 in the PTPN22 gene and rs231775 in the CTLA-4 gene. Data extraction and assessments for risk of bias were independently performed by two reviewers. Fixed-effect model and random-effect model were used to pool the odds ratios; meanwhile, heterogeneity test, publication bias and sensitive analysis were explored. The minor T allele at rs2476601 and the minor G at rs231775 carried estimated relative risks (odds ratio) of 1.52 (95 % CI 1.29–1.79) and 1.39 (95 % CI 1.11–1.74), respectively. These alleles contributed to an absolute lowering of the risk of all LADA by 4.88 and 14.93 % when individuals do not carry these alleles. The estimated lambdas were 0.49 and 0.63, suggesting a codominant model of effects was most likely for two genes. In summary, our systematic review has demonstrated that PTPN22 rs2476601 and CTLA-4 rs231775 are potential risk factors for LADA. An updated meta-analysis is required when more studies are published to increase the power of these polymorphisms and LADA.
Electronic supplementary material
The online version of this article (doi:10.1007/s00592-014-0613-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4176954  PMID: 25005490
PTPN22; CTLA-4; Polymorphism; LADA; Systematic review; Meta-analysis
25.  Different Patterns of White Matter Disruption among Amnestic Mild Cognitive Impairment Subtypes: Relationship with Neuropsychological Performance 
Amnestic mild cognitive impairment (aMCI) is recognized as the prodromal phase of Alzheimer’s disease (AD). Evidence showed that patients with multiple-domain (MD) aMCI were at higher risk of converting to dementia and exhibited more severe gray matter atrophy than single-domain (SD) aMCI. The investigation of the microstructural abnormalities of white matter (WM) among different subtypes of aMCI and their relations with cognitive performances can help to understand the variations among aMCI subtypes and to construct potential imaging based biomarkers to monitor the progression of aMCI. Diffusion-weighted MRI data were acquired from 40 patients with aMCI (aMCI-SD: n = 19; aMCI-MD: n= 21) and 37 healthy controls (HC). Voxel-wise and atlas-based analyses of whole-brain WM were performed among three groups. The correlations between the altered diffusion metrics of the WM tracts and the neuropsychological scores in each subtype of aMCI were assessed. The aMCI-MD patients showed disrupted integrity in multiple WM tracts across the whole-brain when compared with HCs or with aMCI-SD. In contrast, only few WM regions with diffusion changes were found in aMCI-SD as compared to HCs and with less significance. For neuropsychological correlations, only aMCI-MD patients exhibited significant associations between disrupted WM connectivity (in the body of the corpus callosum and the right anterior internal capsules) and cognitive impairments (MMSE and Digit Symb-Coding scores), whereas no such correlations were found in aMCI-SD. These findings indicate that the degeneration extensively exists in WM tracts in aMCI-MD that precedes the development of AD, whereas underlying WM pathology in aMCI-SD is imperceptible. The results are consistent with the view that aMCI is not a uniform disease entity and presents heterogeneity in the clinical progression.
PMCID: PMC4085483  PMID: 23603396
Amnestic mild cognitive impairment; diffusion tensor imaging; multiple-domain; single-domain; TBSS; white matter

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